Case Report

Breast Cancer in a RAD51D Mutation Carrier: Case Report and Review of the Literature Jennifer L. Baker,1 Richard B. Schwab,2,3 Anne M. Wallace,1,3 Lisa Madlensky3,4 Clinical Practice Points  Multigene panel testing can be performed when he-

 Tumors that develop in patients with germline

reditary breast cancer is suspected.  Germline RAD51D pathogenic mutations have been observed in families with breast and ovarian cancer.  Germline RAD51D pathogenic mutations are associated with an increased risk of ovarian cancer, although their contribution to breast cancer susceptibility is less clear.

RAD51D deleterious variants might respond better to certain therapies.  The treatment of patients with pathogenic mutations in genes with unclear penetrance such as RAD51D relies on expert opinion and individualized risk assessment.

Clinical Breast Cancer, Vol. 15, No. 1, e71-5 ª 2015 Elsevier Inc. All rights reserved. Keywords: Cancer risk, Clinical trial, Genetic testing, Hereditary breast cancer, RAD51D

Introduction Heritable factors can greatly increase the susceptibility to cancer, and, in recent years, researchers have uncovered > 100 cancer predisposition genes.1-3 In the appropriate setting, identifying clinically relevant germline pathogenic mutations will allow for accurate risk estimation, optimized screening and early detection programs, and an opportunity for risk-reducing interventions.4-6 Germline genetic information can also have significant treatment implications, because pathogenic mutations have typically disturbed a molecular pathway or repair system in the tumors they precipitate. Novel molecular therapeutic agents are increasingly being developed to target these pathway alterations.7,8 BRCA1 and BRCA2 are high-penetrance cancer predisposition genes with wide clinical recognition that they greatly increase the risk of breast, ovarian, and other cancers.9 However,  20 other genes have been implicated in breast cancer through linkage analysis, association studies, and mutational screening.3,9,10 These include rare, but highly penetrant, variants, such as p53, STK11, 1 Department of Surgery, University of California, San Diego, School of Medicine, La Jolla, CA 2 Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 3 Moores Cancer Center, University of California, San Diego, La Jolla, CA 4 Department of Family and Preventive Medicine, University of California, San Diego, School of Medcine, La Jolla, CA

Submitted: Jun 12, 2014; Revised: Aug 21, 2014; Accepted: Aug 25, 2014; Epub: Sep 23, 2014 Address for correspondence: Lisa Madlensky, PhD, CGC, Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, MC #0901, La Jolla, CA 92093-0901 E-mail contact: [email protected]

1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.08.005

and PTEN, and moderate to low penetrance variants, such as ATM, CHEK2, BRIP 1, and PALB2.5,10 Uncovering low or moderate penetrance variants can present clinical challenges, because the relative risk of many of these variants has not been characterized, and, therefore, the management recommendations are not clear.4,9 Nevertheless, the development of next-generation sequencing techniques has allowed for rapid analysis of multiple genes and at a more affordable cost, making multigene panel testing more widely available.9 We present a case of triple negative breast cancer diagnosed in a young woman in whom a RAD51D pathogenic mutation was discovered after multigene panel testing.

Case Report A healthy, 36-year-old woman presented with a palpable right breast mass in September 2011. Her family history was notable for multiple relatives on her maternal side with breast cancer, including a distant male relative with breast cancer (Figure 1). Physical examination of her right breast confirmed a discrete mass (2.9 cm by palpation) without inflammatory skin changes or nipple discharge. She underwent mammography and ultrasound imaging, which confirmed a 2.1-cm mass. The mass was biopsied and revealed a highgrade, triple negative invasive ductal carcinoma (estrogen receptor 0%, progesterone receptor 0%, and human epidermal growth factor receptor 2 [HER2] immunohistochemistry 1þ). She was clinically node negative. She met the current clinical criteria for BRCA testing and therefore underwent analysis of BRCA1 and BRCA2 (sequencing and full rearrangement analysis), with negative findings. Her tumor size and triple negative tumor status qualified her to participate in the Investigation of Serial Studies to Predict Your

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Breast Cancer in a RAD51D Mutation Carrier Figure 1 Extended Pedigree of Index Patient

d. 65

d. 53

(+) d. 81

+

79

Bone Ca dx 67 Prostate dx 70

74

+

67

+

d. 87

Br Ca dx 61

41

Br Ca dx 58

d. 66 Pros. Ca dx ?

Br Ca dx 38

d. 72

d. 59

d. 84

65

Medullary Br Ca Dx 54

-

d. 24

Male Br Ca dx 46

+

Br Ca dx ?

Br Ca dx 50

40

Br Ca dx 36

e72

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Therapeutic Response with Imaging and molecular Analysis 2 (I-SPY 2) trial. The I-SPY 2 trial is a multicenter study designed to use adaptive randomization to test novel agents to treat high-risk breast cancer in the neoadjuvant setting.11 With University of California, San Diego, institutional review board approval, she provided informed consent for the screening and treatment phases of the study. On the trial, novel therapy (typically including weekly paclitaxel) is followed by standard chemotherapy with doxorubicin (Adriamycin) and cyclophosphamide (AC). The response to the investigational drug was ascertained by serial magnetic resonance imaging (MRI) studies.12 She was randomized to the neratinib and paclitaxel arm and received a total of 12 doses of weekly paclitaxel (80 mg/m2) with weekly neratinib (240 mg orally). Her clinical response to therapy was very rapid, and, by the start of week 4, her right breast mass was no longer palpable. Serial MRI studies confirmed a shrinking mass at 3 weeks (from 1.6 cm to 1.2 cm), and a radiographic complete response was seen by the end of the experimental therapy (12 weeks after treatment initiation), with no masses or areas of enhancement visualized. She subsequently completed 4 cycles of standard chemotherapy with dosedense AC (60 mg/m2 and 600 mg/m2, respectively, given every 2 weeks) followed by bilateral nipple-sparing mastectomy with tissue expander reconstruction and a right sentinel lymph node biopsy. Surgical pathologic examination revealed no cancer in 1 sentinel lymph node (0 of 1) and no residual invasive disease. Her final cancer stage was clinical T2N0 followed by a pathologic complete response. During a follow-up oncology visit, our patient reported that 2 additional maternal third-degree relatives had been diagnosed with breast cancer, and her oncologist referred her for genetic counseling.

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Despite having tested negative for BRCA mutations, the suspicion for a hereditary breast cancer syndrome was significant on the basis of her pedigree analysis. Thus, the option of multigene panel testing was discussed with a genetic counselor. The patient was counseled extensively regarding the risks, benefits, and limitations of this type of genetic testing. After providing informed consent, the patient decided to undergo multigene panel testing with the BreastNext (Ambry Genetics, Aliso Viejo, CA) 18-gene panel, which revealed a truncating pathogenic mutation in RAD51D (p.R186X; c. 556C>T). RAD51D pathogenic mutations have been reported to confer a high risk of ovarian cancer.13-15 Thus, the patient was counseled to undergo riskreducing bilateral salpingo-oophorectomy (RR-BSO). The patient was also educated that each of her children would have a 50% chance of having inherited this mutation and that single-site mutation analysis is available for adult relatives.4 At the latest follow-up point, the patient was 2.5 years after the diagnosis with no evidence of disease. She recently underwent RR-BSO at age 39. Serial sectioning of the ovaries and fallopian tubes was performed with no evidence of malignancy. Single site testing of the patient’s mother confirmed the maternal origin of the mutation, and she decided to also undergo RR-BSO. A maternal aunt with medullary breast cancer diagnosed at age 54 also carried the mutation (Figure 1), as does the maternal half-uncle with bone and prostate cancers.

RAD51D Gene RAD51D is 1 of 5 RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) involved in repairing DNA

Jennifer L. Baker et al double-strand breaks by homologous recombination repair (HRR).16 Functionally, the RAD51 complex assembles around single-stranded DNA at a break site and catalyzes strand invasion and homologous DNA sequence exchange.16 An intact HRR mechanism is essential to maintain genome integrity in a cell, and HRR loss of function has been strongly linked to breast cancer.17 BRCA1 and BRCA2 facilitate RAD51-mediated HRR by targeting the site of DNA damage, preparing the site for assembly, and stabilizing RAD51 proteins.18 RAD51D is overexpressed in many tumors and has been especially observed in BRCA-deficient cells.19 A possible explanation for this is a compensatory mechanism to reverse genetic instability during malignant progression.8,16

RAD51D Variants and Cancer Predisposition Through linkage analysis and association studies, germline loss of function variants in RAD51D were recently identified in women affected by familial ovarian cancer, with or without breast cancer.13-15,20,21 The gene was first implicated by Loveday et al,13 who identified 8 inactivating RAD51D mutations among 911 breast-ovarian cancer families compared with only 1 such variant among 1060 population controls. Pathogenic mutations were most

frequent in families with  3 ovarian cancer cases, and no inactivating RAD51D variants were identified among the 737 breast cancereonly families studied.13 Three subsequent studies verified these results, finding pathogenic RAD51D mutations in 0.5% to 0.8% of breast and ovarian cancer families but identifying none in the families affected only by hereditary breast cancer.14,15,21 All these studies concluded that RAD51D is a moderate penetrance susceptibility gene for ovarian cancer and likely does not contribute significantly to breast cancer risk.13-15,22 A list of the RAD51D mutations described in the published data to date is presented in Table 1. In contrast to the studies reported to date, which have identified no pathogenic RAD51D mutations in > 2000 probands of breast cancer-only families, we found a truncating mutation (p.R186X) in a breast cancer-affected proband with a family history that includes multiple cases of breast cancer (including male breast cancer) but without any known cases of ovarian cancer. This particular mutation has been previously reported.13,14,21 However, the population frequency of RAD51D mutations appears to be low, even in studies of high-risk families, such that precise estimates of penetrance will be difficult to calculate. It is also possible that the RAD51D mutation uncovered was not the causative factor of her familial breast cancer and that

Table 1 Summary of RAD51D Mutations Identified in Previous Studies

Study

Population Screened for RAD51D Mutations

Frequency of Truncating RAD51 Variants

Inactivating Mutation

911 BC/OC 737 BC 1060 controls

8/911 (0.88) 0/737 (0.0) 1/1060 (0.09)

c.363delA c.803G>A c.556C>T (2 families)

Cancer History of Proband, Age (year)

Other Study Findings

Loveday et al13

c.480þ1G>A c.345G>C c.757C>T c.270_271du pTA c.748delC

bc, 34; bc, 52 oc, 58 oc, 38; bc, 39; bc, 58; bc, 53; bc, 35 bc, 51 oc, 45; oc, 74 oc, 51; bc, 47 oc, 51; bc, 65 None

23 Nontruncating variants identified Frequency of variants did not differ between cases and controls Of the 7 breast cancer cases with documented histologic findings, 1 was a medullary breast cancer

Wickramanyake et al15 226 BC 360 oc

0/226 3/360 (0.83)

c.580delA c.694C>T c.131_144þ24del38^

oc, 34 oc, 43 oc, 75

175 BC/OC

1/175 (0.57)

c.556C>T

oc, 56; oc, 56; bc, 34

Loss of function RAD51D mutations are more likely in families with  2 OC cases

1330 Early-onset bc 1123 Controls

0/1330 0/1123

None

None

12 Rare variants in 10 cases (0.75) and 9 controls (0.80)

95 BC/OC

2/95 (0.02)

c.576þ1G>A

bc, NA; bc, NA

The c.576þ1G>A mutation was screened further in OC and BC families and detected in 5/707 (0.71%) with OC but was not elevated in frequency among those with BC (2/2105, 0.01%)

741 BC 245 oc

0/741 2/245 (0.04)

c.556C>T c.803G>A

oc, 66 oc, 70

Osher et al21

Le Calvez-Kelm et al29

Pelttari et al22

Thompson et al14

Data in parentheses are percentages. Abbreviations: BC ¼ breast cancer-only family; bc ¼ personal history of breast cancer; BC/OC ¼ breast and ovarian cancer family; OC ¼ ovarian cancer-only family; oc ¼ personal history of ovarian cancer.

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Breast Cancer in a RAD51D Mutation Carrier alternative genetic or environmental factors were responsible. Testing of additional family members is underway, and the results might be illustrative. It is notable that 2 cases of medullary breast cancer in association with a RAD51D mutation have been reported, 1 identified by Loveday et al13 and the second was our proband’s aunt. Future studies of medullary breast cancer might shed light on whether RAD51D is clearly associated with this rare subtype of breast cancer.

HRR Gene Mutations and Targeted Therapies Genetic information can direct more targeted molecular therapies. For example, poly (ADP-ribose) polymerase (PARP) inhibitors, which inhibit a distinct pathway of DNA repair, have been used to target cancer cells with impaired HRR such as BRCAdeficient cells.7 The mechanism might be a synthetic lethal interaction in which a cell retains viability with loss of either PARP or BRCA function in isolation; however, the loss of both repair mechanisms causes cell death or increases susceptibility to DNA damaging chemotherapy. Preclinical studies have shown that RAD51D-deficient cells respond to PARP inhibition similarly to BRCA2-silenced cells,13 likely because of the similar role in HRR. Additionally, the loss of HRR might confer sensitivity to DNA cross-linking agents, such as platinum-based drugs.23,24 In 1 series, 3 patients with ovarian cancer and RAD51D mutations had a complete response to platinum-based chemotherapy, including 1 patient who had presented with stage IV disease.15 Our patient responded very rapidly to chemotherapy with paclitaxel and neratinib. Neratinib is an irreversible panHER inhibitor that includes inhibition of epidermal growth factor receptor (EGFR).25 EGFR is known to be overexpressed in > 60% of triple negative tumors26; however, despite this, previous trials did not find any benefit from adding a dual tyrosine kinase inhibitor of EGFR and HER2 in HER2-negative tumors.27 Thus, the RAD51 mutation might play a role in the susceptibility to this treatment and our patient’s rapid response to therapy.

Risk Management

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To appropriately assess which patients will benefit from surveillance and prophylactic interventions, accurate risk estimation is necessary. In general, high-penetrance variants increase the risk of cancer > 10-fold, intermediate-penetrance variants increase the risk 2- to 4-fold, and low-penetrance variants increase the risk < 1.5fold compared with the risk in the general population.9 Modified segregation analysis found the relative risk of ovarian cancer in RAD51D mutation carriers to be 6.3 (95% confidence interval, 2.86-13.85), which equals about a 10% risk of ovarian cancer by age 80.13 Given the lack of early detection methods and the poor prognosis of advanced ovarian cancer, it is reasonable to make recommendations for risk-reducing surgery similar to that of BRCA-mutation carriers. The current recommendations include prophylactic bilateral salpingo-oophorectomy at age 35 to 40 years on completion of childbearing, unless a case of earlier onset ovarian cancer is known in the family.28 To date, studies have not demonstrated an elevated risk of breast cancer in RAD51D mutation carriers.13 However, owing to the rarity of these variants, additional study is needed. In patients with a

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strong family history of breast cancer (with or without an identified deleterious variant), screening with mammography should begin at age 40 or 5 to 10 years before the youngest age of family breast cancer diagnosis.28 Additionally, risk-reducing mastectomies should be discussed on an individualized basis. In our patient’s case, she decided to undergo contralateral prophylactic mastectomy because of her extensive family history, young age, and high-risk tumor profile, because her RAD51D mutation was uncovered only after her surgery. Ongoing clarification of the risk conferred by novel predisposition genes is necessary. Until then, clinical recommendations should be made according to individualized refinement of risk according to the family history and other factors.

Genetic Testing Recommendations The American Society of Clinical Oncology has recommended genetic testing when 3 criteria are met: a personal or family history is present suggesting genetic cancer susceptibility; the test can be adequately interpreted; and the results will aid in the diagnosis or influence the medical or surgical treatment of the patient or family with a hereditary risk of cancer.6 The National Comprehensive Cancer Network has set forth specific criteria for genetic testing for BRCA1 and BRCA2 mutations when hereditary breast and ovarian cancer syndrome is suspected. However, if a patient tests negative for BRCA1 and BRCA2, but a hereditary cancer syndrome is still suspected, additional genetic testing with a multigene panel should be considered. Depending on the laboratory or panel, a single panel can include  21 genes associated with hereditary breast cancer. However, important risks and limitations of multigene panels must be considered before testing. These include the high likelihood of identifying a variant of uncertain significance, the lack of evidence-based guidelines for the appropriate treatment of carriers of mutations of many of the panel genes (including RAD51D), and that identifying a variant in some of the panel genes (Tp53; PTEN; STK11) would lead to a diagnosis of a hereditary cancer syndrome.6,28 Therefore, professional cancer and genetic societies recommend ordering gene panels only in consultation with a cancer genetics professional and when appropriate pre- and post-test counseling is available.6,28

Disclosure The authors have stated that they have no conflicts of interest.

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Jennifer L. Baker et al 9. Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genom Hum Genet 2008; 9:321-45. 10. Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell 2007; 11: 103-5. 11. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 2009; 86:97-100. 12. Hylton NM, Blume JD, Bernreuter WK, et al. Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy—results from ACRIN 6657/I-SPY trial. Radiology 2012; 263:663-72. 13. Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 2011; 43:879-82. 14. Thompson ER, Rowley SM, Sawyer S, et al. Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS One 2013; 8:e54772. 15. Wickramanyake A, Bernier G, Pennil C, et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol 2012; 127:552-5. 16. Schild D, Wiese C. Overexpression of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability. Nucleic Acids Res 2010; 38: 1061-70. 17. Venkitaraman AR. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu Rev Pathol 2009; 4:461-87. 18. Jensen RB, Carreira A, Kowalczykowski SC. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 2010; 467:678-83. 19. Martin RW, Orelli BJ, Yamazoe M, Minn AJ, Takeda S, Bishop DK. RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1deficient breast tumors. Cancer Res 2007; 67:9658-65.

20. Meindl A, Hellebrand H, Wiek C, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010; 42:410-4. 21. Osher DJ, De Leeneer K, Michils G, et al. Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. Br J Cancer 2012; 106:1460-3. 22. Pelttari LM, Kiiski J, Nurminen R, et al. A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer. J Med Genet 2012; 49:429-32. 23. Powell SN, Kachnic LA. Therapeutic exploitation of tumor cell defects in homologous recombination. Anticancer Agents Med Chem 2008; 8:448-60. 24. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 2014; 20: 764-75. 25. Bose P, Ozer H. Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Expert Opin Invest Drugs 2009; 18: 1735-51. 26. Park HS, Jang MH, Kim EJ, et al. High EGFR gene copy number predicts poor outcome in triple-negative breast cancer. Mod Pathol 2014; 27:1212-22. 27. Di Leo A, Gomez HL, Aziz Z, et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 2008; 26:5544-52. 28. Daly MB, Pilarski R, Axilbund JE, et al. Genetic/Familial high-risk assessment: breast and ovarian, version 1.2014. J Natl Compr Canc Netw 2014; 12:1326-38. 29. Le Calvez-Kelm F, Oliver J, Damiola F, et al. RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study. PLoS One 2012; 7:e52374.

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Breast cancer in a RAD51D mutation carrier: case report and review of the literature.

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