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Diagnostic and Interventional Imaging (2014) xxx, xxx—xxx
CONTINUING EDUCATION PROGRAM: FOCUS. . .
The management of breast cancer M. Espié Department of Medical Oncology, Breast Diseases Center, Saint-Louis Hospital, Paris Public Hospitals Health Service, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France
KEYWORDS Breast; Tumor; Neoadjuvant; Targeted therapy; Triple negative
Abstract Because of its prevalence, breast cancer is a major public health problem although its prognosis has improved as a result of early screening and improvement in treatments. We now no longer refer to breast cancer in the singular, but to breast cancers, which have different prognoses and treatments depending on their molecular profile. ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved. © 2014 Éditions franc
Epidemiological findings, a few figures Because of its prevalence, breast cancer is still a major public health problem. It has been estimated that 53,000 women suffered from it in France in 2012 [1]. Incidence of breast cancer in France and that it killed more than 11,000 people. Its incidence is low under the age of 30-years-old and then increases up to the age of 60—69-years-old when it is over 320 per 100,000 women per year. Rates fall slightly after the age of 85-years-old (245 per 100,000). These figures make breast cancer the leading cause of cancer deaths in women with an estimated figure for 2012 of 11,289 deaths in France. Death rates increase with age from 10/100,000 women between 35 and 40-years-old to 80/100,000 at around 65-years-old, 102/100,000 between 70 and 74-years-old and 245 per 100,000 over 85-years-old. Of these 11,289 women who died from breast cancer in France 1075 were under 40-years-old and 4113 were under 65-years-old [2]. These figures highlight the magnitude of the problem in postmenopausal women, particularly as the mortality rate is continuing to increase, mostly in elderly women. Five-year survival has been estimated to be 86%, compared to a 10-year rate of 76%.
E-mail address: [email protected] http://dx.doi.org/10.1016/j.diii.2014.04.003 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Espié M. The management of breast cancer. Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.04.003
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Locoregional treatments Surgery remains the main treatment for breast cancer. Changes in surgery have included a reduction in the indications for mastectomy (which is still however occasionally necessary) and an increase of conservative treatments, particularly incorporating plastic surgery techniques into breast surgery (oncoplasty), which allows more bulky tumors to be excised. Initial (neoadjuvant) chemotherapy can also make surgery more conservative by reducing tumor volume. In parallel to this increase in conservative treatment, the ‘sentinel lymph node’ technique has emerged, which allows the initial axillary lymph nodes, which are most likely to be diseased, to be removed without carrying out axillary curettage if these lymph nodes are not invaded. This technique therefore helps to reduce the adverse effects of axillary curettage, and particularly the risks of lymphedema. It requires preoperative injection of a blue dye and a radioactive isotope around the tumor or areola. This dual technique helps to reduce the risk of false negative results [3]. Treatment intensity may also be reducing in radiotherapy. In conservative treatment, the general rule is to irradiate the whole breast with additional radiotherapy to the tumor bed and irradiation of the lymph node regions if these are diseased. Changes in radiotherapy dose and methods are being studied in some patients and partial breast irradiation is occasionally being offered (elderly patients and small, relatively non-aggressive tumors) [4]. Reconstruction surgery has also advanced in patients with mastectomy, with the development of same stage reconstruction techniques although these are not always possible and need patients to fully understand that their breast will not return to what it was before, together with advances in mucocutaneous and skin and fatty tissue flaps (DIEP1 ) [5].
Prognostic indicators for breast cancer and poor prognostic indicators for response to treatments In addition to the conventional prognostic indicators (size of tumor, lymph node invasion, grade and age), in recent years, hormone-receptors (estrogens and progesterone) and overexpression of HER2 (or CerbB2) (an epithelial growth factor) reflecting self-encasement of the tumor have been added. The Ki67 test is also useful as this can quantify cellular proliferation (the Ki-67 labeling index represents the percentage of nuclei stained by the Ki-67 antibody). Genomic tests are currently being developed with the aim of analyzing each tumor to ‘predict’ its prognosis and also to determine whether adjuvant chemotherapy or hormone therapy are or are not essential. The concept of breast cancer is now increasingly being broken down and several tumor subtypes have been identified: • luminal A cancers: these are breast cancers which carry a good prognosis, progress slowly and strongly express estrogen and progesterone receptors. They do not overexpress HER2 and are therefore ER+++, PR+++, and CerbB2 1
DIEP: deep inferior epigastric.
negative. These are the relatively non-proliferative hormone dependent tumors, which often do not require chemotherapy, particularly if the Ki67 index is under 10%; • luminal B cancers: these carry a less good prognosis than luminal A, are less hormone-sensitive, and often have a higher Ki67 index. Some may be associated with HER2 overexpression and the combination of chemotherapy and hormone therapy is often required together with trastuzumab (Herceptin) if HER2 is overexpressed; • HER2 cancers: these are aggressive breast cancers, which carry a poor prognosis. They are estrogen and progesterone receptor negative and their HER2 overexpression is graded +++. These cancers require chemotherapy combined with trastuzumab which has changed their poor prognosis; • ‘triple negative’ cancers: these are also poor prognosis cancers, which are completely undifferentiated and are estrogen and progesterone receptor negative. They do not overexpress HER2 (ER−, PR−, HER2−) (Figs. 1 and 2). There is other less common subtypes, which are still being studied and gene analysis (genomics) is developing. This can be used to characterize tumor genes, and to test for amplifications, mutations and the level of expression (gain or loss) of a given gene. Apart from the genes involved in hormone-receptors and HER2 expression, other genes are being examined which are involved in invasion, and interactions with the tumor stroma, etc. It is hoped that by guiding treatment and predicting sensitivity to treatments an attempt can be made to individualize them to avoid chemotherapy, which is of no benefit for one person whereas it may be essential for another. Several tests have been developed: the Mammaprint which is a test performed from a DNA probe which shows the expression of 70 genes, Oncotype DX which shows 21 genes, and genomic grade, which is an analysis of the expression of 97 genes on frozen samples, etc. These tests incorporate a number of different genes although, overall and apart from hormone and HER2 receptors, these are mostly genes involved in proliferation. They have not as yet been shown to be more effective than conventional immune-histochemical indicators. Prospective studies are therefore ongoing and we should have an answer to the question of their actual utility in a few years. They have however been validated in retrospective studies and do identify groups with a good or bad prognosis. They do not have marketing authorization in France pending their possible validation in the ongoing prospective studies.
Adjuvant treatments: chemotherapy, hormone therapy, targeted therapies Changes in chemotherapy In the 1980s, chemotherapy was often restricted to patients whose tumors were associated with lymph node invasion, although metastases were found for 20 to 30% of tumors when lymph node invasion was not present. It was therefore extended to forms of the disease without lymph nodes invasion, which carried a poor prognosis (large size, grade II or III, vascular emboli+, or negative hormone-receptors).
Please cite this article in press as: Espié M. The management of breast cancer. Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.04.003
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Figure 1. Mammography (a,b). Triple negative breast cancer. Images provided by Martine Boisserie-Lacroix, Bergonié Institute.
Trastuzumab is currently administered IV every 3 weeks for a year and is always combined with chemotherapy. A subcutaneous form is currently being developed as are many other molecules, which target this pathway. As a result of the use of this molecule, the relative risk of relapse has fallen by approximately 50% [8]. This molecule requires the LVEF5 to be monitored by echocardiography or myocardial scintigraphy as it can often produce a usually transient decline.
Current reference treatments
Figure 2. Triple negative cancer. MR (magnetic resonance) appearances: ring-shaped enhancement.
In parallel, the type of chemotherapy has changed from a reference protocol known as CMF2 to FAC or FEC3 regimens including anthracyclines and then to regimens including taxanes4 [6], as a result of the randomized trials which have shown the benefit of these new molecules [7].
Chemotherapy generally involving a sequential combination of anthracyclines and taxanes are offered for N+ or N− cancers with poor prognostic indicators which do not overexpress HER2: 3 FEC 100 3 Docetaxel, 4 EC 4 Docetaxel, 3 FEC 100 12 weekly Paclitaxel. . . or a simultaneous combination with 6 TAC. For cancers which overexpress HER2, as soon as they are over 5 mm in size a combination of chemotherapy and trastuzumab is often proposed: 3 FEC 100 + 3 Taxotere + Herceptin for a year started at the same time as trastuzumab, 6 TCH particularly if anthracyclines are contraindicated, 4EC 4 TH6 . . .
Toxicities Targeted therapies In 2005, trastuzumab (Herceptin) was proposed as an adjuvant therapy because of its effectiveness in metastatic disease. This monoclonal antibody blocks the HER2 receptor and therefore interrupts the cascade leading to cellular proliferation. As a result of trastuzumab, cancers which overexpress HER2 no longer carry such a poor prognosis. 2
CMF: Cyclophosphamide, Methotrexate, 5-Fluorouracil. FAC: 5-Fluorouracil, Doxorubicin (Adriamycin), Cyclophosphamide; FEC: 5-Fluorouracil, Epidoxorubicin, Cyclophosphamide. 4 Taxanes: Docetaxel (Taxotere), Paclitaxel (Taxol). 3
The immediate toxicities of chemotherapy are well known and include alopecia, nausea/vomiting, fatigue, risk of fever and infections, muscle pains, paresthesiae, repercussions on sexual function, and cognitive disorders, etc. These are common but reversible. The late toxicities include cardiotoxicity and occasional chemo-induced leukemia (1 to 2%) although these toxicities are not always reversible (heart) 5
LVEF: left ventricular ejection fraction. TAC: Docetaxel (Taxotere), Doxorubicin (Adriamycin), Cyclophosphamide, EC: Epirubicin Cyclophosphamide, TCH: Docetaxel (taxotere), Carboplatin, Herceptin. 6
Please cite this article in press as: Espié M. The management of breast cancer. Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.04.003
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or curable (leukemia). The risk of chemotherapy-induced menopause and therefore sterility should not be forgotten in young women and should be discussed and planned for before treatment is started.
Depending on the situation, a complete histological response is achieved in 15 to 40% of patients. The proportion of conservative breast surgery has increased for T2 and T3 tumors and may be achievable in approximately 75% of cases.
Hormone therapy Five years of hormone therapy has been shown to provide benefit when offered to any patient with a hormonereceptor-positive tumor. The treatments vary depending on menopausal status. In the pre-menopausal period, the reference molecule is tamoxifen whereas in the postmenopausal period, the anti-aromatases are preferred. It is occasionally possible to offer a sequence of tamoxifen for 2 or 3 years followed by anti-aromatases during the peri-menopausal period. An extension of treatment beyond 5 years can be offered in some cases particularly in patients at high risk of recurrence (N+) [9,10]. It is essential to be certain about a woman’s menopausal status as the aromatase inhibitors are ineffective before the menopause and it is important to be aware that amenorrhea is not synonymous with the menopause. A minimum of 2 years of amenorrhea is required in a young woman before referring to the menopause. Hormone measurements are of limited use as they only reflect the situation on the day when the blood sample was taken.
Toxicities The most common adverse effects reported by patients on tamoxifen are hot flushes, weakness or a tendency towards depression, weight gain and leucorrhea. Very rare but potentially serious toxic reactions are due to thrombo-embolic events and endometrial cancer. Excess cataracts develop and occasional cases of hepatitis and thrombocytopenia are also seen. Patients receiving aromatase inhibitors complain of arthralgia, vaginal dryness and reduced libido. Hypercholesterolemia may develop particularly involving LDL-cholesterol. Bone mineral density is reduced with an increased fracture rate and an increase in coronary artery events [11]. The choice between these molecules should also therefore take account of each patient’s individual risk profile.
Neoadjuvant therapies
New treatments The major advances have mostly been made for tumors overexpressing HER2. Many protocols are currently used with a combination of two targeted therapies and chemotherapy and have produced good results in both the neoadjuvant and metastatic situation. In the metastatic stage, the combination of trastuzumab + pertuzumab (another anti-HER2 monoclonal antibody with a different binding site) does better than trastuzumab alone [13]. The same results have been shown in the neoadjuvant situation with a combination of lapatinib (an anti-tyrosine kinase) and trastuzumab [14]. It has been possible to design a molecule, which combines both chemotherapy and targeted therapy, trastuzumab and maytansine. The term used to describe this is vectorized chemotherapy, in which the chemotherapy is carried to and released only in the tumor cells. This is both effective and less toxic [15]. In HR+ hormone dependent cancers, patients with metastasis cease to respond to hormone therapy after treatment for 8 to 12 months. Molecules are being developed to ‘reverse’ its resistance. Everolimus (Afinitor) has been tested in this situation and showing to be effective [16].
Conclusion The management of patients suffering from breast cancer is becoming complicated and we are moving gradually from the ‘off the peg’ to the ‘tailor-made’. Considerable advances have been achieved over the last 30 years in the management of these women and this is leading to higher cure rates. TAKE-HOME MESSAGES • The following types of cancers can be distinguished: ◦ luminal A: highly positive ER and PR ◦ luminal B: +ER ± PR, high Ki67, occasionally HER2 +++ ◦ HER2 +++ ER neg, PR neg ◦ triple negative: ER negative, PR negative, HER2 negative • Advances in treatment will involve better individualizing therapies through genomics and pharmacogenomics.
These should be offered routinely to patients who have an inflammatory cancer and to many patients with rapidly progressing tumors, and to make tumors, which were inoperable at the time of diagnosis (T4) amenable to surgery, and to permit conservative surgery if this was not possible at the time of diagnosis (bulky T2 and T3)7 . Neoadjuvant chemotherapy does not change survival compared to adjuvant chemotherapy although achieving a complete histological response after chemotherapy does have a positive impact on survival. The histological response to chemotherapy differs depending on the molecular subtypes described above, the more aggressive tumors being the most chemosensitive [12].
Disclosure of interest
7 T2: tumor between 2 and 5 cm size; T3: tumor over 5 cm size; T4: tumor fixed to the deep planes and/or to the skin.
The authors declare that they have no conflicts of interest concerning this article.
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References [1] Esteve J. Incidence of breast cancer in France and other industrialized countries. Presse Med 2007;36(2 Pt 2):315—21. [2] Trétarre B, Guizard AV, Fontaine D, et al. Cancer du sein chez la femme : incidence et mortalité, France 2000. BEH 2004;44:209—10. [3] Hindie E, Groheux D, Brenot-Rossi I, Rubello D, Moretti JL, Espie M. The sentinel node procedure in breast cancer: nuclear medicine as the starting point. J Nucl Med 2011;52(3):405—14. [4] Hildreth NG, Kelsey JL, LiVolsi VA, Fischer DB, Holford TR, Mostow ED, et al. An epidemiologic study of epithelial carcinoma of the ovary. Am J Epidemiol 1981;114(3):398—405. [5] Lepage C, Lantieri L. Breast reconstruction after mastectomy. Rev Prat 2010;60(9):1221—6. [6] Jacquin JP, Jones S, Magne N, Chapelle C, Ellis P, Janni W, et al. Docetaxel-containing adjuvant chemotherapy in patients with early stage breast cancer. Consistency of effect independent of nodal and biomarker status: a meta-analysis of 14 randomized clinical trials. Breast Cancer Res Treat 2012;134(3): 903—13. [7] Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012;379(9814):432—44. [8] Yin W, Jiang Y, Shen Z, Shao Z, Lu J. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS One 2011;6(6):e21030.
5 [9] Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28(3):509—18. [10] Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365(9472):1687—717. [11] Amir E, Seruga B, Niraula S, Carlsson L, Ocana A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 2009;103(17):1299—309. [12] Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 2012;48(18):3342—54. [13] Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366(2):109—19. [14] Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379(9816):633—40. [15] Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367(19):1783—91. [16] Baselga J, Campone M, Piccart M, Burris 3rd HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. N Engl J Med 2012;366(6):520—9.
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Diagnostic and Interventional Imaging (2014) xxx, xxx—xxx
CONTINUING EDUCATION PROGRAM: FOCUS. . .
The management of breast cancer M. Espié Department of Medical Oncology, Breast Diseases Center, Saint-Louis Hospital, Paris Public Hospitals Health Service, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France
KEYWORDS Breast; Tumor; Neoadjuvant; Targeted therapy; Triple negative
Abstract Because of its prevalence, breast cancer is a major public health problem although its prognosis has improved as a result of early screening and improvement in treatments. We now no longer refer to breast cancer in the singular, but to breast cancers, which have different prognoses and treatments depending on their molecular profile. ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved. © 2014 Éditions franc
Epidemiological findings, a few figures Because of its prevalence, breast cancer is still a major public health problem. It has been estimated that 53,000 women suffered from it in France in 2012 [1]. Incidence of breast cancer in France and that it killed more than 11,000 people. Its incidence is low under the age of 30-years-old and then increases up to the age of 60—69-years-old when it is over 320 per 100,000 women per year. Rates fall slightly after the age of 85-years-old (245 per 100,000). These figures make breast cancer the leading cause of cancer deaths in women with an estimated figure for 2012 of 11,289 deaths in France. Death rates increase with age from 10/100,000 women between 35 and 40-years-old to 80/100,000 at around 65-years-old, 102/100,000 between 70 and 74-years-old and 245 per 100,000 over 85-years-old. Of these 11,289 women who died from breast cancer in France 1075 were under 40-years-old and 4113 were under 65-years-old [2]. These figures highlight the magnitude of the problem in postmenopausal women, particularly as the mortality rate is continuing to increase, mostly in elderly women. Five-year survival has been estimated to be 86%, compared to a 10-year rate of 76%.
E-mail address: [email protected] http://dx.doi.org/10.1016/j.diii.2014.04.003 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
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Locoregional treatments Surgery remains the main treatment for breast cancer. Changes in surgery have included a reduction in the indications for mastectomy (which is still however occasionally necessary) and an increase of conservative treatments, particularly incorporating plastic surgery techniques into breast surgery (oncoplasty), which allows more bulky tumors to be excised. Initial (neoadjuvant) chemotherapy can also make surgery more conservative by reducing tumor volume. In parallel to this increase in conservative treatment, the ‘sentinel lymph node’ technique has emerged, which allows the initial axillary lymph nodes, which are most likely to be diseased, to be removed without carrying out axillary curettage if these lymph nodes are not invaded. This technique therefore helps to reduce the adverse effects of axillary curettage, and particularly the risks of lymphedema. It requires preoperative injection of a blue dye and a radioactive isotope around the tumor or areola. This dual technique helps to reduce the risk of false negative results [3]. Treatment intensity may also be reducing in radiotherapy. In conservative treatment, the general rule is to irradiate the whole breast with additional radiotherapy to the tumor bed and irradiation of the lymph node regions if these are diseased. Changes in radiotherapy dose and methods are being studied in some patients and partial breast irradiation is occasionally being offered (elderly patients and small, relatively non-aggressive tumors) [4]. Reconstruction surgery has also advanced in patients with mastectomy, with the development of same stage reconstruction techniques although these are not always possible and need patients to fully understand that their breast will not return to what it was before, together with advances in mucocutaneous and skin and fatty tissue flaps (DIEP1 ) [5].
Prognostic indicators for breast cancer and poor prognostic indicators for response to treatments In addition to the conventional prognostic indicators (size of tumor, lymph node invasion, grade and age), in recent years, hormone-receptors (estrogens and progesterone) and overexpression of HER2 (or CerbB2) (an epithelial growth factor) reflecting self-encasement of the tumor have been added. The Ki67 test is also useful as this can quantify cellular proliferation (the Ki-67 labeling index represents the percentage of nuclei stained by the Ki-67 antibody). Genomic tests are currently being developed with the aim of analyzing each tumor to ‘predict’ its prognosis and also to determine whether adjuvant chemotherapy or hormone therapy are or are not essential. The concept of breast cancer is now increasingly being broken down and several tumor subtypes have been identified: • luminal A cancers: these are breast cancers which carry a good prognosis, progress slowly and strongly express estrogen and progesterone receptors. They do not overexpress HER2 and are therefore ER+++, PR+++, and CerbB2 1
DIEP: deep inferior epigastric.
negative. These are the relatively non-proliferative hormone dependent tumors, which often do not require chemotherapy, particularly if the Ki67 index is under 10%; • luminal B cancers: these carry a less good prognosis than luminal A, are less hormone-sensitive, and often have a higher Ki67 index. Some may be associated with HER2 overexpression and the combination of chemotherapy and hormone therapy is often required together with trastuzumab (Herceptin) if HER2 is overexpressed; • HER2 cancers: these are aggressive breast cancers, which carry a poor prognosis. They are estrogen and progesterone receptor negative and their HER2 overexpression is graded +++. These cancers require chemotherapy combined with trastuzumab which has changed their poor prognosis; • ‘triple negative’ cancers: these are also poor prognosis cancers, which are completely undifferentiated and are estrogen and progesterone receptor negative. They do not overexpress HER2 (ER−, PR−, HER2−) (Figs. 1 and 2). There is other less common subtypes, which are still being studied and gene analysis (genomics) is developing. This can be used to characterize tumor genes, and to test for amplifications, mutations and the level of expression (gain or loss) of a given gene. Apart from the genes involved in hormone-receptors and HER2 expression, other genes are being examined which are involved in invasion, and interactions with the tumor stroma, etc. It is hoped that by guiding treatment and predicting sensitivity to treatments an attempt can be made to individualize them to avoid chemotherapy, which is of no benefit for one person whereas it may be essential for another. Several tests have been developed: the Mammaprint which is a test performed from a DNA probe which shows the expression of 70 genes, Oncotype DX which shows 21 genes, and genomic grade, which is an analysis of the expression of 97 genes on frozen samples, etc. These tests incorporate a number of different genes although, overall and apart from hormone and HER2 receptors, these are mostly genes involved in proliferation. They have not as yet been shown to be more effective than conventional immune-histochemical indicators. Prospective studies are therefore ongoing and we should have an answer to the question of their actual utility in a few years. They have however been validated in retrospective studies and do identify groups with a good or bad prognosis. They do not have marketing authorization in France pending their possible validation in the ongoing prospective studies.
Adjuvant treatments: chemotherapy, hormone therapy, targeted therapies Changes in chemotherapy In the 1980s, chemotherapy was often restricted to patients whose tumors were associated with lymph node invasion, although metastases were found for 20 to 30% of tumors when lymph node invasion was not present. It was therefore extended to forms of the disease without lymph nodes invasion, which carried a poor prognosis (large size, grade II or III, vascular emboli+, or negative hormone-receptors).
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Figure 1. Mammography (a,b). Triple negative breast cancer. Images provided by Martine Boisserie-Lacroix, Bergonié Institute.
Trastuzumab is currently administered IV every 3 weeks for a year and is always combined with chemotherapy. A subcutaneous form is currently being developed as are many other molecules, which target this pathway. As a result of the use of this molecule, the relative risk of relapse has fallen by approximately 50% [8]. This molecule requires the LVEF5 to be monitored by echocardiography or myocardial scintigraphy as it can often produce a usually transient decline.
Current reference treatments
Figure 2. Triple negative cancer. MR (magnetic resonance) appearances: ring-shaped enhancement.
In parallel, the type of chemotherapy has changed from a reference protocol known as CMF2 to FAC or FEC3 regimens including anthracyclines and then to regimens including taxanes4 [6], as a result of the randomized trials which have shown the benefit of these new molecules [7].
Chemotherapy generally involving a sequential combination of anthracyclines and taxanes are offered for N+ or N− cancers with poor prognostic indicators which do not overexpress HER2: 3 FEC 100 3 Docetaxel, 4 EC 4 Docetaxel, 3 FEC 100 12 weekly Paclitaxel. . . or a simultaneous combination with 6 TAC. For cancers which overexpress HER2, as soon as they are over 5 mm in size a combination of chemotherapy and trastuzumab is often proposed: 3 FEC 100 + 3 Taxotere + Herceptin for a year started at the same time as trastuzumab, 6 TCH particularly if anthracyclines are contraindicated, 4EC 4 TH6 . . .
Toxicities Targeted therapies In 2005, trastuzumab (Herceptin) was proposed as an adjuvant therapy because of its effectiveness in metastatic disease. This monoclonal antibody blocks the HER2 receptor and therefore interrupts the cascade leading to cellular proliferation. As a result of trastuzumab, cancers which overexpress HER2 no longer carry such a poor prognosis. 2
CMF: Cyclophosphamide, Methotrexate, 5-Fluorouracil. FAC: 5-Fluorouracil, Doxorubicin (Adriamycin), Cyclophosphamide; FEC: 5-Fluorouracil, Epidoxorubicin, Cyclophosphamide. 4 Taxanes: Docetaxel (Taxotere), Paclitaxel (Taxol). 3
The immediate toxicities of chemotherapy are well known and include alopecia, nausea/vomiting, fatigue, risk of fever and infections, muscle pains, paresthesiae, repercussions on sexual function, and cognitive disorders, etc. These are common but reversible. The late toxicities include cardiotoxicity and occasional chemo-induced leukemia (1 to 2%) although these toxicities are not always reversible (heart) 5
LVEF: left ventricular ejection fraction. TAC: Docetaxel (Taxotere), Doxorubicin (Adriamycin), Cyclophosphamide, EC: Epirubicin Cyclophosphamide, TCH: Docetaxel (taxotere), Carboplatin, Herceptin. 6
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or curable (leukemia). The risk of chemotherapy-induced menopause and therefore sterility should not be forgotten in young women and should be discussed and planned for before treatment is started.
Depending on the situation, a complete histological response is achieved in 15 to 40% of patients. The proportion of conservative breast surgery has increased for T2 and T3 tumors and may be achievable in approximately 75% of cases.
Hormone therapy Five years of hormone therapy has been shown to provide benefit when offered to any patient with a hormonereceptor-positive tumor. The treatments vary depending on menopausal status. In the pre-menopausal period, the reference molecule is tamoxifen whereas in the postmenopausal period, the anti-aromatases are preferred. It is occasionally possible to offer a sequence of tamoxifen for 2 or 3 years followed by anti-aromatases during the peri-menopausal period. An extension of treatment beyond 5 years can be offered in some cases particularly in patients at high risk of recurrence (N+) [9,10]. It is essential to be certain about a woman’s menopausal status as the aromatase inhibitors are ineffective before the menopause and it is important to be aware that amenorrhea is not synonymous with the menopause. A minimum of 2 years of amenorrhea is required in a young woman before referring to the menopause. Hormone measurements are of limited use as they only reflect the situation on the day when the blood sample was taken.
Toxicities The most common adverse effects reported by patients on tamoxifen are hot flushes, weakness or a tendency towards depression, weight gain and leucorrhea. Very rare but potentially serious toxic reactions are due to thrombo-embolic events and endometrial cancer. Excess cataracts develop and occasional cases of hepatitis and thrombocytopenia are also seen. Patients receiving aromatase inhibitors complain of arthralgia, vaginal dryness and reduced libido. Hypercholesterolemia may develop particularly involving LDL-cholesterol. Bone mineral density is reduced with an increased fracture rate and an increase in coronary artery events [11]. The choice between these molecules should also therefore take account of each patient’s individual risk profile.
Neoadjuvant therapies
New treatments The major advances have mostly been made for tumors overexpressing HER2. Many protocols are currently used with a combination of two targeted therapies and chemotherapy and have produced good results in both the neoadjuvant and metastatic situation. In the metastatic stage, the combination of trastuzumab + pertuzumab (another anti-HER2 monoclonal antibody with a different binding site) does better than trastuzumab alone [13]. The same results have been shown in the neoadjuvant situation with a combination of lapatinib (an anti-tyrosine kinase) and trastuzumab [14]. It has been possible to design a molecule, which combines both chemotherapy and targeted therapy, trastuzumab and maytansine. The term used to describe this is vectorized chemotherapy, in which the chemotherapy is carried to and released only in the tumor cells. This is both effective and less toxic [15]. In HR+ hormone dependent cancers, patients with metastasis cease to respond to hormone therapy after treatment for 8 to 12 months. Molecules are being developed to ‘reverse’ its resistance. Everolimus (Afinitor) has been tested in this situation and showing to be effective [16].
Conclusion The management of patients suffering from breast cancer is becoming complicated and we are moving gradually from the ‘off the peg’ to the ‘tailor-made’. Considerable advances have been achieved over the last 30 years in the management of these women and this is leading to higher cure rates. TAKE-HOME MESSAGES • The following types of cancers can be distinguished: ◦ luminal A: highly positive ER and PR ◦ luminal B: +ER ± PR, high Ki67, occasionally HER2 +++ ◦ HER2 +++ ER neg, PR neg ◦ triple negative: ER negative, PR negative, HER2 negative • Advances in treatment will involve better individualizing therapies through genomics and pharmacogenomics.
These should be offered routinely to patients who have an inflammatory cancer and to many patients with rapidly progressing tumors, and to make tumors, which were inoperable at the time of diagnosis (T4) amenable to surgery, and to permit conservative surgery if this was not possible at the time of diagnosis (bulky T2 and T3)7 . Neoadjuvant chemotherapy does not change survival compared to adjuvant chemotherapy although achieving a complete histological response after chemotherapy does have a positive impact on survival. The histological response to chemotherapy differs depending on the molecular subtypes described above, the more aggressive tumors being the most chemosensitive [12].
Disclosure of interest
7 T2: tumor between 2 and 5 cm size; T3: tumor over 5 cm size; T4: tumor fixed to the deep planes and/or to the skin.
The authors declare that they have no conflicts of interest concerning this article.
Please cite this article in press as: Espié M. The management of breast cancer. Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.04.003
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The management of breast cancer
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Please cite this article in press as: Espié M. The management of breast cancer. Diagnostic and Interventional Imaging (2014), http://dx.doi.org/10.1016/j.diii.2014.04.003
