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Management of Early Invasive Breast Cancer in Very Young Women (<35 years)
Review
Management of Early Invasive Breast Cancer in Very Young Women (⬍35 years) Steffi Hartmann, Toralf Reimer, Bernd Gerber Abstract Background: To give an overview about current treatment recommendations and special problems concerning the management of women ⬍35 years with early breast cancer. Methods: We performed a selective systematic literature review. We discussed with reference to key studies and meta-analyses, current standards of care, and controversies regarding patient management. Results: Breast cancer in patients younger than 35 years is rare but associated with an unsatisfactory prognosis. Local treatment should not differ from general guidelines, but awareness of the high risk of local recurrence must be maintained. Adjuvant polychemotherapy is almost always indicated, standard endocrine therapy is tamoxifen. Before the start of systemic therapy, the patient must be offered different types of fertility preservation. Pregnancy related breast cancer is not associated with a worse prognosis, but with delayed diagnosis. Therefore, every suspicious lesion in the breast or axilla must be imaged and biopsied. The optimal time to delay pregnancy following the diagnosis is unknown. Hormonal contraceptives are contraindicated after breast cancer. Every woman ⬍35 years diagnosed with breast cancer should be offered genetic counseling. Conclusion: The management of breast cancer in very young women requires a multidisciplinary team to find the optimal treatment and to solve their specific problems. Clinical Breast Cancer, Vol. 11, No. 4, 196-203 © 2011 Published by Elsevier Inc. Keywords: Breast cancer, Contraception, Fertility, Genetic counseling, Young women
Introduction Breast cancer is rare in very young women. Only 1.9% of all breast cancers occur in women ⬍35 years,1 but the diagnosis is physically and emotionally devastating for these women. Mostly healthy young women face a life-threatening disease, which thwarts their plans for the future, especially regarding their professions and family planning. Young survivors of breast cancer have to face the fear of recurrence and the elevated risk of transmitting a gene mutation that increases the risk of cancer in their offspring over a very long period of time. The management of breast cancer in very young patients is a challenge not only for the affected women and their environment, but also for the multidisciplinary team treating them. Our article deals with the special problems of women ⬍35 years of age with breast cancer, such as prognosis, fertility, pregnancy, contraception, and genetic counseling, and highlights current recommendations for early breast cancer treatment, knowing that informa-
tion for these patients is limited due to the small number of very young women included in studies.
Methods We performed a selective PubMed literature search for the period 2000 until August 2010 using the key words “breast cancer in young patients” (activated limits: clinical trial, meta-analysis, practice guidelines, randomized controlled trial, humans, female, adult 19-44 years). We reviewed treatment recommendations of the German Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) breast commission and the National Comprehensive Cancer Network (NCCN). Important presentations from the San Antonio Breast Cancer Symposium 2009 and the American Society of Clinical Oncology meeting 2010 were considered. We emphasized current controversies and unanswered questions regarding disease management.
Results Prognosis
Department of Obstetrics and Gynecology, University of Rostock, Rostock, Germany Submitted: Sep 30, 2010; Revised: Nov 19, 2010; Accepted: Nov 21, 2010 Address for correspondence: Steffi Hartmann, Department of Obstetrics and Gynecology, Südring 81, 18059 Rostock, Germany Fax: ⫹49-381-44014599; e-mail contact: [email protected]
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Several studies have reported significantly worse outcomes in younger women with breast cancer than in older women.2,3 An age of less than 35 years was found to be a reasonable cut-off point for defining young age-onset breast cancer. This age group showed a significantly worse outcome compared with older premenopausal women, and their risk of death rose by 5% for every
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1-year reduction in age.4 This negative impact on survival was especially seen in patients with positive lymph nodes and those with positive hormonal receptors,5 underlining the key role of hormonal mechanisms in young patients with breast cancer. Most studies analyzing histopathological factors found higher lymph node involvement, histologic grading, stage at presentation, greater tumor size, and more triple-negative tumors in younger patients.6,7 However, even after adjustment of those prognostic factors, women aged 35 or younger still have a worse prognosis. Therefore, the unfavorable common prognostic criteria cannot be the only explanation for the more aggressive disease.8 Different gene expression profiles could explain the differences between the young and the elderly. Currently, Anders et al7 revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women and concluded that this could define a unique biologic entity. It should be noted that in spite of the still poorer prognosis compared with older women, mortality in the younger age group decreased between 2000 and 2004 by around 30% (10 years followup).9 This effect can partly be explained by the fact that younger patients are highly motivated and often have access to innovative therapeutic strategies, especially in clinical trials.
Diagnostic Procedures Young women have a higher density of the glandular parenchyma, making it more difficult to differentiate between tumors and normal breast tissue by mammography. Sonography is more sensitive than mammography in evaluating breast masses in women younger than 45.10 A small retrospective study postulated magnetic resonance imaging (MRI) to be a useful supplementation to conventional mammography for the detection of breast cancer in premenopausal women.11 The COMICE-trial, which included 23% of women younger than 50 years (n ⫽ 374) and 87% of patients with breast density ACR BI-RADS type 2, 3 or 4 (n ⫽ 1415), showed that the addition of MRI to conventional triple assessment (clinical, radiologic including mammography and ultrasound and pathologic including fine-needle aspiration cytology or core biopsy), did not reduce the reoperation rate. The authors conclude that preoperative MRI may not be necessary and can result in extra use of resources with little or no benefit to residual health.12 Therefore, in symptomatic young women, breast ultrasound should be the diagnostic method of choice and in case of a suspicious finding it should be supplemented by digital mammography and histologic assessment. In case of conventional imaging difficulties because of dense tissue, preoperative MRI may provide benefit in very young patients with breast cancer.13 Screening (except clinical breast examination once a year starting at age 30) is not recommended for women younger than 50 years of age in Germany. The NCCN guidelines recommend clinical breast examination every 1-3 years starting at age 20 and annual mammograms starting at age 40.14 Only two high-risk populations should start radiologic screening earlier: first, women treated with chest radiation for pediatric and young adult cancers presenting with cumulative incidence of breast cancer from 13%-20% by 40-45 years of age. Their risk of breast cancer increases 8 years after chest radiation with a median age at diagnosis of 35-44. Therefore, the current recommendation for this population includes annual surveillance
mammography and MRI starting at the age of 25 or 8 years after the completion of radiation therapy.15 Second, young BRCA-1/-2-mutation carriers and patients with a strong family history should start multimodal screening at the age of 25-30 depending on national recommendations or 5-10 years before the youngest breast cancer case in the family.14,16,17
Local Treatment Surgical management is not different from that in older patients. The decision about breast-conservation versus mastectomy is influenced by the fact that young women frequently present at an advanced stage.6 If mastectomy is necessary, primary or secondary reconstructive surgery should be offered. If myocutaneous tissue alone is not sufficient to reach a satisfactory cosmetic result and postmastectomy radiotherapy is not considered, primary reconstruction using an implant and skin or nipple-sparing mastectomy is possible and oncologically safe.18 Otherwise (T3/T4-tumors or node-positive disease) secondary reconstruction should be preferred to avoid implantrelated complications due to radiotherapy. In practice, sentinel lymph node (SLN) biopsy can be conducted as the first surgical procedure.19 After getting the histopathological result, the decision can be made as to whether postmastectomy radiation is necessary or not and what the best time point for reconstruction is (Figure 1). This recommendation is restricted due to the ongoing international debate about postmastectomy radiotherapy in case of 1-3 positive lymph nodes.20,21 If breast-conserving surgery (BCS) is possible, one must be aware of the higher risk for local recurrence in women ⬍35 years compared with older women.22 The risk is increased up to 9-fold compared with women 60 years and older,23 but survival is not compromised by breast-conserving therapy combined with radiation.24 Therefore, young patients should be monitored closely to detect local recurrence at an early stage. The optimal local management for patients with BRCA-associated breast cancer remains controversial. Initial reports on this issue were conflicting; some studies suggested that these patients may be at higher risk for local recurrence after BCS.25-28 In the opposite, a multi-institutional study and two clinic-based series showed no significant differences in local recurrence rates after BCS between BRCA mutation carriers and controls, with a 10-year risk of ipsilateral breast tumor recurrence (IBTR) of 14% in carriers.29-31 According to updated data of the multi-institutional study, the risk of an IBTR seems to be related to oophorectomy preference in mutation carriers.32 If risk-reducing salpingo-oophorectomy is planned, BCS with whole breast irradiation could be considered because the difference in IBTR was not statistically significant between mutation carriers with oophorectomy and sporadic controls without oophorectomy. If the preference is to preserve the ovaries, the patients interested in BCS must be aware about the increased risk of IBTR and the higher rate of new primary tumors in mutation carriers.28 Radiotherapy in young patients should be recommended corresponding to current guidelines. After breast-conserving therapy, radiotherapy reduces local recurrence significantly in all women.33 Especially young women (⬍40 years) benefit from a local 16 Gy boost, which can significantly reduce the local recurrence rate, but not mortality.34 Patients younger than 50 years are currently unsuitable for
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Breast Cancer in Young Women Figure 1 Flowchart Diagram for Surgical Strategies in Case of Mastectomy and Wish for Reconstruction
Mastectomy required Postmastectomy radiotherapy recommendation
Postmastectomy radiotherapy recommendation unclear
c/iN +* T-3,4-tumor
c/iN – T-1,2,(3)-tumor#
No implant required
Implant required
No implant required
Implant required
Primary reconstruction
Secondary reconstruction
Primary reconstruction
SLN biopsy
pN+
Secondary reconstruction
pN–
Primary reconstruction
*Postmastectomy radiotherapy is recommended by the German AGO also in case of 1-3 positive lymphnodes (recommendation: ⫹), while NCCN guidelines recommend routine postmastectomy radiotherapy in case of ⬎ 3 positive lymphnodes. #Postmastectomy radiotherapy is recommended for patients with a primary tumor greater than 5cm in node-negative disease according to NCCN guidelines. The German AGO does not consider routine postmastectomy radiotherapy in pT3pN0 situation (⫹/⫺ recommendation)
partial breast irridiation.35,36 Postmastectomy radiotherapy is advised to all patients who have a high risk of local relapse (T3/T4tumors, node-positive disease, R-1-resection).37
Adjuvant Systemic Treatment Adjuvant systemic treatment offers high benefit to young patients with breast cancer. Therefore, chemotherapy, endocrine therapy (in hormone receptor-positive tumors), and trastuzumab (in HER-2overexpressing tumors) are almost always indicated.37 The annual breast cancer death rate for women younger than 50 years is reduced by 38% by anthracycline-based polychemotherapy without significant differences between age groups ⬍35 years and 35-50 years.38 Current AGO-guidelines recommend taxane-based chemotherapy for node-positive patients and high-risk node-negative patients.37 Overall survival was shown to be improved in patients with chemotherapy induced amenorrhea (CIA) for 6 months or more.39 Despite this prognostic advantage, CIA has many objective (osteoporosis, cardiovascular, urogenital atrophy, cognitive) and subjective (hot flushes, sleep disturbances, change of mood) consequences,40 which could affect especially young breast cancer survivors for a long period. Endocrine standard treatment for premenopausal women with hormone receptor-positive tumors is tamoxifen 20 mg/day for 5 years, which reduces the annual breast cancer death rate by 31%.38 A current meta-analysis of randomized adjuvant trials concluded that there are insufficient data to compare the combination of gonadotropin-releasing hormone analogs (GnRHa) plus tamoxifen to tamoxifen alone (only two trials, about 360 patients).41 Therefore, the
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additional administration of GnRHa should be carried out in randomized clinical trials like Suppression of Ovarian Function Trial (tamoxifen 5 years vs. ovarian function suppression ⫹ tamoxifen 5 years vs. ovarian function suppression ⫹ exemestane 5 years). GnRHa only showed a small benefit when used after chemotherapy alone or with tamoxifen in women aged 40 years or younger. This effect could be explained by the fact that, in this age group, permanent amenorrhea is less likely to be induced by chemotherapy.42 If tamoxifen is contraindicated, GnRHa alone can be given. Three trials comparing tamoxifen to GnRHa suggest that these treatments are comparable regarding recurrence-free survival.41 Aromatase inhibitors should not be applied in premenopausal women except as a part of clinical trials. The ABCSG-12-trial revealed a trend to worse overall survival in premenopausal patients treated with anastrozole ⫹ GnRHa compared with tamoxifen ⫹ GnRHa (number of events 84 months since randomization anastrozole n ⫽ 27, tamoxifen n ⫽ 15, P ⫽ .07, HR 1.8)43,44 (Figure 2).
Fertility Preservation The tendency to delay childbearing in developed countries increases the number of women who have not yet completed their family at the time of breast cancer diagnosis. The median age at first delivery in Germany increased from 22 in 1961 to 30 years in 2008.45 The very young patient with breast cancer must be informed about the toxic effect of chemotherapy on ovarian follicles, which adds an average of 10 years to ovarian age, and the age-related decline of fertility after 5 years of endocrine therapy.46 This problem has to be discussed before the start of adjuvant systemic treatment. Women have to be aware that fertility preservation options can be both time
Steffi Hartmann et al Figure 2 Recommendations for Antihormonal Therapy in Premenopausal Women [adapted from 37]
Low or intermediate risk, no adjuvant chemotherapy • Tamoxifen 5 yrs. • Tamoxifen 5 yrs. + GnRHa Intermediate or high risk, adjuvant chemotherapy • ≥40 yrs. Tamoxifen 5 yrs. • <40 yrs. Tamoxifen 5 yrs. + GnRHa GnRHa alone (contraindications for tamoxifen) Aromatase inhibitors
++ +* ++ +* + –*
++ Investigation/therapeutic intervention highly beneficial for patients, can be recommended without restriction + Investigation/therapeutic intervention of limited benefit for patients, can be performed – Investigation/therapeutic intervention can be of disadvantage for patients and might not be performed * Study participation recommended
Table 1 Fertility Preserving Strategies [adapted from 46] Option
Advantages
Disadvantages
– Relatively effective in achieving pregnancy – Clinically available
– Requires male partner – Likely to increase estrogen levels – May delay chemotherapy – Gene-mutation carriers can transmit increased cancer risk to offspring
Ovarian Stimulation and Oocyte Cryopreservation
– Does not require male partner
– Few successful pregnancies – Likely to increase estrogen levels – May delay chemotherapy – Gene-mutation carriers can transmit increased cancer risk to offspring
Ovarian Tissue Cryopreservation and Xenotransplantation
– Does not require male partner – No increased estrogen levels – No delay of chemotherapy
– Very few successful pregnancies – May reimplant ovarian tissue affected by micrometastases – Gene-mutation carriers can transmit increased cancer risk to offspring – Surgical procedure
IVF and Embryo Cryopreservation
and money consuming (Table 1). The only clinically tested procedure is embryo cryopreservation. But hormonal stimulation during fertility measures may have unfavorable effects in patients with hormone-sensitive and hormone-insensitive tumors.47 By using a stimulation protocol containing letrozole and FSH, a higher yield of embryos and lower serum levels of estrogen can be achieved during stimulation.48 To obtain mature oocytes, ovarian stimulation must be performed and, therefore, a delay of 2-6 weeks may be necessary.49 Typically, there is a gap of 4-6 weeks between women undergoing breast cancer surgery and the postoperative chemotherapy. Early referral to reproductive specialists before breast surgery results in the initiation of chemotherapy on average 3 weeks earlier compared with patients referred after breast surgery.50 Currently there are no data available regarding hormonal stimulation and neoadjuvant chemotherapy. Ovarian protection by GnRHa given concurrently with chemotherapy is not allowed in cases of hormone receptor-positive tumors because an impairment of the chemotherapy effect cannot be excluded. In patients with hormone receptor-negative tumors, it is not effective. Recent trials revealed no differences in recovery of regular menses dependent on GnRHa-application. The interim report of the ZORO-trial after 2 years follow-up was presented at the ASCOmeeting in 2009. Sixty premenopausal patients with hormone recep-
tor-negative tumors were randomized to either chemotherapy alone or chemotherapy ⫹ goserelin 3.6 mg 4-weekly subcutaneously. There was no difference in median time to restoration of menstruation and after 2 years regular menses recovered in all patients.51 At the ASCO meeting in 2010, the OPTION trial was presented, a randomized multicenter study to determine the impact of goserelin on the incidence of premature ovarian failure after chemotherapy for operable breast cancer. Even this trial revealed no difference in premature menopause dependent on goserelin substitution.52 On the contrary, Badawy et al53 published an effect on resumption of menses, but in this trial an unusual chemotherapy regimen (6 x FA500C d1 q6-8w) was administered. Del Mastro et al54 administered triptorelin to patients with hormone receptor-positive and receptor-negative tumors during chemotherapy and showed a significant absolute reduction of early menopause of 19%, but there are no data available regarding the effect on recurrence risk or survival, especially in patients with hormone receptor-positive tumors. There are relatively few randomized or definitive trials examining the success and impact of fertility preservation methods. Currently there are no proven methods or recommendations for effective preservation of ovarian function in patients with breast cancer.
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Breast Cancer in Young Women Pregnancy Associated Breast Cancer Pregnancy associated breast cancer (PABC) is defined as breast cancer that develops during or 1 year after pregnancy55 with an incidence of 1:3000.56,57 Because in developed countries women delay childbearing and breast cancer incidence increases with increasing age, we will probably be confronted with this situation more often in the future. The conflict for the patient and the medical team is always to find a way to apply the optimal treatment to the mother without compromising the development of the fetus. Retrospective case-control studies did not reveal a worse prognosis for PABC.58 But the diagnosis of breast cancer in pregnancy is often delayed. The reasons for this can include “simply not thinking about it” and that clinical examination can be more difficult because of the enlargement of the breast tissue. The median delay of diagnosis in pregnancy was found to be 2.5 months; during lactation 6 months.59 A 1-month delay in tumor treatment increases the risk of axillary metastases by 0.9%; a 6-month delay by 5.1%. Pregnant women have positive nodes at diagnosis in 56%-83% compared with 38%54% in the nonpregnant population.60 The risk for primary metastatic disease is increased 2.5-fold.61 Therefore, all pregnant women should have a clinical breast examination and every suspicious or persisting breast and/or axillary mass should be imaged and biopsied.58 Ultrasound poses no harm to the developing fetus62 and with abdominal shielding a dose of 0.5 Gy is delivered by modern bilateral mammography to the fetus, which is less than the estimated environmental background radiation per week (2 mGy).58 BreastMRI is not recommended in pregnancy because of difficulties of positioning the patient on her stomach and concerns over the safety of gadolinium, which crosses the placenta and is associated with fetal abnormalities in animal experiments.63 The risk for developing milk fistula after biopsy is overestimated. Only few case reports can be found in the literature.64 Surgery can be safely performed during all trimesters as in nonpregnant patients, breast-conserving therapy is possible.58 SLN biopsy after the first trimester, using technetium, can be safely performed with minimal risk to the fetus.65,66 Blue staining is not recommended because of the anaphylactic and teratogenic risk.58 Radiotherapy should be postponed until after pregnancy, because of the risk of malformations, a decrease in intelligence, mental retardation (threshold dose ⬍0.12 Gy) and cancer induction in the fetus. In the first 8 weeks of pregnancy, the fetus is exposed to 0.05-0.15 Gy (reference dose 50 Gy), whereas at the end of pregnancy the fetus lies closer to the radiation field and could receive ⬎1 Gy.67 Chemotherapy can be applied after the first trimester and follows guidelines for nonpregnant patients. Anthracycline-containing regimens like FAC, AC, and EC are safe37,68 and also taxanes seem to be a safe option.69 Trastuzumab use in pregnancy is not recommended because of limited experience regarding its safety and few case reports about an association between trastuzumuab and oligo-/anhydramnion.70 Endocrine treatment is not recommended during pregnancy. Animal studies and case reports showed congenital abnormalities after exposure to tamoxifen in utero, especially malformations of the genital tract.71-73 Breast feeding is contraindicated if further systemic treatment is needed after delivery because the placental excretion function disap-
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pears and the newborn may not be able to metabolize the excreted chemotherapeutics in the milk.37
Pregnancy After Breast Cancer Few studies have addressed the impact of pregnancy after breast cancer. Women are often advised to wait at least 2 years after treatment before they attempt to conceive, although there are no data available that postponing conception will alter the prognosis of the breast cancer or the outcome of pregnancy. This recommendation is given because of the generally highest risk of relapse between year 1 and 2 after surgery (13.3%).74 Pregnancy does not seem to worsen prognosis in case of history of breast cancer. On the contrary, 5-year and 10-year overall survival rates were found to be better in women who subsequently conceived. Pregnancy has a significant overall survival benefit in those women who waited 24 months to become pregnant and a nonsignificant protective effect for women who waited at least 6 months.75 This effect can partly be explained by the “healthy mother effect,” because those women are a self-selected group with a better prognosis.76 The use of adjuvant chemotherapy does not affect the outcome of pregnancy if the woman becomes pregnant at least 6 months after diagnosis.75 There are very little data available regarding chemotherapy and its consequences for the offspring. It seems not to increase the incidence of prematurity, stillbirth, congenital malformations, or long-term side-effects.77-79 Tamoxifen may stimulate ovulation. There have been reports about craniofacial and genital tract abnormalities in humans after exposition in utero.71,72 Therefore, the patient should stop tamoxifen 2 months before attempting pregnancy or use contraception. Patients must be informed about the possible detrimental effect of stopping tamoxifen and the benefit of taking it over a period of 5 years. They risk missing its beneficial effect on disease-free survival without having the guarantee to become pregnant.80 Breast feeding after breast cancer is possible. Data suggests that there is no effect on breast cancer prognosis81 and it seems to be feasible and safe.82 After breast conserving therapy and subsequent radiotherapy in the treated breast, functional lactation is possible but significantly diminished in most patients. Nevertheless, successful lactation can be experienced in the contralateral breast.83 Breast feeding during tamoxifen use is not possible because the drug inhibits milk production.84 BRCA-1/-2-mutation carriers need to cope with the knowledge that there is a 50% chance that their children will have inherited the cancer predisposition mutation. Risk reduction strategies should be discussed with carriers during counseling sessions depending on the legal situation of the home country. Options to avoid transferring their mutation to the next generation are avoiding pregnancy, ovum donation (or sperm donation when concerning male carriers), prenatal diagnosis, or preimplantation genetic diagnosis (PGD). Discussion of these options should be carried out with sensitivity. Seventy-five percent of BRCA-carriers feel that it is acceptable to discuss PGD, but most of them would not consider it for themselves.85
Contraceptive Options After Breast Cancer Hormonal contraceptives are contraindicated (even in patients with hormone insensitive breast cancer), but there are only very few
Steffi Hartmann et al citations available concerning contraception after breast cancer. No trial included women after diagnosis of breast cancer and, therefore, the evidence of harm is difficult to establish. Nonhormonal alternatives are barrier methods (eg, condom, pessary) or sterilization (tubal ligation or vasectomy).37 There is still a discussion about the safety of the low-dose levonorgestrel-releasing intrauterine system (LNG IUS), which delivers high local but low systemic doses of progesterone. In vivo low progestin concentration does not stimulate breast tumor proliferation.86 A postmarketing epidemiologic study carried out in Finland did not find an increased risk of breast cancer in 17,360 LNG IUS users.87 But no prospective data are available regarding recurrence risk after breast cancer. A small retrospective cohort study reported no increased risk of breast cancer recurrence associated with LNG IUS use, but a subgroup analysis revealed a higher risk for women who developed breast cancer while using LNG IUS and who continued the use after diagnosis.88 In our opinion, patients should be advised to remove LNG IUS and not to restart use after breast cancer diagnosis until additional information regarding safety after breast cancer is available.
Genetic Counseling The risk of BRCA-mutation in patients with breast cancer in Germany 35 years or younger is about 12% (8% BRCA-1, 4% BRCA-2).89 Therefore, genetic counseling and testing should be offered to all of these women. In case of hereditary breast cancer, surgical management and adjuvant therapy is recommended according to standard guidelines. Poly(ADP-ribose) polymerase (PARP)-inhibitors are a new therapeutic strategy for the treatment of cancers with specific DNA-repair defects. Currently they are not recommended for patients outside of clinical trials, but therapy seems to be effective and quite safe.90 In vitro studies found a distinct chemosensitivity profile of BRCA-associated breast carcinomas. Recent data suggest the benefit of new therapeutic strategies containing PARPinhibitors and platinum drugs.91 Retrospective and small prospective studies have shown a high response rate to cisplatin (90%) in neoadjuvant setting in BRCA-mutation carriers,92,93 but results of ongoing trials will provide key information before a change outside of clinical studies. The proof of BRCA-1/-2-mutation results in a multimodal screening program for noncancer-affected relatives including clinical examination, mammography, breast ultrasound, and breastMRI16,17 starting at the age of 25. Affected BRCA-1/-2-mutation carriers have to face an increased risk of contralateral breast cancer (30%-40% in 10 years).94,95 The risk of contralateral breast cancer can be reduced by taking tamoxifen or bilateral oophorectomy.94 Additionally, prophylactic bilateral oophorectomy can reduce the increased risk of ovarian cancer in breast cancer-affected women and, therefore, should be recommended in BRCA-1/-2-mutation carriers with a good prognosis.96 Recently a reduction of mortality was reported also.97 Affected BRCA-mutation carriers require comprehensive counseling and should be referred to centers for familial breast and ovarian cancer.
Conclusion Breast cancer in very young women (⬍35 years) is rare and needs multidisciplinary treatment. The prognosis of this age group is worse than that of older women. Although limited information is available, the following recommendations can be given for clinical management: 1. Diagnostic Procedures ● breast ultrasound, digital mammography ⫹ biopsy in case of suspicious lesion; ● no indication for routine MRI before surgery; ● multimodal screening including MRI starting at age 25-30 for BRCA-1/-2-mutation carriers, in case with a strong family history and after chest radiation in childhood or adolescence. 2. Local Treatment ● not different from current common guidelines. 3. Adjuvant Chemotherapy ● polychemotherapy almost always indicated. 4. Adjuvant Endocrine Therapy ● tamoxifen 20 mg/day 5 years; ● GnRHa /aromatase inhibitors in clinical trials. 5. Fertility Preservation ● information and if necessary start fertility preservation measures before starting systemic therapy; ● no ovary protection by GnRHa during chemotherapy (inconsistent data). 6. Pregnancy Associated Breast Cancer ● immediate imaging/ biopsying of suspicious masses; ● after first trimester surgery including SLN biopsy and chemotherapy like in nonpregnant women; ● during pregnancy no radiotherapy, endocrine treatment or trastuzumab. 7. Pregnancy After Breast Cancer ● optimal time point is unclear; ● no bad effect on prognosis for breast cancer and pregnancy outcome if woman becomes pregnant at least 6 months after diagnosis; ● breast feeding is possible (if not taking tamoxifen). 8. Contraception ● no hormonal contraceptives; ● LNG IUS should be removed and not be inserted after diagnosis (lack of data). 9. Genetic Counseling ● should be offered to all women with breast cancer ⬍ 35 years. All these points must be considered and discussed with very young patients to ensure optimal treatment. Further important topics, not only for very young patients with breast cancer, are psychologic care, sexual problems, and the management of side effects.
Disclosure All authors have no conflict of interest.
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Kuhl CK, Schrading S, Leutner CC, et al. Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. J Clin Oncol 2005; 23:8469-76. 17. Schmutzler R, Schlegelberger B, Meindl A, et al. Counselling, genetic testing and prevention in women with hereditary breast- and ovarian cancer. Interdisciplinary recommendations of the consortium “Hereditary Breast- and Ovarian Cancer” of the German Cancer AiD. Zentralbl Gynakol 2003; 125:494-506 [in German]. 18. Gerber B, Krause A, Dieterich M, et al. The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended follow-up study. Ann Surg 2009; 249:461-8. 19. Klauber-Demore N, Calvo BF, Hultman CS, et al. Staged sentinel lymph node biopsy before mastectomy facilitates surgical planning for breast cancer patients. Am J Surg 2005; 190:595-7. 20. Russell NS, Kunkler IH, van Tienhoven G, et al. Postmastectomy radiotherapy: will the selective use of postmastectomy radiotherapy study end the debate? J Clin Oncol 2009; 27:996-7. 21. Marks LB, Zeng J, Prosnitz LR. One to three versus four or more positive nodes and postmastectomy radiotherapy: time to end the debate. J Clin Oncol 2008; 26: 2075-7. 22. de Bock GH, van der Hage JA, Putter H, et al. Isolated loco-regional recurrence of breast cancer is more common in young patients and following breast conserving therapy: long-term results of European Organisation for Research and Treatment of Cancer studies. Eur J Cancer 2006; 42:351-6. 23. Voogd AC, Nielsen M, Peterse JL, et al. Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials. J Clin Oncol 2001; 19:1688-97. 24. Kroman N, Holtveg H, Wohlfahrt J, et al. Effect of breast-conserving therapy versus radical mastectomy on prognosis for young women with breast carcinoma. Cancer 2004; 100:688-93. 25. Turner BC, Harrold E, Matloff E, et al. BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy or radiation therapy: implications for breast conserving management in patients with BRCA1/BRCA2 mutations. J Clin Oncol 1999; 17:3017-24. 26. Haffty BG, Harrold E, Khan AJ, et al. Outcome of conservatively managed earlyonset breast cancer by BRCA1/2 status. Lancet 2002; 359:1471-7. 27. Seynaeve C, Verhoog LC, van de Bosch LM, et al. Ipsilateral breast tumour recurrence in hereditary breast cancer following breast-conserving therapy. Eur J Cancer 2004; 40:1150-8. 28. Garcia-Etienne CA, Barile M, Gentilini OD, et al. Breast conserving surgery in BRCA1/2 mutation carriers: are we approaching an answer? Ann Surg Oncol 2009; 16:3380-7.
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29. Pierce LJ, Strawderman M, Narod SA, et al. Effect of radiotherapy after breastconserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 2000; 18:3360-9. 30. Robson M, Svahn T, McCormick B, et al. Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic based series. Cancer 2005; 103:44-51. 31. Kirova YM, Stoppa-Lyonnet D, Savignoni A, et al. Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer 2005; 41:2304-11. 32. Pierce LJ, Levin AM, Rebbeck TR, et al. Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 2006; 24:2437-43. 33. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:2087-106. 34. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007; 25:3259-65. 35. Offersen BV, Overgaard M, Kroman N, Overgaard J. Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: a systematic review. Radiother Oncol 2009; 90:1-13. 36. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009; 74:987-1001. 37. AGO Breast Commission. Diagnosis and treatment of patients with primary and metastatic breast cancer. Guidelines of the AGO breast commission. Available at: http://www.ago-online.de/index.php?lang⫽de&site⫽mamma_guide_topical& topic⫽mamma_guide. Accessed August 28, 2010. 38. 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; 365:1687-717. 39. Swain SM, Jeong JH, Geyer CE Jr, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 2010; 362:2053-65. 40. Gerber B, Dieterich M, Müller H, Reimer T. Controversies in preservation of ovary function and fertility in patients with breast cancer. Breast Cancer Res Treat 2007; 108:1-7. 41. Goel S, Sharma R, Hamilton A, Beith J. LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst Rev 2009; 4:CD004562. 42. LHRH-agonists in Early Breast Cancer Overview group, Cuzick J, Ambroisine L, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007; 369: 1711-23. 43. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360:679-91. 44. Reimer T, Gerber B. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360:2368. 45. Statistisches Bundesamt Deutschland. Bevölkerung - Geburten. Available at: http:// www.destatis.de/. Accessed August 28, 2010. 46. Hickey M, Peate M, Saunders CM, Friedlander M. Breast cancer in young women and its impact on reproductive function. Hum Reprod Update 2009; 15:323-39. 47. Gupta PB, Kupferwasser C. Contributions of estrogen to ER-negative breast tumor growth. J Steroid Biochem Mol Biol 2006; 102:71-8. 48. Oktay K, Buyuk E, Libertella N, et al. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 2005; 23:4747-53. 49. Rodriguez-Wallberg KA, Oktay K. Fertility preservation in women with breast cancer. Clin Obstet Gynecol 2010; 53:753-62. 50. Lee S, Ozkavukcu S, Heytens E, et al. Value of early referral to fertility preservation in young women with breast cancer. J Clin Oncol 2010; 28:4683-6. 51. Gerber B, Stehle H, Ricardo F, et al. ZORO: a prospective randomized multicenter study to prevent chemotherapy-induced ovarian failure with the GnRH-agonist goserelin in young hormone-insensitive breast cancer patients receiving anthracycline-containing (neo-)adjuvant chemotherapy (GBG 37). J Clin Oncol 2009; 27: 15s (Abstract #526). 52. Leonard RC, Adamson D, Anderson R et al. The OPTION trial of adjuvant ovarian protection by goserelin in adjuvant chemotherapy for early breast cancer. J Clin Oncol 2010; 28:89s (Abstract #590). 53. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009; 91:694-7. 54. Del Mastro L, Boni L, Michelotti A, et al. Role of luteinizing hormone-releasing hormone analog (LHRHa) triptorelin (T) in preserving ovarian function during chemotherapy for early breast cancer patients: results of a multicenter phase III trial of Gruppo Italiano Mammella (GIM) group. J Clin Oncol 2010; 28:74s (Abstract #528). 55. Beadle BM, Woodward WA, Middleton LP, et al. The impact of pregnancy on breast cancer outcomes in women ⬍ or⫽35 years. Cancer 2009; 115:1174-84. 56. White TT. Prognosis of breast cancer for pregnant and nursing women. Surg Gynecol Obstet 1955; 100:661-6. 57. Anderson JM. Mammary cancers and pregnancy. BMJ 1979; 1:1124-7.
Steffi Hartmann et al 58. Loibl S, von Minckwitz G, Gwyn K, et al. Breast carcinoma during pregnancy. International recommendations from an expert meeting. Cancer 2006; 106:237-46. 59. Tretli S, Kvalheim G, Thoresen S, Høst H. Survival of breast cancer patients diagnosed during pregnancy or lactation. Br J Cancer 1988; 58:382-4. 60. Woo JC, Yu T, Hurd TC. Breast cancer in pregnancy: a literature review. Arch Surg 2003; 138:91-8. 61. Zemlickis D, Lishner M, Degendorfer P, et al. Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 1992; 166:781-7. 62. Liberman L, Giess C, Dershaw DD, et al. Imaging of pregnancy associated breast cancer. Radiology 1994; 191:245-8. 63. Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer patient. Semin Oncol 2000; 27:623-32. 64. Schackmuth EM, Harlow CL, Norton LW. Milk fistula: a complication after core biopsy. AJR Am J Roentgenol 1993; 161:961-2. 65. Khera SY, Kiluk JV, Hasson DM, et al. Pregnancy-associated breast cancer patients can safely undergo lymphatic mapping. Breast J 2008; 14:250-4. 66. Gentilini O, Cremonesi M, Toesca A, et al. Sentinel lymph node biopsy in pregnant patients with breast cancer. Eur J Nucl Med Mol Imaging 2009; 37:78-83. 67. Kal HB, Struikmans H. Breast cancer during pregnancy. International recommendations from an expert meeting. Cancer 2006; 107:882-3. 68. Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17:855-61. 69. Mir O, Berveiller P, Ropert S, et al. Emerging therapeutic options for breast cancer chemotherapy during pregnancy. Ann Oncol 2007; 19:607-13. 70. Goodyer MJ, Ismail JR, O’Reilly SP, et al. Safety of trastuzumab (Herceptin) during pregnancy: two case reports. Cases J 2009; 2:9329. 71. Cunha GR, Taguchi O, Namikawa R, et al. Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genital tract. Hum Pathol 1987; 18:1132-43. 72. Cullins SL, Pridjian G, Sutherland CM. Goldenhar‘s syndrome associated with tamoxifen given to the mother during gestation. JAMA 1994; 271:1905a-6. 73. Tewari K, Bonebrake RG, Asrat T, Shanberg AM. Ambiguous genitalia in infant exposed to tamoxifen in utero. Lancet 1997; 350:183. 74. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14:2738-46. 75. Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ 2007; 334:194. 76. Sankila R, Heinävaara S, Hakulinen T. Survival of breast cancer patients after subsequent term pregnancy: “healthy mother effect. Am J Obstet Gynecol 1994; 170:818-23. 77. Mintzer D, Glassburn J, Mason BA, Sataloff D. Breast cancer in the very young patient: a multidisciplinary case presentation. Oncologist 2002; 7:547-54. 78. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004; 5:283-91. 79. Aviles A, Neri N. Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymphoma 2001; 2:173-7.
80. Barthelmes L, Davidson LA, Gaffney C, et al. Clinical review: pregnancy and breast cancer. BMJ 2005; 330:1375-8. 81. Helewa M, Lëvesque P, Provencher D, et al. Breast cancer, pregnancy, and breastfeeding. J Obstet Gynaecol Can 2002; 24:164-80. 82. de Bree E, Makrigiannakis A, Askoxylakis J, et al. Pregnancy after breast cancer. A comprehensive review. J Surg Oncol 2010; 101:534-42. 83. Moran MS, Colasanto JM, Haffty BG, et al. Effects of breast-conserving therapy on lactation after pregnancy. Cancer J 2005; 11:399-403. 84. Kleinberg DL, Todd J, Babitsky G. Inhibition by estradiol on the lactogenic effect of prolactin in primate mammary tissue: reversal by antiestrogens LY156758 and tamoxifen. Proc Natl Acad Sci USA 1983; 80:4144-8. 85. Sagi M, Weinberg N, Eilat A, et al. Preimplantation genetic diagnosis for BRCA1/2- a novel clinical experience. Prenat Diagn 2009; 29:508-13. 86. van der Burg B, Kalkhoven E, Isbrücker L, de Laat SW. Effects of progestins on the proliferation of estrogen-dependent human breast cancer cells under growth factordefined conditions. J Steroid Biochem Mol Biol 1992; 42:457-65. 87. Backman T, Rauramo I, Jaakkola K, et al. Use of levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol 2005; 106:813-7. 88. Trinh XB, Tjalma WA, Makar AP, et al. Use of levonorgestrel-releasing intrauterine system in breast cancer patients. Fertil Steril 2008; 90:17-22. 89. Meindl A, German Consortium for Hereditary Breast and Ovarian Cancer. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 2002; 97:472-80. 90. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361:123-34. 91. Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci USA 2008; 105:17079-84. 92. Byrski T, Gronwald J, Huzarski T, et al. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat 2007; 108: 289-96. 93. Byrski T, Huzarski T, Dent R, et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 2008; 115:359-63. 94. Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328-35. 95. Pierce LJ, Phillips KA, Griffith KA, et al. Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. Breast Cancer Res Treat 2010; 121:389-98. 96. Metcalfe KA, Lynch HT, Ghadirian P, et al. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol 2005; 96:222-6. 97. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010; 304:967-75.
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Management of Early Invasive Breast Cancer in Very Young Women (⬍35 years) Steffi Hartmann, Toralf Reimer, Bernd Gerber Abstract Background: To give an overview about current treatment recommendations and special problems concerning the management of women ⬍35 years with early breast cancer. Methods: We performed a selective systematic literature review. We discussed with reference to key studies and meta-analyses, current standards of care, and controversies regarding patient management. Results: Breast cancer in patients younger than 35 years is rare but associated with an unsatisfactory prognosis. Local treatment should not differ from general guidelines, but awareness of the high risk of local recurrence must be maintained. Adjuvant polychemotherapy is almost always indicated, standard endocrine therapy is tamoxifen. Before the start of systemic therapy, the patient must be offered different types of fertility preservation. Pregnancy related breast cancer is not associated with a worse prognosis, but with delayed diagnosis. Therefore, every suspicious lesion in the breast or axilla must be imaged and biopsied. The optimal time to delay pregnancy following the diagnosis is unknown. Hormonal contraceptives are contraindicated after breast cancer. Every woman ⬍35 years diagnosed with breast cancer should be offered genetic counseling. Conclusion: The management of breast cancer in very young women requires a multidisciplinary team to find the optimal treatment and to solve their specific problems. Clinical Breast Cancer, Vol. 11, No. 4, 196-203 © 2011 Published by Elsevier Inc. Keywords: Breast cancer, Contraception, Fertility, Genetic counseling, Young women
Introduction Breast cancer is rare in very young women. Only 1.9% of all breast cancers occur in women ⬍35 years,1 but the diagnosis is physically and emotionally devastating for these women. Mostly healthy young women face a life-threatening disease, which thwarts their plans for the future, especially regarding their professions and family planning. Young survivors of breast cancer have to face the fear of recurrence and the elevated risk of transmitting a gene mutation that increases the risk of cancer in their offspring over a very long period of time. The management of breast cancer in very young patients is a challenge not only for the affected women and their environment, but also for the multidisciplinary team treating them. Our article deals with the special problems of women ⬍35 years of age with breast cancer, such as prognosis, fertility, pregnancy, contraception, and genetic counseling, and highlights current recommendations for early breast cancer treatment, knowing that informa-
tion for these patients is limited due to the small number of very young women included in studies.
Methods We performed a selective PubMed literature search for the period 2000 until August 2010 using the key words “breast cancer in young patients” (activated limits: clinical trial, meta-analysis, practice guidelines, randomized controlled trial, humans, female, adult 19-44 years). We reviewed treatment recommendations of the German Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) breast commission and the National Comprehensive Cancer Network (NCCN). Important presentations from the San Antonio Breast Cancer Symposium 2009 and the American Society of Clinical Oncology meeting 2010 were considered. We emphasized current controversies and unanswered questions regarding disease management.
Results Prognosis
Department of Obstetrics and Gynecology, University of Rostock, Rostock, Germany Submitted: Sep 30, 2010; Revised: Nov 19, 2010; Accepted: Nov 21, 2010 Address for correspondence: Steffi Hartmann, Department of Obstetrics and Gynecology, Südring 81, 18059 Rostock, Germany Fax: ⫹49-381-44014599; e-mail contact: [email protected]
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Several studies have reported significantly worse outcomes in younger women with breast cancer than in older women.2,3 An age of less than 35 years was found to be a reasonable cut-off point for defining young age-onset breast cancer. This age group showed a significantly worse outcome compared with older premenopausal women, and their risk of death rose by 5% for every
1526-8209/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.clbc.2011.06.001
1-year reduction in age.4 This negative impact on survival was especially seen in patients with positive lymph nodes and those with positive hormonal receptors,5 underlining the key role of hormonal mechanisms in young patients with breast cancer. Most studies analyzing histopathological factors found higher lymph node involvement, histologic grading, stage at presentation, greater tumor size, and more triple-negative tumors in younger patients.6,7 However, even after adjustment of those prognostic factors, women aged 35 or younger still have a worse prognosis. Therefore, the unfavorable common prognostic criteria cannot be the only explanation for the more aggressive disease.8 Different gene expression profiles could explain the differences between the young and the elderly. Currently, Anders et al7 revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women and concluded that this could define a unique biologic entity. It should be noted that in spite of the still poorer prognosis compared with older women, mortality in the younger age group decreased between 2000 and 2004 by around 30% (10 years followup).9 This effect can partly be explained by the fact that younger patients are highly motivated and often have access to innovative therapeutic strategies, especially in clinical trials.
Diagnostic Procedures Young women have a higher density of the glandular parenchyma, making it more difficult to differentiate between tumors and normal breast tissue by mammography. Sonography is more sensitive than mammography in evaluating breast masses in women younger than 45.10 A small retrospective study postulated magnetic resonance imaging (MRI) to be a useful supplementation to conventional mammography for the detection of breast cancer in premenopausal women.11 The COMICE-trial, which included 23% of women younger than 50 years (n ⫽ 374) and 87% of patients with breast density ACR BI-RADS type 2, 3 or 4 (n ⫽ 1415), showed that the addition of MRI to conventional triple assessment (clinical, radiologic including mammography and ultrasound and pathologic including fine-needle aspiration cytology or core biopsy), did not reduce the reoperation rate. The authors conclude that preoperative MRI may not be necessary and can result in extra use of resources with little or no benefit to residual health.12 Therefore, in symptomatic young women, breast ultrasound should be the diagnostic method of choice and in case of a suspicious finding it should be supplemented by digital mammography and histologic assessment. In case of conventional imaging difficulties because of dense tissue, preoperative MRI may provide benefit in very young patients with breast cancer.13 Screening (except clinical breast examination once a year starting at age 30) is not recommended for women younger than 50 years of age in Germany. The NCCN guidelines recommend clinical breast examination every 1-3 years starting at age 20 and annual mammograms starting at age 40.14 Only two high-risk populations should start radiologic screening earlier: first, women treated with chest radiation for pediatric and young adult cancers presenting with cumulative incidence of breast cancer from 13%-20% by 40-45 years of age. Their risk of breast cancer increases 8 years after chest radiation with a median age at diagnosis of 35-44. Therefore, the current recommendation for this population includes annual surveillance
mammography and MRI starting at the age of 25 or 8 years after the completion of radiation therapy.15 Second, young BRCA-1/-2-mutation carriers and patients with a strong family history should start multimodal screening at the age of 25-30 depending on national recommendations or 5-10 years before the youngest breast cancer case in the family.14,16,17
Local Treatment Surgical management is not different from that in older patients. The decision about breast-conservation versus mastectomy is influenced by the fact that young women frequently present at an advanced stage.6 If mastectomy is necessary, primary or secondary reconstructive surgery should be offered. If myocutaneous tissue alone is not sufficient to reach a satisfactory cosmetic result and postmastectomy radiotherapy is not considered, primary reconstruction using an implant and skin or nipple-sparing mastectomy is possible and oncologically safe.18 Otherwise (T3/T4-tumors or node-positive disease) secondary reconstruction should be preferred to avoid implantrelated complications due to radiotherapy. In practice, sentinel lymph node (SLN) biopsy can be conducted as the first surgical procedure.19 After getting the histopathological result, the decision can be made as to whether postmastectomy radiation is necessary or not and what the best time point for reconstruction is (Figure 1). This recommendation is restricted due to the ongoing international debate about postmastectomy radiotherapy in case of 1-3 positive lymph nodes.20,21 If breast-conserving surgery (BCS) is possible, one must be aware of the higher risk for local recurrence in women ⬍35 years compared with older women.22 The risk is increased up to 9-fold compared with women 60 years and older,23 but survival is not compromised by breast-conserving therapy combined with radiation.24 Therefore, young patients should be monitored closely to detect local recurrence at an early stage. The optimal local management for patients with BRCA-associated breast cancer remains controversial. Initial reports on this issue were conflicting; some studies suggested that these patients may be at higher risk for local recurrence after BCS.25-28 In the opposite, a multi-institutional study and two clinic-based series showed no significant differences in local recurrence rates after BCS between BRCA mutation carriers and controls, with a 10-year risk of ipsilateral breast tumor recurrence (IBTR) of 14% in carriers.29-31 According to updated data of the multi-institutional study, the risk of an IBTR seems to be related to oophorectomy preference in mutation carriers.32 If risk-reducing salpingo-oophorectomy is planned, BCS with whole breast irradiation could be considered because the difference in IBTR was not statistically significant between mutation carriers with oophorectomy and sporadic controls without oophorectomy. If the preference is to preserve the ovaries, the patients interested in BCS must be aware about the increased risk of IBTR and the higher rate of new primary tumors in mutation carriers.28 Radiotherapy in young patients should be recommended corresponding to current guidelines. After breast-conserving therapy, radiotherapy reduces local recurrence significantly in all women.33 Especially young women (⬍40 years) benefit from a local 16 Gy boost, which can significantly reduce the local recurrence rate, but not mortality.34 Patients younger than 50 years are currently unsuitable for
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Breast Cancer in Young Women Figure 1 Flowchart Diagram for Surgical Strategies in Case of Mastectomy and Wish for Reconstruction
Mastectomy required Postmastectomy radiotherapy recommendation
Postmastectomy radiotherapy recommendation unclear
c/iN +* T-3,4-tumor
c/iN – T-1,2,(3)-tumor#
No implant required
Implant required
No implant required
Implant required
Primary reconstruction
Secondary reconstruction
Primary reconstruction
SLN biopsy
pN+
Secondary reconstruction
pN–
Primary reconstruction
*Postmastectomy radiotherapy is recommended by the German AGO also in case of 1-3 positive lymphnodes (recommendation: ⫹), while NCCN guidelines recommend routine postmastectomy radiotherapy in case of ⬎ 3 positive lymphnodes. #Postmastectomy radiotherapy is recommended for patients with a primary tumor greater than 5cm in node-negative disease according to NCCN guidelines. The German AGO does not consider routine postmastectomy radiotherapy in pT3pN0 situation (⫹/⫺ recommendation)
partial breast irridiation.35,36 Postmastectomy radiotherapy is advised to all patients who have a high risk of local relapse (T3/T4tumors, node-positive disease, R-1-resection).37
Adjuvant Systemic Treatment Adjuvant systemic treatment offers high benefit to young patients with breast cancer. Therefore, chemotherapy, endocrine therapy (in hormone receptor-positive tumors), and trastuzumab (in HER-2overexpressing tumors) are almost always indicated.37 The annual breast cancer death rate for women younger than 50 years is reduced by 38% by anthracycline-based polychemotherapy without significant differences between age groups ⬍35 years and 35-50 years.38 Current AGO-guidelines recommend taxane-based chemotherapy for node-positive patients and high-risk node-negative patients.37 Overall survival was shown to be improved in patients with chemotherapy induced amenorrhea (CIA) for 6 months or more.39 Despite this prognostic advantage, CIA has many objective (osteoporosis, cardiovascular, urogenital atrophy, cognitive) and subjective (hot flushes, sleep disturbances, change of mood) consequences,40 which could affect especially young breast cancer survivors for a long period. Endocrine standard treatment for premenopausal women with hormone receptor-positive tumors is tamoxifen 20 mg/day for 5 years, which reduces the annual breast cancer death rate by 31%.38 A current meta-analysis of randomized adjuvant trials concluded that there are insufficient data to compare the combination of gonadotropin-releasing hormone analogs (GnRHa) plus tamoxifen to tamoxifen alone (only two trials, about 360 patients).41 Therefore, the
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additional administration of GnRHa should be carried out in randomized clinical trials like Suppression of Ovarian Function Trial (tamoxifen 5 years vs. ovarian function suppression ⫹ tamoxifen 5 years vs. ovarian function suppression ⫹ exemestane 5 years). GnRHa only showed a small benefit when used after chemotherapy alone or with tamoxifen in women aged 40 years or younger. This effect could be explained by the fact that, in this age group, permanent amenorrhea is less likely to be induced by chemotherapy.42 If tamoxifen is contraindicated, GnRHa alone can be given. Three trials comparing tamoxifen to GnRHa suggest that these treatments are comparable regarding recurrence-free survival.41 Aromatase inhibitors should not be applied in premenopausal women except as a part of clinical trials. The ABCSG-12-trial revealed a trend to worse overall survival in premenopausal patients treated with anastrozole ⫹ GnRHa compared with tamoxifen ⫹ GnRHa (number of events 84 months since randomization anastrozole n ⫽ 27, tamoxifen n ⫽ 15, P ⫽ .07, HR 1.8)43,44 (Figure 2).
Fertility Preservation The tendency to delay childbearing in developed countries increases the number of women who have not yet completed their family at the time of breast cancer diagnosis. The median age at first delivery in Germany increased from 22 in 1961 to 30 years in 2008.45 The very young patient with breast cancer must be informed about the toxic effect of chemotherapy on ovarian follicles, which adds an average of 10 years to ovarian age, and the age-related decline of fertility after 5 years of endocrine therapy.46 This problem has to be discussed before the start of adjuvant systemic treatment. Women have to be aware that fertility preservation options can be both time
Steffi Hartmann et al Figure 2 Recommendations for Antihormonal Therapy in Premenopausal Women [adapted from 37]
Low or intermediate risk, no adjuvant chemotherapy • Tamoxifen 5 yrs. • Tamoxifen 5 yrs. + GnRHa Intermediate or high risk, adjuvant chemotherapy • ≥40 yrs. Tamoxifen 5 yrs. • <40 yrs. Tamoxifen 5 yrs. + GnRHa GnRHa alone (contraindications for tamoxifen) Aromatase inhibitors
++ +* ++ +* + –*
++ Investigation/therapeutic intervention highly beneficial for patients, can be recommended without restriction + Investigation/therapeutic intervention of limited benefit for patients, can be performed – Investigation/therapeutic intervention can be of disadvantage for patients and might not be performed * Study participation recommended
Table 1 Fertility Preserving Strategies [adapted from 46] Option
Advantages
Disadvantages
– Relatively effective in achieving pregnancy – Clinically available
– Requires male partner – Likely to increase estrogen levels – May delay chemotherapy – Gene-mutation carriers can transmit increased cancer risk to offspring
Ovarian Stimulation and Oocyte Cryopreservation
– Does not require male partner
– Few successful pregnancies – Likely to increase estrogen levels – May delay chemotherapy – Gene-mutation carriers can transmit increased cancer risk to offspring
Ovarian Tissue Cryopreservation and Xenotransplantation
– Does not require male partner – No increased estrogen levels – No delay of chemotherapy
– Very few successful pregnancies – May reimplant ovarian tissue affected by micrometastases – Gene-mutation carriers can transmit increased cancer risk to offspring – Surgical procedure
IVF and Embryo Cryopreservation
and money consuming (Table 1). The only clinically tested procedure is embryo cryopreservation. But hormonal stimulation during fertility measures may have unfavorable effects in patients with hormone-sensitive and hormone-insensitive tumors.47 By using a stimulation protocol containing letrozole and FSH, a higher yield of embryos and lower serum levels of estrogen can be achieved during stimulation.48 To obtain mature oocytes, ovarian stimulation must be performed and, therefore, a delay of 2-6 weeks may be necessary.49 Typically, there is a gap of 4-6 weeks between women undergoing breast cancer surgery and the postoperative chemotherapy. Early referral to reproductive specialists before breast surgery results in the initiation of chemotherapy on average 3 weeks earlier compared with patients referred after breast surgery.50 Currently there are no data available regarding hormonal stimulation and neoadjuvant chemotherapy. Ovarian protection by GnRHa given concurrently with chemotherapy is not allowed in cases of hormone receptor-positive tumors because an impairment of the chemotherapy effect cannot be excluded. In patients with hormone receptor-negative tumors, it is not effective. Recent trials revealed no differences in recovery of regular menses dependent on GnRHa-application. The interim report of the ZORO-trial after 2 years follow-up was presented at the ASCOmeeting in 2009. Sixty premenopausal patients with hormone recep-
tor-negative tumors were randomized to either chemotherapy alone or chemotherapy ⫹ goserelin 3.6 mg 4-weekly subcutaneously. There was no difference in median time to restoration of menstruation and after 2 years regular menses recovered in all patients.51 At the ASCO meeting in 2010, the OPTION trial was presented, a randomized multicenter study to determine the impact of goserelin on the incidence of premature ovarian failure after chemotherapy for operable breast cancer. Even this trial revealed no difference in premature menopause dependent on goserelin substitution.52 On the contrary, Badawy et al53 published an effect on resumption of menses, but in this trial an unusual chemotherapy regimen (6 x FA500C d1 q6-8w) was administered. Del Mastro et al54 administered triptorelin to patients with hormone receptor-positive and receptor-negative tumors during chemotherapy and showed a significant absolute reduction of early menopause of 19%, but there are no data available regarding the effect on recurrence risk or survival, especially in patients with hormone receptor-positive tumors. There are relatively few randomized or definitive trials examining the success and impact of fertility preservation methods. Currently there are no proven methods or recommendations for effective preservation of ovarian function in patients with breast cancer.
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Breast Cancer in Young Women Pregnancy Associated Breast Cancer Pregnancy associated breast cancer (PABC) is defined as breast cancer that develops during or 1 year after pregnancy55 with an incidence of 1:3000.56,57 Because in developed countries women delay childbearing and breast cancer incidence increases with increasing age, we will probably be confronted with this situation more often in the future. The conflict for the patient and the medical team is always to find a way to apply the optimal treatment to the mother without compromising the development of the fetus. Retrospective case-control studies did not reveal a worse prognosis for PABC.58 But the diagnosis of breast cancer in pregnancy is often delayed. The reasons for this can include “simply not thinking about it” and that clinical examination can be more difficult because of the enlargement of the breast tissue. The median delay of diagnosis in pregnancy was found to be 2.5 months; during lactation 6 months.59 A 1-month delay in tumor treatment increases the risk of axillary metastases by 0.9%; a 6-month delay by 5.1%. Pregnant women have positive nodes at diagnosis in 56%-83% compared with 38%54% in the nonpregnant population.60 The risk for primary metastatic disease is increased 2.5-fold.61 Therefore, all pregnant women should have a clinical breast examination and every suspicious or persisting breast and/or axillary mass should be imaged and biopsied.58 Ultrasound poses no harm to the developing fetus62 and with abdominal shielding a dose of 0.5 Gy is delivered by modern bilateral mammography to the fetus, which is less than the estimated environmental background radiation per week (2 mGy).58 BreastMRI is not recommended in pregnancy because of difficulties of positioning the patient on her stomach and concerns over the safety of gadolinium, which crosses the placenta and is associated with fetal abnormalities in animal experiments.63 The risk for developing milk fistula after biopsy is overestimated. Only few case reports can be found in the literature.64 Surgery can be safely performed during all trimesters as in nonpregnant patients, breast-conserving therapy is possible.58 SLN biopsy after the first trimester, using technetium, can be safely performed with minimal risk to the fetus.65,66 Blue staining is not recommended because of the anaphylactic and teratogenic risk.58 Radiotherapy should be postponed until after pregnancy, because of the risk of malformations, a decrease in intelligence, mental retardation (threshold dose ⬍0.12 Gy) and cancer induction in the fetus. In the first 8 weeks of pregnancy, the fetus is exposed to 0.05-0.15 Gy (reference dose 50 Gy), whereas at the end of pregnancy the fetus lies closer to the radiation field and could receive ⬎1 Gy.67 Chemotherapy can be applied after the first trimester and follows guidelines for nonpregnant patients. Anthracycline-containing regimens like FAC, AC, and EC are safe37,68 and also taxanes seem to be a safe option.69 Trastuzumab use in pregnancy is not recommended because of limited experience regarding its safety and few case reports about an association between trastuzumuab and oligo-/anhydramnion.70 Endocrine treatment is not recommended during pregnancy. Animal studies and case reports showed congenital abnormalities after exposure to tamoxifen in utero, especially malformations of the genital tract.71-73 Breast feeding is contraindicated if further systemic treatment is needed after delivery because the placental excretion function disap-
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pears and the newborn may not be able to metabolize the excreted chemotherapeutics in the milk.37
Pregnancy After Breast Cancer Few studies have addressed the impact of pregnancy after breast cancer. Women are often advised to wait at least 2 years after treatment before they attempt to conceive, although there are no data available that postponing conception will alter the prognosis of the breast cancer or the outcome of pregnancy. This recommendation is given because of the generally highest risk of relapse between year 1 and 2 after surgery (13.3%).74 Pregnancy does not seem to worsen prognosis in case of history of breast cancer. On the contrary, 5-year and 10-year overall survival rates were found to be better in women who subsequently conceived. Pregnancy has a significant overall survival benefit in those women who waited 24 months to become pregnant and a nonsignificant protective effect for women who waited at least 6 months.75 This effect can partly be explained by the “healthy mother effect,” because those women are a self-selected group with a better prognosis.76 The use of adjuvant chemotherapy does not affect the outcome of pregnancy if the woman becomes pregnant at least 6 months after diagnosis.75 There are very little data available regarding chemotherapy and its consequences for the offspring. It seems not to increase the incidence of prematurity, stillbirth, congenital malformations, or long-term side-effects.77-79 Tamoxifen may stimulate ovulation. There have been reports about craniofacial and genital tract abnormalities in humans after exposition in utero.71,72 Therefore, the patient should stop tamoxifen 2 months before attempting pregnancy or use contraception. Patients must be informed about the possible detrimental effect of stopping tamoxifen and the benefit of taking it over a period of 5 years. They risk missing its beneficial effect on disease-free survival without having the guarantee to become pregnant.80 Breast feeding after breast cancer is possible. Data suggests that there is no effect on breast cancer prognosis81 and it seems to be feasible and safe.82 After breast conserving therapy and subsequent radiotherapy in the treated breast, functional lactation is possible but significantly diminished in most patients. Nevertheless, successful lactation can be experienced in the contralateral breast.83 Breast feeding during tamoxifen use is not possible because the drug inhibits milk production.84 BRCA-1/-2-mutation carriers need to cope with the knowledge that there is a 50% chance that their children will have inherited the cancer predisposition mutation. Risk reduction strategies should be discussed with carriers during counseling sessions depending on the legal situation of the home country. Options to avoid transferring their mutation to the next generation are avoiding pregnancy, ovum donation (or sperm donation when concerning male carriers), prenatal diagnosis, or preimplantation genetic diagnosis (PGD). Discussion of these options should be carried out with sensitivity. Seventy-five percent of BRCA-carriers feel that it is acceptable to discuss PGD, but most of them would not consider it for themselves.85
Contraceptive Options After Breast Cancer Hormonal contraceptives are contraindicated (even in patients with hormone insensitive breast cancer), but there are only very few
Steffi Hartmann et al citations available concerning contraception after breast cancer. No trial included women after diagnosis of breast cancer and, therefore, the evidence of harm is difficult to establish. Nonhormonal alternatives are barrier methods (eg, condom, pessary) or sterilization (tubal ligation or vasectomy).37 There is still a discussion about the safety of the low-dose levonorgestrel-releasing intrauterine system (LNG IUS), which delivers high local but low systemic doses of progesterone. In vivo low progestin concentration does not stimulate breast tumor proliferation.86 A postmarketing epidemiologic study carried out in Finland did not find an increased risk of breast cancer in 17,360 LNG IUS users.87 But no prospective data are available regarding recurrence risk after breast cancer. A small retrospective cohort study reported no increased risk of breast cancer recurrence associated with LNG IUS use, but a subgroup analysis revealed a higher risk for women who developed breast cancer while using LNG IUS and who continued the use after diagnosis.88 In our opinion, patients should be advised to remove LNG IUS and not to restart use after breast cancer diagnosis until additional information regarding safety after breast cancer is available.
Genetic Counseling The risk of BRCA-mutation in patients with breast cancer in Germany 35 years or younger is about 12% (8% BRCA-1, 4% BRCA-2).89 Therefore, genetic counseling and testing should be offered to all of these women. In case of hereditary breast cancer, surgical management and adjuvant therapy is recommended according to standard guidelines. Poly(ADP-ribose) polymerase (PARP)-inhibitors are a new therapeutic strategy for the treatment of cancers with specific DNA-repair defects. Currently they are not recommended for patients outside of clinical trials, but therapy seems to be effective and quite safe.90 In vitro studies found a distinct chemosensitivity profile of BRCA-associated breast carcinomas. Recent data suggest the benefit of new therapeutic strategies containing PARPinhibitors and platinum drugs.91 Retrospective and small prospective studies have shown a high response rate to cisplatin (90%) in neoadjuvant setting in BRCA-mutation carriers,92,93 but results of ongoing trials will provide key information before a change outside of clinical studies. The proof of BRCA-1/-2-mutation results in a multimodal screening program for noncancer-affected relatives including clinical examination, mammography, breast ultrasound, and breastMRI16,17 starting at the age of 25. Affected BRCA-1/-2-mutation carriers have to face an increased risk of contralateral breast cancer (30%-40% in 10 years).94,95 The risk of contralateral breast cancer can be reduced by taking tamoxifen or bilateral oophorectomy.94 Additionally, prophylactic bilateral oophorectomy can reduce the increased risk of ovarian cancer in breast cancer-affected women and, therefore, should be recommended in BRCA-1/-2-mutation carriers with a good prognosis.96 Recently a reduction of mortality was reported also.97 Affected BRCA-mutation carriers require comprehensive counseling and should be referred to centers for familial breast and ovarian cancer.
Conclusion Breast cancer in very young women (⬍35 years) is rare and needs multidisciplinary treatment. The prognosis of this age group is worse than that of older women. Although limited information is available, the following recommendations can be given for clinical management: 1. Diagnostic Procedures ● breast ultrasound, digital mammography ⫹ biopsy in case of suspicious lesion; ● no indication for routine MRI before surgery; ● multimodal screening including MRI starting at age 25-30 for BRCA-1/-2-mutation carriers, in case with a strong family history and after chest radiation in childhood or adolescence. 2. Local Treatment ● not different from current common guidelines. 3. Adjuvant Chemotherapy ● polychemotherapy almost always indicated. 4. Adjuvant Endocrine Therapy ● tamoxifen 20 mg/day 5 years; ● GnRHa /aromatase inhibitors in clinical trials. 5. Fertility Preservation ● information and if necessary start fertility preservation measures before starting systemic therapy; ● no ovary protection by GnRHa during chemotherapy (inconsistent data). 6. Pregnancy Associated Breast Cancer ● immediate imaging/ biopsying of suspicious masses; ● after first trimester surgery including SLN biopsy and chemotherapy like in nonpregnant women; ● during pregnancy no radiotherapy, endocrine treatment or trastuzumab. 7. Pregnancy After Breast Cancer ● optimal time point is unclear; ● no bad effect on prognosis for breast cancer and pregnancy outcome if woman becomes pregnant at least 6 months after diagnosis; ● breast feeding is possible (if not taking tamoxifen). 8. Contraception ● no hormonal contraceptives; ● LNG IUS should be removed and not be inserted after diagnosis (lack of data). 9. Genetic Counseling ● should be offered to all women with breast cancer ⬍ 35 years. All these points must be considered and discussed with very young patients to ensure optimal treatment. Further important topics, not only for very young patients with breast cancer, are psychologic care, sexual problems, and the management of side effects.
Disclosure All authors have no conflict of interest.
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