Breast cancer is the leading cause of cancer-related deaths in young women, and survival rates for young women with breast cancer are lower than for older women with breast cancer. This inferior survival is seen in spite of the fact that younger women often receive more aggressive therapy, as detailed in Dr. Peppercorn’s thoughtful review. Furthermore, young women are more likely to suffer psychologically after a breast cancer diagnosis, and young survivors generally have a longer time to experience long-term or late effects of aggressive therapy. Thus, careful consideration of systemic therapy choices for younger women is warranted.
Dr. Peppercorn reviews significant controversies regarding optimal care for young women with breast cancer, emphasizing the fragile balance between maximizing reduction of recurrence risk and minimizing toxicities of prescribed therapies. After describing each major area in which there is uncertainty, the author explains his own relevant clinical practice. He begins with a brief discussion of emerging evidence that breast cancer in young women may be biologically distinct from breast cancer in older women. While Dr. Peppercorn appropriately highlights the value of further research to explore potential unique biologic features of breast cancers in young women, we believe that less breast cancer awareness and diagnostic difficulties in younger women (eg, delays in diagnosis), as well as potentially less adherence with therapy, may also play a role in the poorer outcomes seen in younger women. Further research in these areas is clearly warranted.
Dr. Peppercorn’s article focuses solely on treatment of early-stage disease, which is sensible because there is little age-specific controversy regarding treatment in the metastatic setting. For early-stage disease, however, the limitations of current data produce substantial disagreement regarding several clinical practices. For example, the value of adjuvant bisphosphonate therapy in patients who are not similar to women on the Austrian Breast Cancer Study Group (ABCSG)-12 trial (diagnosed premenopausally, treated primarily with ovarian suppression and tamoxifen/aromatase inhibitor therapy for HER2-negative disease) is unclear. Ongoing trials should address this issue more definitively in more diverse populations.
Based on current data, we recommend 5 years of adjuvant tamoxifen therapy as the standard endocrine therapy for premenopausal women with hormone-receptor–positive breast cancer. Because ovarian suppression can cause severe vaginal dryness, loss of libido, hot flashes, bone thinning, depression, and perhaps even cardiovascular and cognitive impairment in the long term, these concerns and associated declines in quality of life with ovarian suppression must be measured against any potential reduction of risk of disease recurrence (which remains unproven for ovarian suppression in the presence of tamoxifen therapy).
Long-Term Side Effects
Because young women tend to receive more aggressive breast cancer treatment based on their poorer prognoses, fewer comorbidities, and longer life expectancies, they are presumed to be at higher risk for long-term consequences of initial treatments. However, it remains unknown whether the non–menopause-related chemotherapy side effects such as cardiac dysfunction, hematologic malignancy, and neuropathy are more or less severe in a younger vs an older woman in the long term. Research has repeatedly demonstrated that the experience of menopausal transition with breast cancer treatment is associated with menopausal symptoms, sexual dysfunction, and impaired quality of life.[4-6] Ongoing trials of ovarian suppression such as the Suppression of Ovarian Function Trial (SOFT) will investigate whether younger premenopausal patients experience worse side effects and also receive more benefit from ovarian suppression than older premenopausal patients because they possess greater ovarian function at baseline.
It will be important to continue to study the long-term impact of premature menopause on bones, cognition, and cardiovascular health at different ages. As Dr. Peppercorn notes, we do not have 20- or 30-year follow-up data for many current breast cancer therapies. Rates of heart failure soon after treatment are higher in women over age 65, but the impact of current regimens on cardiac function many years later is unknown. An assessment of acute toxicities from breast cancer chemotherapy found that older patients had more hematologic toxicity and higher rates of death during chemotherapy. Similarly, blood clots and uterine cancer associated with tamoxifen therapy are extremely rare in women under 40 but more common in elderly women.
Although a recent analysis of rates of malignancies following breast cancer in more than 400,000 women in the Surveillance, Epidemiology and End Results (SEER) database showed an increased relative risk of leukemia associated with younger age at diagnosis (classified as under 50), this finding may simply reflect higher rates of chemotherapy usage in a younger population. Lost fertility due to chemotherapy is certainly problematic for premenopausal women who have not completed their desired childbearing, and concerns over infertility may be significant following breast cancer. Attention to this issue and referral to a reproductive specialist should be considered for young women who are interested in fertility preservation.
While there is growing evidence for the importance of the CYP2D6 genotype in determining the benefit of tamoxifen because certain mutations prevent optimal metabolism of tamoxifen into active metabolites, there has been little study of this gene in young women. Data regarding whether hot flashes predict adequate metabolism of tamoxifen are mixed in postmenopausal populations, and virtually nonexistent in premenopausal populations. Furthermore, it is unclear whether premenopausal women who are poor metabolizers should be switched to ovarian suppression with an aromatase inhibitor or should just have ovarian suppression added to tamoxifen. Ongoing research should help to determine the importance of CYP2D6 testing in younger women.
Many questions remain regarding the optimal treatment of young women with early-stage breast cancer. Fortunately, we expect ongoing research to inform clinical decision-making for this vulnerable population in the future. In the meantime, as Dr. Peppercorn recommends, we should continue to share with patients what is known and what is unknown about any particular intervention in the care of young women (and older ones!). In this way, we can assist patients in making informed decisions that are consonant with their preferences and values in the face of uncertainty.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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