The Challenge of Selecting Adjuvant Breast Cancer Chemotherapy for Older Patients

Dr. Hy Muss is a well recognized expert in the treatment of elderly women with breast cancer, and his article “Adjuvant Chemotherapy of Breast Cancer in the Older Woman” is an extremely important addition to the limited existing literature on this topic. As he points out, nearly half of all breast cancer diagnoses occur in women over 65 years of age. As the total number of women in that demographic increases with the aging of our population, medical oncologists will be faced with a growing number of elderly breast cancer patients, for whom evidence-based recommendations on treatment are needed. As any medical oncologist who sits face-to-face with these older women knows, it is not acceptable to simply tell the patient that there are inadequate data to guide recommendations for adjuvant chemotherapy in her age group, though this is what the EBCTCG (Early Breast Cancer Trialists Collaborative Group) overview has concluded.[1]

In the article by Dr. Muss, the data shown in Figure 1, depicting the increase in breast cancer incidence and mortality with age, are staggering and underscore the need for improved understanding of how to best treat older women with this disease.

Dr. Muss gives clear, concise advice on how one should approach the difficult problem of selecting adjuvant chemotherapy in an older woman with breast cancer. First, he identifies the two primary considerations in treatment selection: (1) tumor characteristics-including stage and biology, and (2) the patient’s life expectancy. He then addresses the three main breast cancer biologic subtypes: ER+ (estrogen receptor–positive)/HER2−, HER2+ (human epidermal growth factor receptor 2 negative or positive), and triple-negative. The implications of comorbidity and functional limitation on treatment tolerability are also addressed, and opportunities for improving our ability to evaluate these factors are described.

Addressing the Biologic Subtypes

Perhaps the most difficult setting in which to recommend for or against adjuvant chemotherapy is in the elderly woman with an ER+ HER2– breast cancer. As Dr. Muss describes, historic series and meta-analyses demonstrate that the benefit of adjuvant chemotherapy, even in younger groups, is smaller in women with ER+ compared with ER− cancers. For example, in the EBCTCG overview, the relative risk of recurrence for the addition of polychemotherapy to tamoxifen in women 50–69 years of age was 0.85 for ER+ vs 0.75 for ER− disease.[1] Importantly, through the use of gene-expression profiling, we now know that all ER+ HER2-negative cancers are not equal.

Multigene assays such as Oncotype DX have been shown to predict chemotherapy benefit in both node-negative and node-positive patients with ER+ HER2– breast cancers,[2,3] in which patients with low recurrence scores (RS) appear to derive no benefit from addition of adjuvant chemotherapy to tamoxifen, but patients with a high RS derive significant benefit. The benefit in patients with intermediate scores will be clarified in ongoing prospective trials. These data suggest that the chemotherapy benefit in the high RS or luminal B type cancers is perhaps as large as it is in ER– cancers, but that benefit has been diluted in historic series by analyzing those tumors together with the low RS or luminal A cancers.

This may be particularly true when analyzing cohorts of older women. In the analysis of Oncotype DX score in NSABP B-20, 30% of patients were age 60 or over. While there was not a direct analysis of RS and correlation to chemotherapy benefit in this age group, the RS distribution by age was described.[2] In the women aged 60 years and older, 19% had a high RS, while 21% had an intermediate score and 60% a low RS. This demonstrated that among the older women, there were slightly more low RS compared with the younger groups. There was still a sizable proportion with a high RS, however, suggesting that there are substantial numbers of older women who would derive benefit from the addition of chemotherapy. It is hoped that future trials will include analysis of gene-expression profiles, and their correlation to treatment outcome, by age. This is an area of great opportunity in research trial design.

Another important area of interest is in elderly women with HER2-positive cancers. While other HER2-targeted drugs are being used in patients with advanced disease and are now being studied in early-stage disease, trastuzumab (Herceptin) is currently the only HER2-targeted agent approved for early-stage disease. One side effect of great concern with trastuzumab is cardiotoxicity, which appears to increase with age and other cardiac risk factors. Dr. Muss points out that for elderly women, it is important to try to minimize risk of cardiotoxicity by optimizing blood pressure control and diabetes management, and by avoiding other cardiac toxins such as anthracyclines. It would be interesting to study medications such as beta-blockers or ACE (angiotensin converting enzyme)-inhibitors, which are used as cardioprotectants in other disease states, to evaluate their ability to prevent trastuzumab-associated cardiac toxicity.

The triple-negative histology is less common in elderly women compared with younger ones, but it is still seen and is associated with a high risk of recurrence. Dr. Muss advocates that elderly women with triple-negative cancers should be offered adjuvant chemotherapy unless their life expectancy is limited by comorbidities. Importantly, as novel drugs such as the poly-(ADP-ribose) polymerase (PARP)-inhibitors are studied in triple-negative disease, we will need to assess their efficacy and tolerability in elderly populations.

In conclusion, Dr. Muss’s contributions to the field of geriatric breast oncology are well known, and this article adds to that collection. The very common problem of how to best treat an elderly woman with early-stage breast cancer will be made easier by his suggestions, and by continued work in the field.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Early Breast Cancer Trialists Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687–1717, 2005.

2. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor–positive breast cancer. J Clin Oncol 24:3726–3734, 2006.

3. Albain K, Barlow WE, Shak S, et al: Prognostic and predictive value of the 21-gene recurrence score assay in post-menopausal women with node-positive oestrogen-receptor-positive breast cancer on chemotherapy: A retrospective analysis of a randomized trial. Lancet Oncol 11:55–65, 2010.