CURRENT CLINICAL PRACTICE
Synchronous Primary Carcinoma of Breast and Ovary Versus Ovarian Metastases Budhi S. Yadav, S.C. Sharma, Tyler P. Robin, Sharon Sams, Anothony D. Elias, Virginia Kaklamani, P. Kelly Marcom, Sara Schaefer, and Gloria J. Morris
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at dr.gjmor [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor
A
ccording to American Cancer Society statistics, breast cancer is the most common malignant neoplastic process and the second most common cause of death for women.1 Address correspondence to Gloria J. Morris, MD, PhD, Editor, Current Clinical Practice, Hematology/Oncology Associates of Central New York, East Syracuse, NY 11102. E-mail: [email protected] 0093-7754/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.12.020
Ovarian cancer, despite having a lower incidence, represents an important cause of morbidity and mortality because it is usually discovered in advanced stages.2,3 Concomitant synchronous tumors are rare, but can be explained in syndromes that heighten a woman's risk for both cancers. Metastases to the ovary from primary breast cancer are common, but metastases from extramammary primaries to the breast are very rare. Discrimination between primary breast carcinomas and metastatic tumors is usually accomplished by clinical and pathological evaluation, including immunohistochemistry. Here we report two cases of synchronous carcinomas of the breast and ovary, juxtaposed with two additional cases of breast cancers metastasized to the pelvis. We have posed the following clinical questions to an international multidisciplinary panel: (1) Do these patients truly have synchronous primary carcinomas or metastases from one site to the other? (2) Are the combinations of proposed antineoplastic agents adequate to have activity in both cancers if they have separate pathologies? (3) What should be the optimal surgical intervention and follow-up in such cases?
CASE REPORTS Case No. 1 A 54-year-old Indian woman presented with an 8-month history
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of pain in the lower abdomen with a heavy “dragging” sensation; she also complained of lower back pain without any neurological deficit. There was no history of palpable masses to her recollection. Outpatient computerized tomography (CT) scan detected an adnexal mass as well as a lump incidentally in the left breast; the patient was referred to a tertiary care hospital for further management. Her surgical history had included vaginal hysterectomy for utero-vaginal prolapse 1 year prior. Family history was positive for her mother and two maternal aunts with histories of breast cancer, one at age 62 and the other in her 40s, but there was no family history of ovarian cancers. On examination, there was a 3 3 cm, mobile lump in the upper outer quadrant (UOQ) of the left breast with a 2 2 cm, mobile lymph node in the left axilla. On abdominal examination, there was resistance in the hypogastrium and left iliac fossa. Her vaginal examination revealed irregularity at vault and a hard nodular mass in the pouch of Douglas. CT scan of the abdomen and pelvis showed bilateral adenexal solid and cystic masses with omental thickening, peritoneal deposits, ascites, and a mass in the left breast and axillary lymph node (Figure 1). Mammography showed a highdensity speculated 3 2 1 cm mass with internal calcification and surrounding architectural e13
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Figure 1. CT scan abdomen and pelvis (case 1) showing bilateral adnexal masses and peritoneal deposits.
distortion in the UOQ of the left breast (Figure 2). Panendoscopy and bone scan were normal. Laboratory and pathologic investigations were as follows: CA-125 was 234 U/mL (range 0– 35). Core biopsy from the left breast was reported as infiltrating ductal carcinoma, grade 2; both estrogen receptor (ER) and progesterone receptor (PR) were positive and HER2 neu was negative. Fineneedle aspiration cytology from the right adnexal mass showed papillary adenocarcinoma. Considering the clinical and pathological details, a diagnosis of synchronous primaries in both the breast and ovary was made and she was started on neoadjuvant chemotherapy with a combination of paclitaxel, doxorubicin, and carboplatin. She was given three cycles of chemotherapy and after palpable response in the breast, underwent left total mastectomy with axillary lymph node dissection; she also underwent bilateral oopho-rectomy and infracolic
omentectomy as debulking surgery. Histopathology from the breast was reported as a sclerotic
area measuring 3.5 3 2 cm, containing residual infiltrating ductal carcinoma, grade 2, with one of 15 lymph nodes involved with carcinoma. Immunohistochemistry (IHC) confirmed the phenotype as ER- and PR-positive and HER2 neu– negative (1þ by immunotherapy chemistry). Pathology of the ovaries showed poorly differentiated carcinoma with similar tumor deposits in the omentum. Lymphovascular emboli were present. She was further given three more cycles of the same chemotherapy postoperatively. After the completion of chemotherapy, contrast enhanced CT of the abdomen and pelvis was within normal limits with no evidence of disease. CA-125 level was 8.9 U/mL. She was started on tablet letrozole 2.5 mg once daily and radiotherapy (RT) 35 Gy was given to the chest wall and 40 Gy to the draining area in 15 fractions over 3 weeks. Positron emission tomography (PET)-CT after 2 months of completion of radiotherapy was within normal limits.
Figure 2. Mammogram of left breast (case 1) showing speculated mass with calcifications.
Synchronous primary carcinoma of breast and ovary
Figure 3. (A and B) PET-CT scan (case 2) showing hypermetabolic (SUV42) bilateral adnexal and omental masses.
On regular follow-up at 7 months, she presented with left-sided weakness and headache. Contrast-enhanced brain CT scanning was done, which showed multiple metastatic lesions throughout the frontal lobes. Her CA-125 rose to 23.8 U/mL. She was treated with palliative RT, 20 Gy five times per 1 week to the brain and was started on systemic chemotherapy with capecitabine.
but showed dullness to percussion in the lung bases. There was noted to be a 2 2 cm, mobile lump in the UOQ of the right breast. On abdominal examination, there were multiple nodular masses
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palpable in the right iliac fossa and the hypogastrium. Subsequent vaginal examination revealed multiple hard nodules in the pouch of Douglas. Chest x-ray showed bilateral pleural effusions, greater on the left side than the right. Abdominal ultrasonography showed the presence of free fluid in the pelvis, left paracolic gutter, perihepatic spaces, and bilateral pleural effusion, greater on the left side. PET-CT revealed ill-defined hypermetabolic mixed-density soft tissues in bilateral adnexa, omentum, and hypermetabolic moderate to severe bilateral pleural effusion (Figure 3A and B). There was an ill-defined hypermetabolic 2.1 2.0 cm soft tissue lesion in the UOQ of the right breast (Figure 4). Mammography showed an irregular, asymmetrical density with surrounding architectural distortion in the UOQ of the right breast. CA-125 level was 596 U/mL (reference range 0–37). Core biopsy from right breast mass revealed infiltrating ductal carcinoma, grade 3, ER-negative, PR-negative, and HER2-neu–negative. She underwent both thoracentesis and paracentesis, and pleural and ascitic fluid cytology revealed papillary adenocarcinoma. Fine needle aspiration cytology from the right adnexal mass confirmed papillary adenocarcinoma.
Case No. 2 A 47-year-old premenopausal woman, previously in good health, presented in the outpatient department with complaints of breathlessness and cough for a period of 1 month. She had no family history of cancer. On examination, the lungs were clear to auscultation in the apices,
Figure 4. PET-CT scan (case 2) showing hypermetabolic (SUV42) mass in right breast and bilateral pleural effusions.
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Figure 5. CT scan of abdomen and pelvis (case 3) showing measurable pelvic mass unable to be reached by needle biopsy.
She was given docetaxel, doxorubicin, and cyclophosphamide chemotherapy every 3 weeks for six cycles. Post-chemotherapy, CA-125 was 6 U/mL. PET-CT scan revealed complete metabolic response in the breast and non-flouro deoxyglucose (FDG)–avid hypodense lesions in both adnexae. She then underwent right total mastectomy with axillary lymph node dissection, as well as total abdominal hysterectomy, with bilateral salphingo-oophorectomy, and infracolic omentectomy. Histopathology from the breast was reported as no residual tumor with all 21 lymph nodes examined. Both ovaries revealed cystadenocarcinoma with microscopic metastatic tumor deposits in the omentum. Lymphovascular emboli were present. Cytology from peritoneal washings were positive for malignancy. The patient was further given three cycles of paclitaxel and carboplatin every 3 weeks. She is now undergoing regular surveillance, and is clinically and radiologically without evidence of disease.
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modified mastectomy with reconstruction, chemotherapy with doxorubin/cyclophosphamide, and paclitaxel, post-mastectomy chest wall irradiation, and who took tamoxifen for 2 years, followed by an aromatase inhibitor in the postmenopausal state. Due to her young age, she had been tested for BRCA mutation and was found to have a variant of undetermined significance in the BRCA2 gene at locus T2250A, not deleterious in current databases.4,5 Two years later, she presented with a several weeks history of worsening back and abdominal pain, nausea, vomiting, and weakness. CT scans showed multiple areas of metastases in the liver, abdominal, and mesenteric lymph nodes, and the bones. CA 27-29 level was 3,368 U/mL (normal 0–38.6); CEA level was 176 ng/mL (normal 0.0–3.0). CT-guided liver biopsy was positive for phenotypically similar metastatic breast cancer. She began systemic therapy with docetaxel and had a good response after 6 months of therapy; CA 27-29 level decreased to 1,223.5, and CEA was 81.2. She continued therapy in the form of fulvestrant for 6 months until follow-up scans with rising tumor markers showed increase in size of bilateral pelvic wall masses (Figure 5). Further
chemotherapy with capecitabine was attempted with further progression of disease into the pelvis, onset of abdominal/pelvic ascites, and development of new peritoneal caking with gastrohepatic lymphadenopathy; CA 27-29 rose to 13,067.5, with a CEA level of 1,091. She was evaluated by a gynecologic oncology service, and neither pelvic masses nor lymphadenopathy was able to be accessed via interventional biopsies due to location near blood vessels. She was started on eribulin and had a dramatic clinical response in malignant ascites, and a decrease in tumor markers to a CA 27-29 level of 1,100.
Case No. 4 A 63-year-old Italian woman presented with a remote history of breast cancer 10 years prior, and was treated with lumpectomy followed by radiation therapy for a 0.8-cm infiltrating mammary carcinoma, which had features of mixed pleiomorphic and solid variants of infiltrating lobular carcinoma, nuclear grade 2, ER-positive and PR-positive (490%), Her-2 neu– negative, p53-negative, with no lymphovascular invasion, and no lymph node involvement. She took tamoxifen for 5 years, and had no
Case No. 3 The patient is a 40-year-old Hispanic woman with a history ERpositive, PR-positive, HER-2 neu– negative, early-stage lymph node– positive breast cancer diagnosed at age 32, who underwent bilateral
Figure 6. CT scan of abdomen and pelvis (case 4) showing omental caking, for which CT-guided biopsy was performed.
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Figure 7. (A) Omental biopsy. Hematoxylin and eosin stain, 10X magnification. (B) Omental biopsy. Hematoxylin and eosin stain, 40X magnification. (C) Omental biopsy. Mammoglobin stain, 100X magnification. (D) Omental biopsy. Estrogen receptor stain, 100X magnification. Courtesy of Dr. Libo Qiu, Department of Pathology, Mount Sinai Hospital of Queens, Long Island City, NY.
evidence of recurrence in the ipsilateral or contralateral breasts. She recently presented to a gastroenterologist with a 5-month history of vague nausea, occasional vomiting, and anorexia, leading to 10-pound weight loss over the same period of time. She underwent endoscopy, and was found to have a mass in the gastric fundus; initial biopsy results described an infiltrating poorly differentiated neoplasm further classified as metastatic lobular mammary carcinoma with immunohistochemical stains positive for CK7, ER, mammaglobin, and
GCDFP-15, focally positive for CA 19-9, and negative for CK20, CDX2, CD3, and CD20. She continued to have weakness, nausea, and vomiting, and required hospitalization for dehydration and abdominal bloating. CT scan of the abdomen and pelvis showed loculated pelvic ascites with thickened omentum and omental caking, and an enlarged right adnexal mass (Figure 6). There was no area of adequate volume amenable to paracentesis. Analysis of peripheral blood tumor markers showed elevations in CEA to 50.6 (normal 0.0–
3.0), CA 27-29 to 311.5 (normal 0– 38.6) CA-125 to 170 (normal o35) but normal CA 19-9. CT-guided biopsy of an omental cake (Figure 7) in the left upper abdomen confirmed metastatic mammary carcinoma, predominantly with lobular features, with immunohistochemical phenotype also positive for ER, mammaglobin, and CK7 but negative for PR, GCDFP-15, CK20, and CDX2. Due to frail performance status, supportive care was optimized with antiemetics, and the patient was started on an aromatase inhibitor.
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PATHOLOGIST’S AND MEDICAL ONCOLOGIST'S EXPERT OPINIONS It is critical to pursue an accurate diagnosis when evaluating a patient with an ovarian mass who is also presenting with a breast mass, or who has a history of breast cancer. Although malignant ovarian masses in patients with a history of breast cancer are more often primary ovarian malignancies than breast cancer metastases,6,7 it is important to understand which breast cancer patients are most likely to present with ovarian metastases, how to differentiate breast metastases from primary ovarian malignancies, and, of course, how to best manage these patients.
report of 29 cases of ovarian metastases from breast cancer, 12 of 29 patients (43.5%) were found to have lobular carcinoma (compared to the reported incidence of lobular carcinoma in the entire breast cancer population of about 15%).11 Therefore, in a patient with a history of ILC, a new malignant ovarian mass is more suspicious for metastatic disease than in the patient with IDC. Particularly challenging are those patients with BRCAmutated breast cancers. When these patients present with a subsequent ovarian mass, one has to be more suspicious of a primary ovarian malignancy, yet these patients’ breast cancers can still metastasize to the ovary.
Clinical Presentation Features
Pathologic Features
In the approach to a patient with breast cancer presenting with an ovarian mass, the subtype of breast cancer is an important factor. Although both invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) have been reported to metastasize to the ovary,7–9 there is evidence to suggest that ILC is more likely to do so than IDC.8,9 In one autopsy study, 36% of patients with a history of ILC had metastases to the ovary, whereas only 2.6% of patients with IDC had ovarian metastases.9 In another study, 52.2% of patients with ILC had ovarian metastases on autopsy versus only 11.3% of patients with IDC.10 Further, in a
Fortunately, there are several immunohistochemical studies that when used in conjunction show utility in differentiating breast from ovarian malignancies. The vast majority of breast cancers, both metastatic and primary, show positive expression for GATA3, and mammaglobin, while ovarian malignancies are negative for these markers.12–17 Expression of GATA3 was observed in a higher percentage of well differentiated tumors including lobular carcinomas and grade I ductal carcinomas, whereas downregulation was seen with progression of tumor grade.13 Gross cystic disease fluid protein 15 (GCDFP-15), another marker of
breast origin, is a useful addition to the panel because, although sensitivity is lower than mammaglobin and GATA3, the specificity for breast is high.12,18–20 Markers with positive expression in ovarian tumors that have shown clinical utility in differentiating between primary ovarian cancer and metastatic breast cancer include: WT-1, Pax8, MUC5AC, CA19-9, and CK20 (see Table 1).19,21–24 Repeating the ER/PR and Her2 stains on the metastatic breast cancer cells is also important. Many series demonstrate that Her2 and ER/PR can be lost in up to 10% and 20% of metastatic deposits, respectively, when present on the original tumor.25 On the other side, ER/PR and Her2 can be newly expressed in the metastasis in about 10% of cases.25 Prospective evaluation of the therapeutic consequences and management of these clonal evolutions is underway, but frequently affects the choice of therapies in the metastatic setting. When the pathologic assessment supports a diagnosis of breast cancer metastatic to the ovary, then the clinician must weigh the evidence for various treatment options. Interestingly, preliminary data indicate that complete surgical resection of metastatic disease involving the ovary may provide a survival benefit. One study showed that patients had significantly improved survival when their metastatic disease involving the ovary or ovaries was completely resected,8 while other
Table 1. Immunohistochemical Markers Useful in Differentiating Breast Versus Ovarian Tissue Ovarian Cancer Marker
Mucinous
Serous
Breast Cancer
GATA 3 Mammoglobin GCDFP-15 MUC5AC CA 19-9 CK20 WT1 PAX8
þþþ þþþ þþþ
þþþ þþþ
ER-pos:þþþ, ER-neg:þþ þþþ þ
Synchronous primary carcinoma of breast and ovary
studies have shown only trends in favor of complete resection, but these values did not reach statistical significance.16,17 Importantly, breast cancer metastatic to the ovaries has been shown to involve both ovaries in about 75% of cases,8,18 which should be taken into consideration if pursuing surgery. However, despite the aforementioned studies, the true value of complete resection of breast cancer ovarian metastases remains uncertain. Therefore, the approach to a breast cancer patient with a malignant ovarian mass should include tissue sampling and a comprehensive immunohistochemical analysis. If the mass is determined to be metastatic breast cancer and is an isolated finding, then in addition to systemic therapy, it may be appropriate to consider a complete surgical resection. We have the following comments regarding the cases presented here. In cases 1 and 2, although the initial pathology suggests two primaries, we would recommend further analysis of the ovarian specimens using the markers described above. Further, we would offer BRCA testing to the patient in case 1. In case 3, it is unfortunate that a tissue diagnosis was not possible; however, it remains that this patient might benefit from further endocrine therapy. Case 4 describes a patient with ILC of the breast presenting with well-characterized abdominal and pelvic metastases that can be seen in these patients. As described above, GATA3 would be a useful additional marker to confirm metastatic breast cancer in this patient. Tyler P. Robin, BS Medical student Sharon Sams, MD Department of Pathology Anthony D. Elias, MD Department of Medicine Division of Medical Oncology University of Colorado School of Medicine
MEDICAL ONCOLOGIST'S AND GENETICIST'S EXPERT OPINION The most common sites of metastasis for breast cancer are the bones, lung, and liver. However, metastases to the peritoneum, stomach, and ovaries are well described in patients with breast cancer.26–28 In a study of 75 patients with metastases to the ovaries, investigators found that the primary sites were stomach (37.3%), colorectal region (28%), lymphoma (12%), breast (6.7%), biliary system (2.7%), appendix (1.3%), and small intestine (1.3%).29 These metastases can sometimes be the first site of presentation of the malignancy. The majority of these metastases will be bilateral30 and are associated with poor prognosis. Several studies have examined the metastatic pattern of breast cancer and noted that ILC was associated with a greater propensity to involve the internal genital organs than IDL.10,31 Synchronous breast and ovarian cancer is a rare phenomenon.32,33 A retrospective analysis of 7,166 cases of breast cancer and 1,758 cases of ovarian cancer identified through the Duke University Medical Center and University of North Carolina Hospitals identified only 50 cases of multiple primary cancers of the breast and ovary. Only four of these were cases of synchronously diagnosed breast and ovarian cancer.34 Since breast cancer can metastasize to the ovaries21 and to a lesser extent ovarian cancer can metastasize to the breast,35 a careful histologic confirmation of both malignancies is important. In cases where these two malignancies are diagnosed in an individual, the possibility of a BRCA1/2 germline mutation should be raised. The treatment of metastatic breast cancer to the peritoneal and pelvic area should follow the practices of treatment of metastatic breast cancer. Complicating factors,
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such as the presence of ascites and bowel obstruction, make these cases challenging for the treating physician. In cases with confirmed breast and ovarian cancer, treatment recommendations would have to take into account the characteristics and treatment practices of both malignancies. Neoadjuvant chemotherapy has a known role in both breast and ovarian cancer and can help decrease the volume of disease.2,3 Chemotherapeutic agents which are active in both diseases, such as platinum drugs, taxanes, and anthracyclines, can be used. Data suggest that BRCA1/2-related breast and ovarian cancers may be more sensitive to platinum agents (carboplatin and cisplatin).36–39 Although not considered standard of care for the treatment of breast cancer, the use of platinum agents in this setting would be a very reasonable approach to cytoreduction prior to surgical excision. Residual disease after neoadjuvant chemotherapy for breast cancer has been associated with higher risk of relapse mostly in triple-negative breast cancers (ER-negative, PR-negative, and HER2-negative), whereas its importance in ER-positive disease is of less clinical importance.40 Finally the addition of endocrine therapy with tamoxifen or an aromatase inhibitor should be considered standard treatment in this patient population.41 A patient with primary breast and ovarian cancer who develops metastatic disease should have a biopsy done on the site of metastatic disease if at all possible. Although chemotherapeutic agents that can treat both malignancies can be identified, the possibility that the metastatic tumor may differ in ER, PR, or HER2 status compared with the primary tumor can be as high as 30%,42,43 having clear implications on treatment recommendations. Furthermore, if the metastatic cancer is found to be consistent with breast cancer, alternative endocrine agents, such as fulvestrant, can be considered,41
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whereas bevacizumab may be used in the case of ovarian cancer.45,46 Virginia Kaklamani, MD, DSc Associate Professor, Director, Translational Breast Cancer Research Co-Director Cancer Genetics Program Division Hematology/Oncology Northwestern University Chicago, IL
MEDICAL ONCOLOGIST’S AND GENETICIST’S EXPERT OPINION This case series presents four patient scenarios having the unifying theme of pelvic cancer in the context of a breast cancer diagnosis. Such scenarios are not rare and appropriate patient management requires determining one primary feature: does the pelvic involvement represent a separate oncologic process, in which case treating with curative intent is the appropriate goal; or is the pelvic involvement metastatic from the breast primary, in which case palliative management is usually the more appropriate goal? The question is stated in this way because metastasis of ovarian cancer to the breast is a rare event, with only 39 cases reported in the literature through 2010.47,48 The answer frames the approach to the management questions posed: Are the combination of proposed antineoplastic drugs adequate to have activity in both the cancers if separate pathologies?; and, what should be the optimal surgical intervention and follow-up in such cases? The mode of presentation has an important influence on interpretation of the clinical data. For this series, the first two cases are synchronous presentations of breast/pelvic pathology. The second two cases demonstrate metachronous events. The cases will be considered accordingly.
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For the synchronous cases, the clinical and pathologic data support the conclusion that the two processes involve simultaneous development of breast and ovarian cancer. In both, the breast pathology is invasive ductal, while the pelvic pathology showed papillary adenocarcinoma. These are distinctive and easily distinguished histologically. Notably, in both cases the CA-125 level was elevated. While often thought of as an ovarian specific circulating tumor antigen, this mucopolysacharide product can be elevated in metastatic breast cancer,49 so in itself does not help to resolve the primary question. However, in the given clinical cases, it doses support the separate primaries conclusion. Any clinical scenario involving breast and ovarian primaries also should raise suspicion for the possibility of breast/ovarian syndrome (ie, germline BRCA1/2 mutation). Detecting a germline BRCA1/2 mutation would have relevance to locoregional management of the breast cancer. The receptor status of the breast cancers can also guide suspicion of BRCA1/2 status; in the second case the breast cancer is “triple-negative,” the subtype most often seen in BRCA1 carriers. For these two cases, we do not know the germline genetic status for these patients. However, using the incomplete information available, the pretest mutation probability in each is 74% by the BRCAPRO model (higher for BRCA2 in case 1 and BRCA1 in case 2).50 Systemic therapy in both cases appropriately included both an anthracycline and a taxane, drugs active against both breast and ovarian cancer. The more controversial issue would be inclusion of a platinum agent. Accumulating data support chemotherapy selection guided by mutation and receptor status, with some indication that BRCA1/2-associated51
and ER-/PR-/HER2-negative cancers36 are sensitive to platinum-based therapy. In 2015, these data are still preliminary, but come from several sources in metastatic and early-stage disease. While the anecdotal responses in these two cases belie these considerations for platinum-based therapy, given that platinum-based therapy is a standard of care for ovarian cancer, using it in both cases is likely indicated. In both cases, surgical management was appropriately aggressive, and applied with curative intent. The metachronous cases are more clearly examples of delayed distant recurrences of early-stage breast cancer. In case 3, despite aggressive and appropriate treatment, the patient’s cancer recurred in a typical pattern for an aggressive ER-positive breast cancer. The sites of involvement, serum tumor markers, and treatment response are all consistent with this interpretation, and further sampling of the pelvic involvement to establish this fact is not standardly required. The BRCA2 variant of uncertain significance should not cloud this interpretation. If clarified as deleterious, such variants may eventually guide use of platinum chemotherapy or a poly-(ADP)ribose polymerase (PARP) inhibitor, but even then would not significantly change interpretation of the clinical picture. Gynecologic surgery might be done if any ambiguity regarding menopausal status in the metastatic setting was present, and would provide further tissue confirmation that the metastatic disease is of breast origin, but is not otherwise indicated. In case 4, the recurrence is classic for an aggressive variant of lobular breast cancer52; it is a late recurrence and involves the gastrointestinal tract and peritoneum. Biopsy of the metastatic disease confirmed this and is also impor-
Synchronous primary carcinoma of breast and ovary
tant for reassessing metastatic disease receptor status. The patient is appropriately managed with endocrine therapy and no additional surgery. P. Kelly Marcom, MD Associate Professor Medical Oncology Co-Director, Breast Cancer Clinical Research Director, Hereditary Cancer Clinic Duke Cancer Institute Duke University Durham, NC
DISCUSSION The first two cases appear to be synchronous primary carcinomas requiring treatment. This is supported by clinical, radiological, biochemical, histopathological, and IHC findings; however, the natural history of disease in the two cases is quite different. The first patient had T2N1 disease in her breast; the initial response to chemotherapy was not favorable in the breast, and she had the subsequent development of CNS metastases presumed to be related to breast cancer. The second patient initially had more advanced ovarian disease but responded to chemotherapy very well, despite IHC phenotype being unfavourable (ie, triple-negative breast cancer and papillary ovarian cancer). The ovary is a common site of metastases for the breast and other (gastrointestinal as a Krukenberg tumor) primary canConversely, the cers.8,29,53 breast is an uncommon site for tumor metastasis. There are only 37 cases that have been reported in the English literature as ovarian cancer metastasizing to breast.54– 61 The frequency of breast metastasis of ovarian carcinoma varies from 0.5% to 1.2% in the clinical setting.62–64 These ovarian cancers are widespread ones and
they have a poor prognosis with breast metastasis. Accurate differentiation of metastatic from primary tumors is important because the treatment and prognosis differ significantly. Using IHC staining solely, as is common in daily practice, to support the histological findings may not be helpful and sometimes may lead to a false diagnosis and an ineffective treatment strategy. The combination of chemotherapy drugs in each of the cases was specifically chosen keeping in view covering both primaries. Paclitaxel can be given in both diseases; doxorubicin and carboplatin were added in cases 1 and 2 for breast and ovarian cancer, respectively. In case 1, however, the patient’s disease in the breast and axilla did not respond to these drugs; conversely, a complete pathological response (pCR) in the breast was seen in the second case. It may be due to treatment with docetaxel and cyclophosphamide; studies have shown that the taxanes are equally effective in breast cancer,65 and the response may have been because the triplenegative phenotype is more chemosensitive. The impact of neoadjuvant chemotherapy in patients with triple-negative breast cancer has been clearly analyzed by Liedtke et al.66 The pCR rate was double in triple-negative patients as compared with non–triple-negative patients, although 3-year disease-free survival (DFS) was worse in the former group. Interestingly, the long-term DFS of patients achieving pCR was similar in the two groups, while the rate of early relapse in patients with residual tumor was dramatically higher in triple-negative patients as compared with the others. It also has been reported that the clearance of the axilla after chemotherapy per se correlates with better survival. Therefore, the persistence of a relevant tumor residual in the axillary nodes can be associated
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with a substantial risk of relapse, regardless of the response in the breast. Recent advances in functional tumor imaging by fluoro deoxyglucose–PET scanning or by dynamic magnetic resonance imaging allow us to select patients early who are not going to achieve a pCR.67–70 These patients should be shifted early (after 3–4 weeks) to another treatment, and maximal effort should be made to select the best possible drugs, doses, and schedule for these patients. The presence of both forms of cancer in a patient is associated with a high risk of BRCA1 gene mutations, which are responsible, together with BRCA2 gene mutations, for most cases of hereditary breast and ovarian cancer syndromes, and hence consideration of the use of platinum agents in their treatment,36,71 although this high-risk landscape is changing rapidly to include other genes. The final decisions toward the treatment program are of great importance because therapeutic strategies differ extremely from each other in metastatic and primary breast tumors. Cases 3 and 4 corroborate metastases in one individual, each considered for possible BRCA mutation carrier status and another with biopsyproven metastases, respectively. The biopsy-proven metastases to the stomach in case 4 is corroborated by the literature, despite being very rare.72,73 Precision is key, and caution is raised because a false diagnosis may result in overtreatment, inaccurate treatment, and/or disparate surgical recommendations, as discussed by Dr Elias and colleagues. We suggest that evaluation of clonality also must be done in patients in whom IHC staining seems to support the diagnosis. We thank our international colleagues for their expert appraisal of these cases and commentary of the significance of intraperitoneal
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disease in women with breast cancer.44 9.
Budhi Yadav, MD S.C. Sharma, MD Sarah Schaefer, MD Department of Hospitalist Medicine, The Mount Sinai Hospital of Queens Astoria, NY Gloria J. Morris, MD, PhD Hematology/Oncology Associates of Central New York East Syracuse, NY
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REFERENCES 1. Siegel R, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29. 2. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. breast cancer, version 3.2014. http://www. nccn.org/professionals/physician_ gls/pdf/breast.pdf. Accessed 5/15/ 14. 3. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. ovarian cancer, version 3.2014. http:// www.nccn.org/professionals/ physician_gls/pdf/ovarian.pdf. Accessed 5/15/14. 4. Lindor NM, Friedman S, Guidugli L, et al. Progress in clinical interpretation of DNA variants of undetermined significance in BRCA1/2. Based on a publication titled "A review of a multifactorial probabilitybased model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)." 222.mayo. edu/research/document/ brca-riskpdf/doc-10026644. 5. Morris G. Assessing genetic variants of undetermined significance: the example of breast cancer. 2013. www.els.net/WileyCDA/EIs Article/refld-a0025220.html. 6. Curtin JP, Barakat RR, Hoskins WJ. Ovarian disease in women with breast cancer. Obstet Gynecol. 1994;84(3):449–52. 7. Simpkins F, Zahurak M, Armstrong D, Grumbine F, Bristow R. Ovarian malignancy in breast cancer patients with an adnexal mass. Obstet Gynecol. 2005;105(3): 507–13. 8. Bigorie V, Morice P, Duvillard P, et al. Ovarian metastases from
12.
13.
14.
15.
16.
17.
18.
19.
breast cancer: report of 29 cases. Cancer. 2010;116(4):799–804. Harris M, Howell A, Chrissohou M, Swindell RI, Hudson M, Sellwood RA. A comparison of the metastatic pattern of infiltrating lobular carcinoma and infiltrating duct carcinoma of the breast. Br J Cancer. 1984;50(1):23–30. Lamovec J, Bracko M. Metastatic pattern of infiltrating lobular carcinoma of the breast: an autopsy study. J Surg Oncol. 1991;48(1): 28–33. Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003; 289(11):1421–4. Chia SY, Thike AA, Cheok PY, Tan PH. Utility of mammaglobin and gross cystic disease fluid protein15 (GCDFP-15) in confirming a breast origin for recurrent tumors. Breast. 2010;19(5):355–9. Liu H, Shi J, Wilkerson ML, Lin F. Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. Am J Clin Pathol. 2012;138(1):57–64. Luo MH, Huang YH, Ni YB, et al. Expression of mammaglobin and gross cystic disease fluid protein15 in breast carcinomas. Hum Pathol. 2013;44(7):1241–50. Miettinen M, McCue PA, SarlomoRikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol. 2014;38(1): 13–22. Ordonez NG. Value of GATA3 immunostaining in tumor diagnosis: a review. Adv Anat Pathol. 2013;20(5):352–60. Shield PW, Papadimos DJ, Walsh MD. GATA3: a promising marker for metastatic breast carcinoma in serous effusion specimens. Cancer Cytopathol. 2014;122(4):307–12. Bhargava R, Beriwal S, Dabbs DJ. Mammaglobin vs GCDFP-15: an immunohistologic validation survey for sensitivity and specificity. Am J Clin Pathol. 2007;127(1): 103–13. Tornos C, Soslow R, Chen S, et al. Expression of WT1, CA 125, and
20.
21.
22.
23.
24.
25.
26.
27.
28.
GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary. Am J Surg Pathol. 2005;29 (11):1482–9. Wick MR, Lillemoe TJ, Copland GT, Swanson PE, Manivel JC, Kiang DT. Gross cystic disease fluid protein-15 as a marker for breast cancer: immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. Hum Pathol. 1989;20(3):281–7. McCluggage WG, Wilkinson N. Metastatic neoplasms involving the ovary: a review with an emphasis on morphological and immunohistochemical features. Histopathology. 2005;47(3):231–47. Ozcan A, Liles N, Coffey D, Shen SS, Truong LD. PAX2 and PAX8 expression in primary and metastatic mullerian epithelial tumors: a comprehensive comparison. Am J Surg Pathol. 2011;35(12): 1837–47. Park SY, Kim BH, Kim JH, Lee S, Kang GH. Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma. Arch Pathol Lab Med. 2007;131(10):1561–7. Young RH. From Krukenberg to today: the ever present problems posed by metastatic tumors in the ovary. Part II. Adv Anat Pathol. 2007;14(3):149–77. Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014;50(2):277–89. Ayhan A, Guvenal T, Salman MC, Ozyuncu O, Sakinci M, Basaran M. The role of cytoreductive surgery in nongenital cancers metastatic to the ovaries. Gynecol Oncol. 2005;98(2):235–41. Eitan R, Gemignani ML, Venkatraman ES, Barakat RR, Abu-Rustum NR. Breast cancer metastatic to abdomen and pelvis: role of surgical resection. Gynecol Oncol. 2003;90(2):397–401. Fujiwara K, Ohishi Y, Koike H, Sawada S, Moriya T, Kohno I. Clinical implications of metastases
Synchronous primary carcinoma of breast and ovary
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
to the ovary. Gynecol Oncol. 1995;59(1):124–8. Turan T, Aykan B, Koc S, et al. Analysis of metastatic ovarian tumors from extragenital primary sites. Tumori. 2006;92:491–5. Gagnon Y, Tetu B. Ovarian metastases of breast carcinoma. A clinicopathologic study of 59 cases. Cancer. 1989;64:892–8. Borst MJ, Ingold JA. Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery. 1993;114: 637–41. Sandor V, Reed E, Sarosy G, Middleton LP, Davis P, Kohn E. Synchronous inflammatory breast cancer and advanced ovarian carcinoma: a case with prolonged disease-free survival. Ann Oncol. 1999;10:585–8. Syed R, Nazir SA, Lwin KY, Bose P, Evans P, Choji K. Occurrence of synchronous invasive lobular breast carcinoma and poorly differentiated ovarian carcinoma in a single peritoneal deposit. Oncology. 2007;73:136–40. Suris-Swartz PJ, Schildkraut JM, Vine MF, Hertz-Picciotto I. Age at diagnosis and multiple primary cancers of the breast and ovary. Breast Cancer Res Treat. 1996; 41:21–9. Recine MA, Deavers MT, Middleton LP, Silva EG, Malpica A. Serous carcinoma of the ovary and peritoneum with metastases to the breast and axillary lymph nodes: a potential pitfall. Am J Surg Pathol. 2004;28:1646–51. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neo-adjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide: CALGB (Alliance). J Clin Oncol. 2015;33(1):13–21. Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28: 1145–53. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triplenegative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56.
39. Muggia F, Safra T. ‘BRCAness’ and its implications for platinum action in gynecologic cancer. Anticancer Res. 2014;34:551–6. 40. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–804. 41. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881–94. 42. Kaklamani VG, Cianfrocca M, Ciccone J, et al. Increased HER2/neu expression in recurrent hormone receptor-positive breast cancer. Biomarkers. 2010;15:191–3. 43. Yao ZX, Lu LJ, Wang RJ, et al. Discordance and clinical significance of ER, PR, and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis. Med Oncol. 2014; 31:798. 44. Schiavon G, Smith IE. Endocrine therapy for advanced/metastatic breast cancer. Hematol.Oncol. Clin.North Am. 2013;27:715–36. 45. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302–8. 46. Zhou M, Yu P, Qu X, Liu Y, Zhang J. Phase III trials of standard chemotherapy with or without bevacizumab for ovarian cancer: a meta-analysis. PLoS.One. 2013;8: e81858. 47. Klein RLBA, Gomez-Castro CM, Chambers SK, Cragun JM, GrassoLeBeau L, Lang JE. Ovarian cancer metastatic to the breast presenting as inflammatory breast cancer: a case report and literature review. J Cancer. 2010;27–31. 48. Micha JP, Goldstein BH, Epstein HD, Rettenmaier MA, Brown JV, III. Ovarian cancer metastatic to the breast. Gynecol Oncol. 2006; 102:386–90. 49. Bast RC, Jr, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB. CA 125: the past and the future. Int J Biol Markers. 1998;13:179–87.
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50. Ca Gene Website. 2014. https:// www4.utsouthwestern.edu/breas thealth/cagene/. 51. Bayraktar S, Glu ¨ ck S. Systemic therapy options in BRCA mutation-associated breast cancer. Breast Cancer Res Treat. 2012; 135:355–66. 52. Lamovec J, Bracko M. Metastatic pattern of infiltrating lobular carcinoma of the breast: an autopsy study. J Surg Oncol. 1991;48: 28–33. 53. Jung Y-E, Lee J-W, Kim B-G, Bae DS. Ovarian metastasis from pulmonary adenocarcinoma. Obstet Gynecol Sci. 2013;56(5):341–4. 54. Yamasaki H, Saw D, Zdanowitz J, et al. Ovarian carcinoma metastasis to the breast case report and review of the literature. Am J Surg Pathol. 1993;17:193–7. 55. Manini C, Pietribiasi F, Sapino A, et al. Serous cystadenocarcinoma of the ovary with simultaneous breast metastases. Description of a case. Pathologica. 1998;90: 152–5. 56. Orris BG, Geisler JP, Geisler HE. Ovarian carcinoma metastatic to bilateral axillary lymph nodes. A case report. Eur J Gynaecol Oncol. 1999;20:189–90. 57. Fondrinier E, Gamelin E, Verriele V. Inflammatory breast metastasis from primary ovarian cancer: case report. Eur J Gynaecol Oncol. 1999;20:16–7. 58. Petersen BL, Hogdall E, KrygerBaggesen N. Metastasis to the breast from an ovarian carcinoma. Acta Obstet Gynecol Scand. 1999;78:826–7. 59. Wadhwa J, Dawar R, Kumar L. Ovarian carcinoma metastatic to the breast. Clin Oncol (R Coll Radiol). 1999;11:419–21. 60. Cormio G, di Vagno G, Melilli GA, et al. Ovarian carcinoma metastatic to the breast. Gynecol Obstet Invest. 2001;52:73–4. 61. Kayikcioglu F, Boran N, Ayhan A, et al. Inflammatory breast metastases of ovarian cancer: a case report. Gynecol Oncol. 2001;83:613–6. 62. Hajdu SI, Urban JA. Cancers metastatic to the breast. Cancer. 1972;29:1691–6. 63. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma: analysis of 1000 autopsied cases. Cancer. 1950;3:74–85.
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64. Sandison AT. Metastatic tumors in the breast. Br J Surg. 1959;47: 54–8. 65. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358: 1663–71. 66. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008; 26:1275–81. 67. Rousseau C, Devillers A, Sagan C, et al. Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron
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emission tomography. J Clin Oncol. 2006;24:5366–72. 68. Berriolo-Riedinger A, Touzery C, Riedinger JM, et al. [18F] FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2007;34 (12):1915–22. 69. Padhani AR, Hayes C, Assersohn L, et al. Prediction of clinicopathologic response of breast cancer to primary chemotherapy at contrast-enhanced MR imaging: initial clinical results. Radiology. 2006;239:361–74. 70. Chen JH, Mehta RS, Carpenter PM, et al. Magnetic resonance imaging in predicting pathological response of triple negative breast
cancer following neoadjuvant chemotherapy. J Clin Oncol. 2007;25 (35):5667–9. 71. Telli M. Optimizing chemotherapy in triple-negative breast cancer: the role of platinum. ASCO Educational Book. 2014;e37–42. www. asco.org/edbook. 72. Eo WK. Breast cancer metastasis to the stomach resembling early gastric cancer. Cancer Res Treat. 2008;40(4):207–10. 73. Jones GE, Strauss DC, Forshaw MJ, et al. Breast cancer metastasis to the stomach may mimic primary gastric cancer: report of two cases and review of the literature. World J Surg Oncol. 2007;5:75.
Synchronous Primary Carcinoma of Breast and Ovary Versus Ovarian Metastases Budhi S. Yadav, S.C. Sharma, Tyler P. Robin, Sharon Sams, Anothony D. Elias, Virginia Kaklamani, P. Kelly Marcom, Sara Schaefer, and Gloria J. Morris
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at dr.gjmor [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor
A
ccording to American Cancer Society statistics, breast cancer is the most common malignant neoplastic process and the second most common cause of death for women.1 Address correspondence to Gloria J. Morris, MD, PhD, Editor, Current Clinical Practice, Hematology/Oncology Associates of Central New York, East Syracuse, NY 11102. E-mail: [email protected] 0093-7754/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.12.020
Ovarian cancer, despite having a lower incidence, represents an important cause of morbidity and mortality because it is usually discovered in advanced stages.2,3 Concomitant synchronous tumors are rare, but can be explained in syndromes that heighten a woman's risk for both cancers. Metastases to the ovary from primary breast cancer are common, but metastases from extramammary primaries to the breast are very rare. Discrimination between primary breast carcinomas and metastatic tumors is usually accomplished by clinical and pathological evaluation, including immunohistochemistry. Here we report two cases of synchronous carcinomas of the breast and ovary, juxtaposed with two additional cases of breast cancers metastasized to the pelvis. We have posed the following clinical questions to an international multidisciplinary panel: (1) Do these patients truly have synchronous primary carcinomas or metastases from one site to the other? (2) Are the combinations of proposed antineoplastic agents adequate to have activity in both cancers if they have separate pathologies? (3) What should be the optimal surgical intervention and follow-up in such cases?
CASE REPORTS Case No. 1 A 54-year-old Indian woman presented with an 8-month history
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of pain in the lower abdomen with a heavy “dragging” sensation; she also complained of lower back pain without any neurological deficit. There was no history of palpable masses to her recollection. Outpatient computerized tomography (CT) scan detected an adnexal mass as well as a lump incidentally in the left breast; the patient was referred to a tertiary care hospital for further management. Her surgical history had included vaginal hysterectomy for utero-vaginal prolapse 1 year prior. Family history was positive for her mother and two maternal aunts with histories of breast cancer, one at age 62 and the other in her 40s, but there was no family history of ovarian cancers. On examination, there was a 3 3 cm, mobile lump in the upper outer quadrant (UOQ) of the left breast with a 2 2 cm, mobile lymph node in the left axilla. On abdominal examination, there was resistance in the hypogastrium and left iliac fossa. Her vaginal examination revealed irregularity at vault and a hard nodular mass in the pouch of Douglas. CT scan of the abdomen and pelvis showed bilateral adenexal solid and cystic masses with omental thickening, peritoneal deposits, ascites, and a mass in the left breast and axillary lymph node (Figure 1). Mammography showed a highdensity speculated 3 2 1 cm mass with internal calcification and surrounding architectural e13
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Figure 1. CT scan abdomen and pelvis (case 1) showing bilateral adnexal masses and peritoneal deposits.
distortion in the UOQ of the left breast (Figure 2). Panendoscopy and bone scan were normal. Laboratory and pathologic investigations were as follows: CA-125 was 234 U/mL (range 0– 35). Core biopsy from the left breast was reported as infiltrating ductal carcinoma, grade 2; both estrogen receptor (ER) and progesterone receptor (PR) were positive and HER2 neu was negative. Fineneedle aspiration cytology from the right adnexal mass showed papillary adenocarcinoma. Considering the clinical and pathological details, a diagnosis of synchronous primaries in both the breast and ovary was made and she was started on neoadjuvant chemotherapy with a combination of paclitaxel, doxorubicin, and carboplatin. She was given three cycles of chemotherapy and after palpable response in the breast, underwent left total mastectomy with axillary lymph node dissection; she also underwent bilateral oopho-rectomy and infracolic
omentectomy as debulking surgery. Histopathology from the breast was reported as a sclerotic
area measuring 3.5 3 2 cm, containing residual infiltrating ductal carcinoma, grade 2, with one of 15 lymph nodes involved with carcinoma. Immunohistochemistry (IHC) confirmed the phenotype as ER- and PR-positive and HER2 neu– negative (1þ by immunotherapy chemistry). Pathology of the ovaries showed poorly differentiated carcinoma with similar tumor deposits in the omentum. Lymphovascular emboli were present. She was further given three more cycles of the same chemotherapy postoperatively. After the completion of chemotherapy, contrast enhanced CT of the abdomen and pelvis was within normal limits with no evidence of disease. CA-125 level was 8.9 U/mL. She was started on tablet letrozole 2.5 mg once daily and radiotherapy (RT) 35 Gy was given to the chest wall and 40 Gy to the draining area in 15 fractions over 3 weeks. Positron emission tomography (PET)-CT after 2 months of completion of radiotherapy was within normal limits.
Figure 2. Mammogram of left breast (case 1) showing speculated mass with calcifications.
Synchronous primary carcinoma of breast and ovary
Figure 3. (A and B) PET-CT scan (case 2) showing hypermetabolic (SUV42) bilateral adnexal and omental masses.
On regular follow-up at 7 months, she presented with left-sided weakness and headache. Contrast-enhanced brain CT scanning was done, which showed multiple metastatic lesions throughout the frontal lobes. Her CA-125 rose to 23.8 U/mL. She was treated with palliative RT, 20 Gy five times per 1 week to the brain and was started on systemic chemotherapy with capecitabine.
but showed dullness to percussion in the lung bases. There was noted to be a 2 2 cm, mobile lump in the UOQ of the right breast. On abdominal examination, there were multiple nodular masses
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palpable in the right iliac fossa and the hypogastrium. Subsequent vaginal examination revealed multiple hard nodules in the pouch of Douglas. Chest x-ray showed bilateral pleural effusions, greater on the left side than the right. Abdominal ultrasonography showed the presence of free fluid in the pelvis, left paracolic gutter, perihepatic spaces, and bilateral pleural effusion, greater on the left side. PET-CT revealed ill-defined hypermetabolic mixed-density soft tissues in bilateral adnexa, omentum, and hypermetabolic moderate to severe bilateral pleural effusion (Figure 3A and B). There was an ill-defined hypermetabolic 2.1 2.0 cm soft tissue lesion in the UOQ of the right breast (Figure 4). Mammography showed an irregular, asymmetrical density with surrounding architectural distortion in the UOQ of the right breast. CA-125 level was 596 U/mL (reference range 0–37). Core biopsy from right breast mass revealed infiltrating ductal carcinoma, grade 3, ER-negative, PR-negative, and HER2-neu–negative. She underwent both thoracentesis and paracentesis, and pleural and ascitic fluid cytology revealed papillary adenocarcinoma. Fine needle aspiration cytology from the right adnexal mass confirmed papillary adenocarcinoma.
Case No. 2 A 47-year-old premenopausal woman, previously in good health, presented in the outpatient department with complaints of breathlessness and cough for a period of 1 month. She had no family history of cancer. On examination, the lungs were clear to auscultation in the apices,
Figure 4. PET-CT scan (case 2) showing hypermetabolic (SUV42) mass in right breast and bilateral pleural effusions.
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Figure 5. CT scan of abdomen and pelvis (case 3) showing measurable pelvic mass unable to be reached by needle biopsy.
She was given docetaxel, doxorubicin, and cyclophosphamide chemotherapy every 3 weeks for six cycles. Post-chemotherapy, CA-125 was 6 U/mL. PET-CT scan revealed complete metabolic response in the breast and non-flouro deoxyglucose (FDG)–avid hypodense lesions in both adnexae. She then underwent right total mastectomy with axillary lymph node dissection, as well as total abdominal hysterectomy, with bilateral salphingo-oophorectomy, and infracolic omentectomy. Histopathology from the breast was reported as no residual tumor with all 21 lymph nodes examined. Both ovaries revealed cystadenocarcinoma with microscopic metastatic tumor deposits in the omentum. Lymphovascular emboli were present. Cytology from peritoneal washings were positive for malignancy. The patient was further given three cycles of paclitaxel and carboplatin every 3 weeks. She is now undergoing regular surveillance, and is clinically and radiologically without evidence of disease.
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modified mastectomy with reconstruction, chemotherapy with doxorubin/cyclophosphamide, and paclitaxel, post-mastectomy chest wall irradiation, and who took tamoxifen for 2 years, followed by an aromatase inhibitor in the postmenopausal state. Due to her young age, she had been tested for BRCA mutation and was found to have a variant of undetermined significance in the BRCA2 gene at locus T2250A, not deleterious in current databases.4,5 Two years later, she presented with a several weeks history of worsening back and abdominal pain, nausea, vomiting, and weakness. CT scans showed multiple areas of metastases in the liver, abdominal, and mesenteric lymph nodes, and the bones. CA 27-29 level was 3,368 U/mL (normal 0–38.6); CEA level was 176 ng/mL (normal 0.0–3.0). CT-guided liver biopsy was positive for phenotypically similar metastatic breast cancer. She began systemic therapy with docetaxel and had a good response after 6 months of therapy; CA 27-29 level decreased to 1,223.5, and CEA was 81.2. She continued therapy in the form of fulvestrant for 6 months until follow-up scans with rising tumor markers showed increase in size of bilateral pelvic wall masses (Figure 5). Further
chemotherapy with capecitabine was attempted with further progression of disease into the pelvis, onset of abdominal/pelvic ascites, and development of new peritoneal caking with gastrohepatic lymphadenopathy; CA 27-29 rose to 13,067.5, with a CEA level of 1,091. She was evaluated by a gynecologic oncology service, and neither pelvic masses nor lymphadenopathy was able to be accessed via interventional biopsies due to location near blood vessels. She was started on eribulin and had a dramatic clinical response in malignant ascites, and a decrease in tumor markers to a CA 27-29 level of 1,100.
Case No. 4 A 63-year-old Italian woman presented with a remote history of breast cancer 10 years prior, and was treated with lumpectomy followed by radiation therapy for a 0.8-cm infiltrating mammary carcinoma, which had features of mixed pleiomorphic and solid variants of infiltrating lobular carcinoma, nuclear grade 2, ER-positive and PR-positive (490%), Her-2 neu– negative, p53-negative, with no lymphovascular invasion, and no lymph node involvement. She took tamoxifen for 5 years, and had no
Case No. 3 The patient is a 40-year-old Hispanic woman with a history ERpositive, PR-positive, HER-2 neu– negative, early-stage lymph node– positive breast cancer diagnosed at age 32, who underwent bilateral
Figure 6. CT scan of abdomen and pelvis (case 4) showing omental caking, for which CT-guided biopsy was performed.
Synchronous primary carcinoma of breast and ovary
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Figure 7. (A) Omental biopsy. Hematoxylin and eosin stain, 10X magnification. (B) Omental biopsy. Hematoxylin and eosin stain, 40X magnification. (C) Omental biopsy. Mammoglobin stain, 100X magnification. (D) Omental biopsy. Estrogen receptor stain, 100X magnification. Courtesy of Dr. Libo Qiu, Department of Pathology, Mount Sinai Hospital of Queens, Long Island City, NY.
evidence of recurrence in the ipsilateral or contralateral breasts. She recently presented to a gastroenterologist with a 5-month history of vague nausea, occasional vomiting, and anorexia, leading to 10-pound weight loss over the same period of time. She underwent endoscopy, and was found to have a mass in the gastric fundus; initial biopsy results described an infiltrating poorly differentiated neoplasm further classified as metastatic lobular mammary carcinoma with immunohistochemical stains positive for CK7, ER, mammaglobin, and
GCDFP-15, focally positive for CA 19-9, and negative for CK20, CDX2, CD3, and CD20. She continued to have weakness, nausea, and vomiting, and required hospitalization for dehydration and abdominal bloating. CT scan of the abdomen and pelvis showed loculated pelvic ascites with thickened omentum and omental caking, and an enlarged right adnexal mass (Figure 6). There was no area of adequate volume amenable to paracentesis. Analysis of peripheral blood tumor markers showed elevations in CEA to 50.6 (normal 0.0–
3.0), CA 27-29 to 311.5 (normal 0– 38.6) CA-125 to 170 (normal o35) but normal CA 19-9. CT-guided biopsy of an omental cake (Figure 7) in the left upper abdomen confirmed metastatic mammary carcinoma, predominantly with lobular features, with immunohistochemical phenotype also positive for ER, mammaglobin, and CK7 but negative for PR, GCDFP-15, CK20, and CDX2. Due to frail performance status, supportive care was optimized with antiemetics, and the patient was started on an aromatase inhibitor.
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PATHOLOGIST’S AND MEDICAL ONCOLOGIST'S EXPERT OPINIONS It is critical to pursue an accurate diagnosis when evaluating a patient with an ovarian mass who is also presenting with a breast mass, or who has a history of breast cancer. Although malignant ovarian masses in patients with a history of breast cancer are more often primary ovarian malignancies than breast cancer metastases,6,7 it is important to understand which breast cancer patients are most likely to present with ovarian metastases, how to differentiate breast metastases from primary ovarian malignancies, and, of course, how to best manage these patients.
report of 29 cases of ovarian metastases from breast cancer, 12 of 29 patients (43.5%) were found to have lobular carcinoma (compared to the reported incidence of lobular carcinoma in the entire breast cancer population of about 15%).11 Therefore, in a patient with a history of ILC, a new malignant ovarian mass is more suspicious for metastatic disease than in the patient with IDC. Particularly challenging are those patients with BRCAmutated breast cancers. When these patients present with a subsequent ovarian mass, one has to be more suspicious of a primary ovarian malignancy, yet these patients’ breast cancers can still metastasize to the ovary.
Clinical Presentation Features
Pathologic Features
In the approach to a patient with breast cancer presenting with an ovarian mass, the subtype of breast cancer is an important factor. Although both invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) have been reported to metastasize to the ovary,7–9 there is evidence to suggest that ILC is more likely to do so than IDC.8,9 In one autopsy study, 36% of patients with a history of ILC had metastases to the ovary, whereas only 2.6% of patients with IDC had ovarian metastases.9 In another study, 52.2% of patients with ILC had ovarian metastases on autopsy versus only 11.3% of patients with IDC.10 Further, in a
Fortunately, there are several immunohistochemical studies that when used in conjunction show utility in differentiating breast from ovarian malignancies. The vast majority of breast cancers, both metastatic and primary, show positive expression for GATA3, and mammaglobin, while ovarian malignancies are negative for these markers.12–17 Expression of GATA3 was observed in a higher percentage of well differentiated tumors including lobular carcinomas and grade I ductal carcinomas, whereas downregulation was seen with progression of tumor grade.13 Gross cystic disease fluid protein 15 (GCDFP-15), another marker of
breast origin, is a useful addition to the panel because, although sensitivity is lower than mammaglobin and GATA3, the specificity for breast is high.12,18–20 Markers with positive expression in ovarian tumors that have shown clinical utility in differentiating between primary ovarian cancer and metastatic breast cancer include: WT-1, Pax8, MUC5AC, CA19-9, and CK20 (see Table 1).19,21–24 Repeating the ER/PR and Her2 stains on the metastatic breast cancer cells is also important. Many series demonstrate that Her2 and ER/PR can be lost in up to 10% and 20% of metastatic deposits, respectively, when present on the original tumor.25 On the other side, ER/PR and Her2 can be newly expressed in the metastasis in about 10% of cases.25 Prospective evaluation of the therapeutic consequences and management of these clonal evolutions is underway, but frequently affects the choice of therapies in the metastatic setting. When the pathologic assessment supports a diagnosis of breast cancer metastatic to the ovary, then the clinician must weigh the evidence for various treatment options. Interestingly, preliminary data indicate that complete surgical resection of metastatic disease involving the ovary may provide a survival benefit. One study showed that patients had significantly improved survival when their metastatic disease involving the ovary or ovaries was completely resected,8 while other
Table 1. Immunohistochemical Markers Useful in Differentiating Breast Versus Ovarian Tissue Ovarian Cancer Marker
Mucinous
Serous
Breast Cancer
GATA 3 Mammoglobin GCDFP-15 MUC5AC CA 19-9 CK20 WT1 PAX8
þþþ þþþ þþþ
þþþ þþþ
ER-pos:þþþ, ER-neg:þþ þþþ þ
Synchronous primary carcinoma of breast and ovary
studies have shown only trends in favor of complete resection, but these values did not reach statistical significance.16,17 Importantly, breast cancer metastatic to the ovaries has been shown to involve both ovaries in about 75% of cases,8,18 which should be taken into consideration if pursuing surgery. However, despite the aforementioned studies, the true value of complete resection of breast cancer ovarian metastases remains uncertain. Therefore, the approach to a breast cancer patient with a malignant ovarian mass should include tissue sampling and a comprehensive immunohistochemical analysis. If the mass is determined to be metastatic breast cancer and is an isolated finding, then in addition to systemic therapy, it may be appropriate to consider a complete surgical resection. We have the following comments regarding the cases presented here. In cases 1 and 2, although the initial pathology suggests two primaries, we would recommend further analysis of the ovarian specimens using the markers described above. Further, we would offer BRCA testing to the patient in case 1. In case 3, it is unfortunate that a tissue diagnosis was not possible; however, it remains that this patient might benefit from further endocrine therapy. Case 4 describes a patient with ILC of the breast presenting with well-characterized abdominal and pelvic metastases that can be seen in these patients. As described above, GATA3 would be a useful additional marker to confirm metastatic breast cancer in this patient. Tyler P. Robin, BS Medical student Sharon Sams, MD Department of Pathology Anthony D. Elias, MD Department of Medicine Division of Medical Oncology University of Colorado School of Medicine
MEDICAL ONCOLOGIST'S AND GENETICIST'S EXPERT OPINION The most common sites of metastasis for breast cancer are the bones, lung, and liver. However, metastases to the peritoneum, stomach, and ovaries are well described in patients with breast cancer.26–28 In a study of 75 patients with metastases to the ovaries, investigators found that the primary sites were stomach (37.3%), colorectal region (28%), lymphoma (12%), breast (6.7%), biliary system (2.7%), appendix (1.3%), and small intestine (1.3%).29 These metastases can sometimes be the first site of presentation of the malignancy. The majority of these metastases will be bilateral30 and are associated with poor prognosis. Several studies have examined the metastatic pattern of breast cancer and noted that ILC was associated with a greater propensity to involve the internal genital organs than IDL.10,31 Synchronous breast and ovarian cancer is a rare phenomenon.32,33 A retrospective analysis of 7,166 cases of breast cancer and 1,758 cases of ovarian cancer identified through the Duke University Medical Center and University of North Carolina Hospitals identified only 50 cases of multiple primary cancers of the breast and ovary. Only four of these were cases of synchronously diagnosed breast and ovarian cancer.34 Since breast cancer can metastasize to the ovaries21 and to a lesser extent ovarian cancer can metastasize to the breast,35 a careful histologic confirmation of both malignancies is important. In cases where these two malignancies are diagnosed in an individual, the possibility of a BRCA1/2 germline mutation should be raised. The treatment of metastatic breast cancer to the peritoneal and pelvic area should follow the practices of treatment of metastatic breast cancer. Complicating factors,
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such as the presence of ascites and bowel obstruction, make these cases challenging for the treating physician. In cases with confirmed breast and ovarian cancer, treatment recommendations would have to take into account the characteristics and treatment practices of both malignancies. Neoadjuvant chemotherapy has a known role in both breast and ovarian cancer and can help decrease the volume of disease.2,3 Chemotherapeutic agents which are active in both diseases, such as platinum drugs, taxanes, and anthracyclines, can be used. Data suggest that BRCA1/2-related breast and ovarian cancers may be more sensitive to platinum agents (carboplatin and cisplatin).36–39 Although not considered standard of care for the treatment of breast cancer, the use of platinum agents in this setting would be a very reasonable approach to cytoreduction prior to surgical excision. Residual disease after neoadjuvant chemotherapy for breast cancer has been associated with higher risk of relapse mostly in triple-negative breast cancers (ER-negative, PR-negative, and HER2-negative), whereas its importance in ER-positive disease is of less clinical importance.40 Finally the addition of endocrine therapy with tamoxifen or an aromatase inhibitor should be considered standard treatment in this patient population.41 A patient with primary breast and ovarian cancer who develops metastatic disease should have a biopsy done on the site of metastatic disease if at all possible. Although chemotherapeutic agents that can treat both malignancies can be identified, the possibility that the metastatic tumor may differ in ER, PR, or HER2 status compared with the primary tumor can be as high as 30%,42,43 having clear implications on treatment recommendations. Furthermore, if the metastatic cancer is found to be consistent with breast cancer, alternative endocrine agents, such as fulvestrant, can be considered,41
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whereas bevacizumab may be used in the case of ovarian cancer.45,46 Virginia Kaklamani, MD, DSc Associate Professor, Director, Translational Breast Cancer Research Co-Director Cancer Genetics Program Division Hematology/Oncology Northwestern University Chicago, IL
MEDICAL ONCOLOGIST’S AND GENETICIST’S EXPERT OPINION This case series presents four patient scenarios having the unifying theme of pelvic cancer in the context of a breast cancer diagnosis. Such scenarios are not rare and appropriate patient management requires determining one primary feature: does the pelvic involvement represent a separate oncologic process, in which case treating with curative intent is the appropriate goal; or is the pelvic involvement metastatic from the breast primary, in which case palliative management is usually the more appropriate goal? The question is stated in this way because metastasis of ovarian cancer to the breast is a rare event, with only 39 cases reported in the literature through 2010.47,48 The answer frames the approach to the management questions posed: Are the combination of proposed antineoplastic drugs adequate to have activity in both the cancers if separate pathologies?; and, what should be the optimal surgical intervention and follow-up in such cases? The mode of presentation has an important influence on interpretation of the clinical data. For this series, the first two cases are synchronous presentations of breast/pelvic pathology. The second two cases demonstrate metachronous events. The cases will be considered accordingly.
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For the synchronous cases, the clinical and pathologic data support the conclusion that the two processes involve simultaneous development of breast and ovarian cancer. In both, the breast pathology is invasive ductal, while the pelvic pathology showed papillary adenocarcinoma. These are distinctive and easily distinguished histologically. Notably, in both cases the CA-125 level was elevated. While often thought of as an ovarian specific circulating tumor antigen, this mucopolysacharide product can be elevated in metastatic breast cancer,49 so in itself does not help to resolve the primary question. However, in the given clinical cases, it doses support the separate primaries conclusion. Any clinical scenario involving breast and ovarian primaries also should raise suspicion for the possibility of breast/ovarian syndrome (ie, germline BRCA1/2 mutation). Detecting a germline BRCA1/2 mutation would have relevance to locoregional management of the breast cancer. The receptor status of the breast cancers can also guide suspicion of BRCA1/2 status; in the second case the breast cancer is “triple-negative,” the subtype most often seen in BRCA1 carriers. For these two cases, we do not know the germline genetic status for these patients. However, using the incomplete information available, the pretest mutation probability in each is 74% by the BRCAPRO model (higher for BRCA2 in case 1 and BRCA1 in case 2).50 Systemic therapy in both cases appropriately included both an anthracycline and a taxane, drugs active against both breast and ovarian cancer. The more controversial issue would be inclusion of a platinum agent. Accumulating data support chemotherapy selection guided by mutation and receptor status, with some indication that BRCA1/2-associated51
and ER-/PR-/HER2-negative cancers36 are sensitive to platinum-based therapy. In 2015, these data are still preliminary, but come from several sources in metastatic and early-stage disease. While the anecdotal responses in these two cases belie these considerations for platinum-based therapy, given that platinum-based therapy is a standard of care for ovarian cancer, using it in both cases is likely indicated. In both cases, surgical management was appropriately aggressive, and applied with curative intent. The metachronous cases are more clearly examples of delayed distant recurrences of early-stage breast cancer. In case 3, despite aggressive and appropriate treatment, the patient’s cancer recurred in a typical pattern for an aggressive ER-positive breast cancer. The sites of involvement, serum tumor markers, and treatment response are all consistent with this interpretation, and further sampling of the pelvic involvement to establish this fact is not standardly required. The BRCA2 variant of uncertain significance should not cloud this interpretation. If clarified as deleterious, such variants may eventually guide use of platinum chemotherapy or a poly-(ADP)ribose polymerase (PARP) inhibitor, but even then would not significantly change interpretation of the clinical picture. Gynecologic surgery might be done if any ambiguity regarding menopausal status in the metastatic setting was present, and would provide further tissue confirmation that the metastatic disease is of breast origin, but is not otherwise indicated. In case 4, the recurrence is classic for an aggressive variant of lobular breast cancer52; it is a late recurrence and involves the gastrointestinal tract and peritoneum. Biopsy of the metastatic disease confirmed this and is also impor-
Synchronous primary carcinoma of breast and ovary
tant for reassessing metastatic disease receptor status. The patient is appropriately managed with endocrine therapy and no additional surgery. P. Kelly Marcom, MD Associate Professor Medical Oncology Co-Director, Breast Cancer Clinical Research Director, Hereditary Cancer Clinic Duke Cancer Institute Duke University Durham, NC
DISCUSSION The first two cases appear to be synchronous primary carcinomas requiring treatment. This is supported by clinical, radiological, biochemical, histopathological, and IHC findings; however, the natural history of disease in the two cases is quite different. The first patient had T2N1 disease in her breast; the initial response to chemotherapy was not favorable in the breast, and she had the subsequent development of CNS metastases presumed to be related to breast cancer. The second patient initially had more advanced ovarian disease but responded to chemotherapy very well, despite IHC phenotype being unfavourable (ie, triple-negative breast cancer and papillary ovarian cancer). The ovary is a common site of metastases for the breast and other (gastrointestinal as a Krukenberg tumor) primary canConversely, the cers.8,29,53 breast is an uncommon site for tumor metastasis. There are only 37 cases that have been reported in the English literature as ovarian cancer metastasizing to breast.54– 61 The frequency of breast metastasis of ovarian carcinoma varies from 0.5% to 1.2% in the clinical setting.62–64 These ovarian cancers are widespread ones and
they have a poor prognosis with breast metastasis. Accurate differentiation of metastatic from primary tumors is important because the treatment and prognosis differ significantly. Using IHC staining solely, as is common in daily practice, to support the histological findings may not be helpful and sometimes may lead to a false diagnosis and an ineffective treatment strategy. The combination of chemotherapy drugs in each of the cases was specifically chosen keeping in view covering both primaries. Paclitaxel can be given in both diseases; doxorubicin and carboplatin were added in cases 1 and 2 for breast and ovarian cancer, respectively. In case 1, however, the patient’s disease in the breast and axilla did not respond to these drugs; conversely, a complete pathological response (pCR) in the breast was seen in the second case. It may be due to treatment with docetaxel and cyclophosphamide; studies have shown that the taxanes are equally effective in breast cancer,65 and the response may have been because the triplenegative phenotype is more chemosensitive. The impact of neoadjuvant chemotherapy in patients with triple-negative breast cancer has been clearly analyzed by Liedtke et al.66 The pCR rate was double in triple-negative patients as compared with non–triple-negative patients, although 3-year disease-free survival (DFS) was worse in the former group. Interestingly, the long-term DFS of patients achieving pCR was similar in the two groups, while the rate of early relapse in patients with residual tumor was dramatically higher in triple-negative patients as compared with the others. It also has been reported that the clearance of the axilla after chemotherapy per se correlates with better survival. Therefore, the persistence of a relevant tumor residual in the axillary nodes can be associated
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with a substantial risk of relapse, regardless of the response in the breast. Recent advances in functional tumor imaging by fluoro deoxyglucose–PET scanning or by dynamic magnetic resonance imaging allow us to select patients early who are not going to achieve a pCR.67–70 These patients should be shifted early (after 3–4 weeks) to another treatment, and maximal effort should be made to select the best possible drugs, doses, and schedule for these patients. The presence of both forms of cancer in a patient is associated with a high risk of BRCA1 gene mutations, which are responsible, together with BRCA2 gene mutations, for most cases of hereditary breast and ovarian cancer syndromes, and hence consideration of the use of platinum agents in their treatment,36,71 although this high-risk landscape is changing rapidly to include other genes. The final decisions toward the treatment program are of great importance because therapeutic strategies differ extremely from each other in metastatic and primary breast tumors. Cases 3 and 4 corroborate metastases in one individual, each considered for possible BRCA mutation carrier status and another with biopsyproven metastases, respectively. The biopsy-proven metastases to the stomach in case 4 is corroborated by the literature, despite being very rare.72,73 Precision is key, and caution is raised because a false diagnosis may result in overtreatment, inaccurate treatment, and/or disparate surgical recommendations, as discussed by Dr Elias and colleagues. We suggest that evaluation of clonality also must be done in patients in whom IHC staining seems to support the diagnosis. We thank our international colleagues for their expert appraisal of these cases and commentary of the significance of intraperitoneal
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disease in women with breast cancer.44 9.
Budhi Yadav, MD S.C. Sharma, MD Sarah Schaefer, MD Department of Hospitalist Medicine, The Mount Sinai Hospital of Queens Astoria, NY Gloria J. Morris, MD, PhD Hematology/Oncology Associates of Central New York East Syracuse, NY
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REFERENCES 1. Siegel R, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29. 2. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. breast cancer, version 3.2014. http://www. nccn.org/professionals/physician_ gls/pdf/breast.pdf. Accessed 5/15/ 14. 3. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. ovarian cancer, version 3.2014. http:// www.nccn.org/professionals/ physician_gls/pdf/ovarian.pdf. Accessed 5/15/14. 4. Lindor NM, Friedman S, Guidugli L, et al. Progress in clinical interpretation of DNA variants of undetermined significance in BRCA1/2. Based on a publication titled "A review of a multifactorial probabilitybased model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)." 222.mayo. edu/research/document/ brca-riskpdf/doc-10026644. 5. Morris G. Assessing genetic variants of undetermined significance: the example of breast cancer. 2013. www.els.net/WileyCDA/EIs Article/refld-a0025220.html. 6. Curtin JP, Barakat RR, Hoskins WJ. Ovarian disease in women with breast cancer. Obstet Gynecol. 1994;84(3):449–52. 7. Simpkins F, Zahurak M, Armstrong D, Grumbine F, Bristow R. Ovarian malignancy in breast cancer patients with an adnexal mass. Obstet Gynecol. 2005;105(3): 507–13. 8. Bigorie V, Morice P, Duvillard P, et al. Ovarian metastases from
12.
13.
14.
15.
16.
17.
18.
19.
breast cancer: report of 29 cases. Cancer. 2010;116(4):799–804. Harris M, Howell A, Chrissohou M, Swindell RI, Hudson M, Sellwood RA. A comparison of the metastatic pattern of infiltrating lobular carcinoma and infiltrating duct carcinoma of the breast. Br J Cancer. 1984;50(1):23–30. Lamovec J, Bracko M. Metastatic pattern of infiltrating lobular carcinoma of the breast: an autopsy study. J Surg Oncol. 1991;48(1): 28–33. Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003; 289(11):1421–4. Chia SY, Thike AA, Cheok PY, Tan PH. Utility of mammaglobin and gross cystic disease fluid protein15 (GCDFP-15) in confirming a breast origin for recurrent tumors. Breast. 2010;19(5):355–9. Liu H, Shi J, Wilkerson ML, Lin F. Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. Am J Clin Pathol. 2012;138(1):57–64. Luo MH, Huang YH, Ni YB, et al. Expression of mammaglobin and gross cystic disease fluid protein15 in breast carcinomas. Hum Pathol. 2013;44(7):1241–50. Miettinen M, McCue PA, SarlomoRikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol. 2014;38(1): 13–22. Ordonez NG. Value of GATA3 immunostaining in tumor diagnosis: a review. Adv Anat Pathol. 2013;20(5):352–60. Shield PW, Papadimos DJ, Walsh MD. GATA3: a promising marker for metastatic breast carcinoma in serous effusion specimens. Cancer Cytopathol. 2014;122(4):307–12. Bhargava R, Beriwal S, Dabbs DJ. Mammaglobin vs GCDFP-15: an immunohistologic validation survey for sensitivity and specificity. Am J Clin Pathol. 2007;127(1): 103–13. Tornos C, Soslow R, Chen S, et al. Expression of WT1, CA 125, and
20.
21.
22.
23.
24.
25.
26.
27.
28.
GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary. Am J Surg Pathol. 2005;29 (11):1482–9. Wick MR, Lillemoe TJ, Copland GT, Swanson PE, Manivel JC, Kiang DT. Gross cystic disease fluid protein-15 as a marker for breast cancer: immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. Hum Pathol. 1989;20(3):281–7. McCluggage WG, Wilkinson N. Metastatic neoplasms involving the ovary: a review with an emphasis on morphological and immunohistochemical features. Histopathology. 2005;47(3):231–47. Ozcan A, Liles N, Coffey D, Shen SS, Truong LD. PAX2 and PAX8 expression in primary and metastatic mullerian epithelial tumors: a comprehensive comparison. Am J Surg Pathol. 2011;35(12): 1837–47. Park SY, Kim BH, Kim JH, Lee S, Kang GH. Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma. Arch Pathol Lab Med. 2007;131(10):1561–7. Young RH. From Krukenberg to today: the ever present problems posed by metastatic tumors in the ovary. Part II. Adv Anat Pathol. 2007;14(3):149–77. Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014;50(2):277–89. Ayhan A, Guvenal T, Salman MC, Ozyuncu O, Sakinci M, Basaran M. The role of cytoreductive surgery in nongenital cancers metastatic to the ovaries. Gynecol Oncol. 2005;98(2):235–41. Eitan R, Gemignani ML, Venkatraman ES, Barakat RR, Abu-Rustum NR. Breast cancer metastatic to abdomen and pelvis: role of surgical resection. Gynecol Oncol. 2003;90(2):397–401. Fujiwara K, Ohishi Y, Koike H, Sawada S, Moriya T, Kohno I. Clinical implications of metastases
Synchronous primary carcinoma of breast and ovary
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
to the ovary. Gynecol Oncol. 1995;59(1):124–8. Turan T, Aykan B, Koc S, et al. Analysis of metastatic ovarian tumors from extragenital primary sites. Tumori. 2006;92:491–5. Gagnon Y, Tetu B. Ovarian metastases of breast carcinoma. A clinicopathologic study of 59 cases. Cancer. 1989;64:892–8. Borst MJ, Ingold JA. Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery. 1993;114: 637–41. Sandor V, Reed E, Sarosy G, Middleton LP, Davis P, Kohn E. Synchronous inflammatory breast cancer and advanced ovarian carcinoma: a case with prolonged disease-free survival. Ann Oncol. 1999;10:585–8. Syed R, Nazir SA, Lwin KY, Bose P, Evans P, Choji K. Occurrence of synchronous invasive lobular breast carcinoma and poorly differentiated ovarian carcinoma in a single peritoneal deposit. Oncology. 2007;73:136–40. Suris-Swartz PJ, Schildkraut JM, Vine MF, Hertz-Picciotto I. Age at diagnosis and multiple primary cancers of the breast and ovary. Breast Cancer Res Treat. 1996; 41:21–9. Recine MA, Deavers MT, Middleton LP, Silva EG, Malpica A. Serous carcinoma of the ovary and peritoneum with metastases to the breast and axillary lymph nodes: a potential pitfall. Am J Surg Pathol. 2004;28:1646–51. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neo-adjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide: CALGB (Alliance). J Clin Oncol. 2015;33(1):13–21. Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28: 1145–53. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triplenegative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56.
39. Muggia F, Safra T. ‘BRCAness’ and its implications for platinum action in gynecologic cancer. Anticancer Res. 2014;34:551–6. 40. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–804. 41. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881–94. 42. Kaklamani VG, Cianfrocca M, Ciccone J, et al. Increased HER2/neu expression in recurrent hormone receptor-positive breast cancer. Biomarkers. 2010;15:191–3. 43. Yao ZX, Lu LJ, Wang RJ, et al. Discordance and clinical significance of ER, PR, and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis. Med Oncol. 2014; 31:798. 44. Schiavon G, Smith IE. Endocrine therapy for advanced/metastatic breast cancer. Hematol.Oncol. Clin.North Am. 2013;27:715–36. 45. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302–8. 46. Zhou M, Yu P, Qu X, Liu Y, Zhang J. Phase III trials of standard chemotherapy with or without bevacizumab for ovarian cancer: a meta-analysis. PLoS.One. 2013;8: e81858. 47. Klein RLBA, Gomez-Castro CM, Chambers SK, Cragun JM, GrassoLeBeau L, Lang JE. Ovarian cancer metastatic to the breast presenting as inflammatory breast cancer: a case report and literature review. J Cancer. 2010;27–31. 48. Micha JP, Goldstein BH, Epstein HD, Rettenmaier MA, Brown JV, III. Ovarian cancer metastatic to the breast. Gynecol Oncol. 2006; 102:386–90. 49. Bast RC, Jr, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB. CA 125: the past and the future. Int J Biol Markers. 1998;13:179–87.
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50. Ca Gene Website. 2014. https:// www4.utsouthwestern.edu/breas thealth/cagene/. 51. Bayraktar S, Glu ¨ ck S. Systemic therapy options in BRCA mutation-associated breast cancer. Breast Cancer Res Treat. 2012; 135:355–66. 52. Lamovec J, Bracko M. Metastatic pattern of infiltrating lobular carcinoma of the breast: an autopsy study. J Surg Oncol. 1991;48: 28–33. 53. Jung Y-E, Lee J-W, Kim B-G, Bae DS. Ovarian metastasis from pulmonary adenocarcinoma. Obstet Gynecol Sci. 2013;56(5):341–4. 54. Yamasaki H, Saw D, Zdanowitz J, et al. Ovarian carcinoma metastasis to the breast case report and review of the literature. Am J Surg Pathol. 1993;17:193–7. 55. Manini C, Pietribiasi F, Sapino A, et al. Serous cystadenocarcinoma of the ovary with simultaneous breast metastases. Description of a case. Pathologica. 1998;90: 152–5. 56. Orris BG, Geisler JP, Geisler HE. Ovarian carcinoma metastatic to bilateral axillary lymph nodes. A case report. Eur J Gynaecol Oncol. 1999;20:189–90. 57. Fondrinier E, Gamelin E, Verriele V. Inflammatory breast metastasis from primary ovarian cancer: case report. Eur J Gynaecol Oncol. 1999;20:16–7. 58. Petersen BL, Hogdall E, KrygerBaggesen N. Metastasis to the breast from an ovarian carcinoma. Acta Obstet Gynecol Scand. 1999;78:826–7. 59. Wadhwa J, Dawar R, Kumar L. Ovarian carcinoma metastatic to the breast. Clin Oncol (R Coll Radiol). 1999;11:419–21. 60. Cormio G, di Vagno G, Melilli GA, et al. Ovarian carcinoma metastatic to the breast. Gynecol Obstet Invest. 2001;52:73–4. 61. Kayikcioglu F, Boran N, Ayhan A, et al. Inflammatory breast metastases of ovarian cancer: a case report. Gynecol Oncol. 2001;83:613–6. 62. Hajdu SI, Urban JA. Cancers metastatic to the breast. Cancer. 1972;29:1691–6. 63. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma: analysis of 1000 autopsied cases. Cancer. 1950;3:74–85.
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64. Sandison AT. Metastatic tumors in the breast. Br J Surg. 1959;47: 54–8. 65. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358: 1663–71. 66. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008; 26:1275–81. 67. Rousseau C, Devillers A, Sagan C, et al. Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron
B.S.Yadav et al
emission tomography. J Clin Oncol. 2006;24:5366–72. 68. Berriolo-Riedinger A, Touzery C, Riedinger JM, et al. [18F] FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2007;34 (12):1915–22. 69. Padhani AR, Hayes C, Assersohn L, et al. Prediction of clinicopathologic response of breast cancer to primary chemotherapy at contrast-enhanced MR imaging: initial clinical results. Radiology. 2006;239:361–74. 70. Chen JH, Mehta RS, Carpenter PM, et al. Magnetic resonance imaging in predicting pathological response of triple negative breast
cancer following neoadjuvant chemotherapy. J Clin Oncol. 2007;25 (35):5667–9. 71. Telli M. Optimizing chemotherapy in triple-negative breast cancer: the role of platinum. ASCO Educational Book. 2014;e37–42. www. asco.org/edbook. 72. Eo WK. Breast cancer metastasis to the stomach resembling early gastric cancer. Cancer Res Treat. 2008;40(4):207–10. 73. Jones GE, Strauss DC, Forshaw MJ, et al. Breast cancer metastasis to the stomach may mimic primary gastric cancer: report of two cases and review of the literature. World J Surg Oncol. 2007;5:75.
