Elsevier

The Breast

Volume 23, Issue 3, June 2014, Pages 209-220
The Breast

Original article
First international consensus guidelines for breast cancer in young women (BCY1)

https://doi.org/10.1016/j.breast.2014.03.011Get rights and content

Abstract

The 1st International Consensus Conference for Breast Cancer in Young Women (BCY1) took place in November 2012, in Dublin, Ireland organized by the European School of Oncology (ESO). Consensus recommendations for management of breast cancer in young women were developed and areas of research priorities were identified. This manuscript summarizes these international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA).

Introduction

Young women with breast cancer face not only the threat of a potentially fatal illness and burdensome treatment, but they have the added burden of unique concerns. Most concerning, young women on average experience increased risk of recurrence, both local and systemic, and death after a diagnosis of breast cancer [1]. This is due in large part to their increased risk of presenting with biologically aggressive types of cancer (i.e., more high grade when ER + disease, increased Her-2-positive and triple negative disease) and at more advanced stage [2], [3], [4], [5], [6]. The biologic, medical and psychosocial underpinnings of this disparity in disease outcomes are an area of active research, particularly whether or not young age alone will remain an independent prognostic factor as we improve our understanding of molecular subtyping of breast cancer. Nevertheless, one of the consequences of this reality is that young women often need and receive aggressive multimodality treatments (i.e., surgery, radiation, chemotherapy, biological therapies and endocrine therapy as appropriate), each of which can cause significant side effects and impact on quality of life. Young women are usually pre-menopausal at diagnosis and systemic therapy may cause amenorrhea (either permanent or temporary, with associated menopausal symptoms) and infertility, a substantial problem for women who are interested in having biologic children in the future. Young women are also more likely to harbor a genetic predisposition to breast cancer (e.g., a BRCA 1 or BRCA 2 mutation) than older women, especially if triple negative, which may impact on their local treatment decisions, considerations for prophylactic contralateral mastectomy and salpingo-oophorectomy, and future risks [7], [8], [9]. Further, likely due in part to the issues raised previously, the relative lack of peer support and information available for young women, as well as their developmental stage in life, young women with breast cancer are at increased risk of psychological distress at diagnosis and in long-term follow-up [10], [11]. Additionally, some young women may be at risk of being overtreated based solely on age, increasing the burden of breast cancer diagnosis and treatment.

The evidence base for treatment of young women with breast cancer is limited given the demographics of the disease. Women aged younger than 40 at diagnosis represent fewer than 7% of women diagnosed with breast cancer in developed countries [12]. While young women do participate in research studies, there are rarely enough young women in any given study to focus on this subset and results to inform the treatment of young women are generally derived from findings among women of older age. In recent years, there have been an increasing number of prospective studies focused on young women, however there remains an urgent need for intervention studies, in particular, to understand and improve outcomes in this population [3], [13], [14]. For the purpose of these recommendations, consistent with prior guidelines focused on young women [15], the panel decided to define “young women” as women under the age of 40 at breast cancer diagnosis out of recognition that these women have specific issues including those related to fertility, genetics and psychosocial concerns that often deserve a different approach compared to older premenopausal and post-menopausal women.

Section snippets

Methodology

Prior to the BCY1 Conference, a set of preliminary recommendation statements on the care of young women with breast cancer were prepared building mainly on the previous work of members of the EUSOMA guidelines [15]. These recommendations were circulated to panel members by email for comments and corrections on content and wording. A final set of statements was presented, discussed and voted on during the consensus session of BCY1. All panel members were instructed to vote on all questions; with

General considerations when caring for young women with breast cancer (Table 2)

The care of women with breast cancer in the modern era has become increasingly complex and generally requires input from a number of specialists with expertise in surgery, medical oncology, radiation oncology, and other areas. Specialized breast clinics have allowed for a focused, multidisciplinary approach, to the care of women with breast cancer in general [17], [18]. In no population is this need more evident and likely to be valuable than in young women with breast cancer given their

Diagnosis, imaging, and staging

Young women are more likely to present with a mass or symptom due to the lack of screening programs and to inadequate imaging for their frequently dense breasts [5], [23]. Screening for breast cancer in young women including women with hereditary risks was beyond the scope of the guideline panel. However, the panel did discuss the presentation of breast cancer in young women and whether there was evidence to support an alternative approach to diagnostic imaging in young women compared with

Genetic counseling and testing (Table 3)

Genetic counseling and testing allows for the identification of women who are at dramatically increased risk of new primary breast cancer and ovarian cancer; further it has implications for the cancer risks of their relatives. Thus, genetic counseling and testing is prudent for all young patients recognizing that 10–15% of unselected patients diagnosed under the age of 35 will harbor a BRCA 1 or BRCA 2 mutation [28]. Further, young women with breast cancer are also at risk of having more rare

Surgery

Breast conserving surgery (BCS) followed by radiotherapy (RT) provides the same long-term survival benefit as modified radical mastectomy in women with stage I–II breast cancer, despite a significantly higher rate of local recurrences [31]. Young age is an independent risk factor for increased local recurrence [32], [33]. The available evidence in young women suggests breast conservation followed by radiotherapy is associated with an acceptable local recurrence rate and a survival rate similar

Radiotherapy

Long-term side effects of radiotherapy to organs at risk (i.e. ipsilateral lung, heart and contralateral breast) are particularly relevant in young women with their potential long-term survival. Modern techniques and high quality standards are therefore mandatory in order to minimize risks/maximize benefits.

An additional boost to the site of local excision must be offered after BCS and whole breast radiotherapy to all young patients given that they are at particularly high risk for local

Adjuvant systemic treatment (Table 5)

Recent evidence suggests that the currently available gene expression signatures add prognostic information to classic clinico-pathologic factors irrespective of age [4], [6], [48], [49]. Prospective data from the two major randomized trials MINDACT and TailorX are awaited to reassess the prognosis and benefit of chemotherapy according to age and tumor biology in the modern era. Taking the above into consideration, the panel believes young age alone should not be a reason to prescribe more

Neoadjuvant endocrine therapy

Neoadjuvant ET should not be proposed to young women outside clinical trials. The limited available evidence suggests that the combination of an aromatase inhibitor and a LH-RH analog can be effective but definitive randomized confirmation is warranted [50], [51].

Endocrine therapy (ET)

Young women with invasive hormone receptor-positive (HR+) breast cancer should be considered for adjuvant tamoxifen regardless of age, lymph-node status or chemotherapy administration [22], [52], [53], [54]. The magnitude of benefit of 5 years of tamoxifen on disease recurrence and mortality is similar for younger as compared to older women and comparable benefits are also reported in very young (<35 years) women irrespective of the lower rate of permanent amenorrhea following adjuvant

Bisphosphonates

The ABCSG 12 demonstrated that adjuvant zoledronic acid, in young patients rendered post-menopausal by GnRH analog, reduced risk of disease-free survival events overall (HR 0.68, 95% CI 0.51–0.91; p = 0.009) at 62 month follow-up, although the difference was not significant in the tamoxifen (HR 0.67, 95% CI 0.44–1.03; p = 0.067) and anastrozole arms (HR 0.68, 95% CI 0.45–1.02; p = 0.061) assessed separately [65]. Further, zoledronic acid did not significantly affect risk of death (30 deaths

Neo/adjuvant chemotherapy

There is no evidence to recommend a specific chemotherapy regimen for young women requiring neo/adjuvant chemotherapy: when ER status is taken into account, age disappears as an independent prognostic factor for the benefit of chemotherapy, with part of the efficacy due to rates of amenorrhea induced by the different regimens [63]. In the last EBCTCG meta-analyses involving taxane- or anthracycline-based regimens, proportional risk reductions were little affected by age [69]. Based on their

Adjuvant anti-HER-2 therapy

There is no evidence to recommend a specific regimen for young women with HER-2 early breast cancer: the benefit of adjuvant trastuzumab appears independent of age in all published studies. Analysis of age and short term outcome in the HERA trial has demonstrated women of all age groups, including very young women, appear to derive similar benefit from adjuvant trastuzumab [6].

Side effects of adjuvant therapy

Overall, young women are not a high-risk group for morbidity of chemotherapy except ovarian failure. However, in a Swedish cohort, the incidence of secondary non-hematologic malignancies ≥30 years after breast cancer diagnosis was specifically elevated among younger women at initial diagnosis [73]. In view of the longer life expectancy of young women, the panel strongly suggests particular attention should be paid to potential additional long-term toxicities (i.e. cardiovascular, bone

Advanced breast cancer (ABC) (Table 6)

For the purpose of the Conference and these recommendations ABC in young women is defined as metastatic disease diagnosed <40 years old.

In the United States, the incidence of breast cancer with distant involvement at diagnosis increased in 25–39-year-old women from 1.53/100.000 in 1976 to 2.90/100.000 in 2009 and the 5-year US survival rate for distant disease for 25–39-year-old women is only 31%, compared with 87% for women with loco-regional breast cancer. In addition, ABC as a proportion of

Endocrine therapy

Endocrine therapy is the preferred option for HR+ disease, unless there is concern or proof of endocrine resistance (i.e. early relapse under adjuvant endocrine therapy) or need for rapid disease and/or symptom control. A meta-analysis comparing GnRH analogs ±tamoxifen showed that the outcomes were significantly improved in patients who received the combination [75].

The combination of GnRH analogs and AIs has proven to be active in small Phase II studies [50], [76], [77]. In addition, in a

Chemotherapy and biological therapy for advanced disease

Therapeutic recommendations should not differ from those for older women with the same disease characteristics. Young age by itself is not an indication to prescribe combination chemotherapy over sequential use of monotherapy. However, the unique medical (e.g., risk of pregnancy) and psychosocial concerns (e.g., body image, hair loss) of young women should be addressed when caring for them in the metastatic disease setting.

BRCA mutation carriers (Table 7)

The panel felt strongly that it is imperative that the oncology providers clarify during the decision-making process that (i) there is no clear evidence that therapeutic mastectomy plus contralateral risk-reducing mastectomy has an impact on survival in a woman with a hereditary cancer syndrome with existing breast cancer and, (ii) breast imaging is a screening/surveillance tool for detecting early disease whereas surgery is a risk-reducing procedure for reducing the risk of the development of

Supportive and follow-up care (Table 8)

In principle, follow-up care in young women should follow the same guidelines as in older women [106]. Supportive treatment of specific symptoms/side effects should also follow current recommendations as for older women.

Young women face specific psychosocial and sexual issues that should be addressed by a multidisciplinary group of providers including breast nurses, breast oncologists, gynecologists and fertility experts among others. In many settings, breast nurses are of crucial importance

Conclusions

Treatment of breast cancer in young women is not substantially different from other age groups because loco-regional and systemic therapy recommendations are mainly based on the stage and biology of the tumor, both in the early and advanced disease setting. However, management of these women must emphasize and address different issues specific to their age and life situation. Fertility and pregnancy-related issues are confined to this age group; long-term toxicities of treatment and

Conflict of interest

Conflict of interest is given in Supplementary Table 1.

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