ABSTRACT: Breast cancer among young women is rare and often associated with high-risk features. Age alone has been shown to be an independent risk factor for recurrence, although the biologic explanation for the increased risk among younger women remains unknown. Due to the higher risk of recurrence and otherwise typically good health of young women with breast cancer, one must carefully consider both the maximally effective approach to treatment and the potential long-term consequences of therapy. This manuscript focuses on the clinical decisions that we confront when considering systemic therapy for young women with early-stage breast cancer and the evolving data to guide the care of these patients.
Breast cancer is the most common cancer in women, with over 180,000 new diagnoses of invasive disease annually in the United States, based on recent estimates.[1] Despite advances in therapy, over 40,000 women still die of breast cancer each year in the US.[1] While most women with breast cancer present with early-stage, potentially curable disease, young women face higher risks of recurrence and death compared to older women, which leads to challenges in selecting the optimal treatment strategy for these patients. The clinician is typically confronted with an otherwise healthy patient facing a life-threatening disease, and we are inclined to offer therapies with maximal benefit and minimal longterm toxicity, in the face of frequently inadequate or evolving data on how to achieve this.
This manuscript will review the challenge of managing breast cancer in women under 40 years old, the therapeutic choices facing us in the clinic, and emerging data from recent clinical trials.
Is Breast Cancer in Women Under 40 a Different Disease?
Given an otherwise similar cancer presentation, should women under 40 be treated differently from older women on the basis of age alone? The answer is not entirely clear. Even the age range that should be viewed as being at higher risk is somewhat controversial, with women under 35, 40, or 45 classified as “young” in different studies.[2-4] While breast cancer in women under 40 is rare, accounting for roughly 6.5% of all cases, it is more likely to be associated with high-risk features than the cancers seen in older women.[5] In addition, breast cancer in women under 40 may signal a BRCA mutation—and testing should be considered in all young patients— but for most young women a specific etiology is not identified.
Breast cancers in young women are more likely to be estrogen receptor–negative and of higher grade.[6,7] Several studies suggest that HER2-positive disease is more common in younger women.[2,8] In addition, young African-American women are more likely to have triple-negative breast cancer (estrogen receptor–negative, progesterone(Drug information on progesterone) receptor–negative, and HER2-negative) compared to older women and to young Caucasian women.[9] Age also appears to play a role in risk of recurrence, independent of other disease features.[10]
A recent study by Anders and colleagues suggests that there may be biologic pathways common to tumors from women under 45 compared to those from women over 65.[2] This research identified differential expression within sets of genes related to cell signaling, survival, immune function, and other possible correlates of tumor pathogenesis that appeared to distinguish tumors in younger women from those in older women. Further investigation is needed to clarify whether any ofthese differences represent a specific high-risk feature of cancers prevalent in younger women but present in some older women vs a common process in all younger women with breast cancer. The latter possibility would suggest a need to view breast cancer in this population as a distinct breast cancer subtype.
At a minimum, it is clear that there are as yet unidentified biologic factors contributing to a higher risk of recurrence for young women with breast cancer. Even if these factors are neither present in all cancers in younger women nor confined to this age group, they still require us to consider more rather than less treatment for this patient population. When appropriate, we also need to discuss emerging treatment strategies and/or participation in clinical trials with these patients. This bias toward what many call “aggressive” treatment should, however, be tempered by the fact that women under 40 are also at higher risk for long-term consequences of initial treatments, and for many of our interventions the side effects 20 years and farther down the road are unknown.
Endocrine Therapy and Other Options
Considerations for Systemic Therapy in Young Women With Endocrine Receptor–Positive Breast Cancer
For premenopausal women with early-stage endocrine receptor–positive disease, standard therapy includes tamoxifen(Drug information on tamoxifen) for 5 years. This strategy is supported by an analysis from the Early Breast Cancer Trialists’ Collaborative Group suggesting a 47% improvement in disease-free survival compared to no endocrine therapy, and a sustained improvement in overall survival of approximately 30% at 15 years, regardless of age.[11,12] Deferring for a moment the challenging question of chemotherapy, major questions for young women with endocrine receptor–positive breast cancer include: (1) How long should we continue tamoxifen? (2) Should we add ovarian suppression? (3) Is the use of aromatase inhibitors plus ovarian suppression superior to tamoxifen plus ovarian suppression? (4) Should we conduct CYP2D6 testing for tamoxifen metabolism? and (5) Should we add adjuvant bisphosphonate therapy (Table 1)?
Duration of Treatment
The standard of tamoxifen for 5 years is based on studies comparing 5 years to 1 or 2 years of therapy, finding 5 years superior in terms of disease-free and overall survival.[12] In addition, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial randomized over 1,000 women with endocrine receptor– positive, lymph node–negative breast cancer completing 5 years of tamoxifen to 5 additional years of therapy vs placebo, and found no difference in outcomes, regardless of age.[13]
Two large studies—the adjuvant Tamoxifen Treatment offer more (aTTom) and Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trials—are continuing to explore the optimal duration of tamoxifen therapy. Although both trials are complicated by a pragmatic community- based design, variable initial duration of tamoxifen therapy, and unclear endocrine receptor status for some patients, these trials will provide data on close to 20,000 patients randomized to stopping tamoxifen (at 4 to 5 years for most patients) vs 5 additional years of therapy.
To date, with roughly 7,000 patients, the aTTom trial demonstrates no significant difference in recurrence risk for 10 vs 5 years of tamoxifen, but a small increase in the risk of endometrial cancer with longer therapy.[14] On the other hand, in a preliminary report of the ATLAS trial, results from over 11,000 patients showed a small benefit in disease-free survival but no difference in overall survival.[15]. At this time, the standard duration of therapy remains 5 years, and further data from these large trials are anticipated. Pending these results, it is reasonable to discuss the pros and cons of additional years of treatment and the limits of data in this area with individual patients who face a high risk of recurrence.
| • | Does breast cancer in women under 40 merit a different approach to therapy? |
| • | How do we balance reduction of recurrence risk and long-term effects of treatment among young women with breast cancer? |
| • | What steps beyond standard therapy merit consideration in young women at highest risk? |
For patients at highest risk of recurrence who experience permanent ammenorhea due to chemotherapy, clinicians should consider the data from the MA.17 trial showing reduction in recurrence risk from 5 years of letrozole(Drug information on letrozole) (Femara), an aromatase inhibitor (AI), following 5 years of tamoxifen.[16] This trial included women rendered postmenopausal due to chemotherapy or ovarian ablation; some form of ovarian ablation/ suppression or frequent monitoring of menopausal status should be implemented if AI therapy is pursued.[17]
Should We Add Ovarian Suppression?
Ovarian suppression is one of the oldest known therapies for breast cancer.[18] The benefits of ovarian suppression alone have been reviewed previously.[19] Whether the addition of ovarian suppression to tamoxifen is more beneficial than tamoxifen alone is currently unclear.[20] This question is being addressed in the Suppression of Ovarian Function Trial (SOFT), in which patients are randomized to tamoxifen, tamoxifen plus ovarian suppression, or an AI plus ovarian suppression; the design of this trial reflects the clinical uncertainty in this area. Several randomized clinical trials, including the ongoing Tamoxifen/ Exemestane(Drug information on exemestane) Trial (TEXT) and the recently reported Austrian Breast Cancer Study Group (ABCSG) 12 trial,[21] have adopted ovarian suppression plus tamoxifen as the standard control arm for comparison with ovarian suppression plus an AI.
Patients who experience temporary or permanent amenorrhea secondary to chemotherapy have a lower risk of recurrence than patients who experience no cessation in menses, and this difference has long been attributed to the endocrine effects of chemotherapy.[22] Presumably, a similar benefit should be seen through administration of ovarian suppression. There is both a greater rationale for administration of ovarian suppression among young women who may not experience the endocrine benefits of chemotherapy, and reason for caution and concern with the quality of life and late effects of early menopause in these patients. Routine use of ovarian suppression among young women with endocrine receptor–positive breast cancer is not recommended, but this author considers it a reasonable topic for discussion and consideration in select patients at high risk for recurrence.[20,23]
Is an AI-Based Strategy Superior to Tamoxifen?
Although AIs are a standard component of adjuvant endocrine therapy for postmenopausal women, their role in adjuvant therapy for younger women, if any, remains unclear. There may be important biologic differences between cancers that arise in pre- and postmenopausal settings and differences in the effect of further estrogen deprivation (above and beyond ovarian suppression), as opposed to estrogen receptor blockade with tamoxifen. As noted above, the SOFT and TEXT trials will address this question. Recent data from the ABCSG 12 trial found no benefit for ovarian suppression plus an AI vs ovarian suppression plus tamoxifen. Thus, tamoxifen remains the standard.[ 21] For young women with endocrine receptor–positive disease who are unable to tolerate tamoxifen or who have a strong contraindication to such therapy, treatment with an AI plus ovarian suppression can be considered a reasonable alternative. The lack of differences in the ABCSG trial is reassuring, although the study was not powered for noninferiority.
Some women will develop permanent or prolonged amenorrhea after treatment with chemotherapy, but AIs may increase the likelihood of ovarian recovery, making concurrent treatment with ovarian suppression—or, at minimum, frequent monitoring of menopausal status—important.[24]
