Is Age Truly Relative in HER2-positive Breast Cancer? 


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Perhaps the next most relevant questions are: (1) how do these results correlate with prior reports? and (2) how do these results affect clinical care moving forward?

—Carey K. Anders, MD

Breast cancer arising in younger women has increasingly become the subject of intense study, and often debate, over the past decade. Retrospective studies have illustrated that breast cancer in young women is more commonly an aggressive subtype (ie, triple-negative/basal-like, HER2-enriched), higher grade, lymph-node positive, and associated with poorer outcome compared to that in older counterparts.1-3 Limitations of the large majority of studies informing us on the characteristics and behavior of breast cancer in young women include the retrospective nature of the data collected and the heterogeneity of commonly “outdated” treatment regimens.

Compelling New Data

Partridge et al sought to ask a very relevant question in a recent study published in the Journal of Clinical Oncology in the context of the Herceptin Adjuvant (HERA) Trial: Is age a prognostic and/or predictive factor among over 3,000 patients with early-stage, HER2-positive breast cancer treated with chemotherapy with or without trastuzumab (Herceptin)?4

Perhaps the most compelling and clinically relevant results of this analysis were that (1) age, as either a dichotomous (≤ 40 vs > 40 years) or continuous variable was not prognostic for disease-free survival or overall survival in the chemotherapy/trastuzumab treatment arm; (2) age was not an independent prognostic factor (for disease-free or overall survival) among patients treated with chemotherapy/trastuzumab; and (3) age was not a predictive factor for trastuzumab benefit.

In sum and consistent with guidelines set forth by the FDA, ASCO, and the National Comprehensive Cancer Network, patients across the entire age spectrum with early-stage, HER2-positive breast cancer should be considered for chemotherapy/trastuzumab since they derive equivalent benefit from combination therapy.

Perhaps the next most relevant questions after reviewing this important analysis are: (1) how do these results correlate with prior reports? and (2) how do these results affect clinical care moving forward?

Looking Back

With regard to the first question, several studies have addressed age-related differences in gene expression and prognosis by breast cancer subtype, including the HER2-positive subset. Specifically, a large-scale genomic analysis of over 750 primary breast cancers initially identified over 350 gene sets unique to breast cancers arising in a younger host (≤ 45 years of age as compared to those aged ≥ 65 years) in a non–subtype-specific manner.3

More recently, these data were reexamined and showed that age-specific gene expression differences were negligible when corrected for intrinsic breast cancer subtype and other significant prognostic factors (ie, hormone receptor status, grade, etc).5 Moreover, Azim et al examined the prognostic effect of age among approximately 3,000 patients with early-stage breast cancer and found that patients aged ≤ 40 years (compared with those aged > 40 years) experienced significantly worse recurrence-free survival (P < .0001).6 When the subset of only HER2-positive patients (n = 432) was examined, there was no significant difference in recurrence-free survival by age (P = .42).

Taken together, these data are consistent with and supportive of the findings of Partridge et al that age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy.

Looking Ahead

Moving forward, there are several points to consider. Breast cancer is a disease of aging, with a median age at diagnosis of 61 years.7 As such, one may choose to look at these data from the other side of the age spectrum—ie, that women aged > 40 years, including elders with adequate cardiac reserve, derive similar benefit from chemotherapy and trastuzumab as their younger counterparts.

Additional information that is not apparent from the body of work on age and breast cancer includes the response by age to newer HER2-directed agents, including lapatinib (Tykerb), ado-trastuzumab emtansine (Kadcyla), and pertuzumab (Perjeta), and whether younger women with estrogen receptor–positive and/or triple-negative breast cancer derive similar benefit from anticancer agents (ie, endocrine therapy and/or chemotherapy). Moreover, we will need to assess the effect of age on response to newer small-molecule targeted agents on the horizon (ie, PI3K inhibitors, mTOR inhibitors).

These questions provide fertile areas for research as we continue to close the gap in reducing the impact of age on breast cancer prognosis and improve our ability to provide optimal therapy. ■

Dr. Anders is Assistant Professor of Medicine and Co-Director, UNC Brain Metastases Specialty Clinic, Division of Hematology-Oncology, University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center

Disclosure: Dr. Anders reported no potential conflicts of interest.

References

1. Colleoni M, Rotmensz N, Robertson C, et al: Very young women (<35 years) with operable breast cancer: features of disease at presentation. Ann Oncol 13:273-279, 2002.

2. Carey LA, Perou CM, Livasy C, et al: Race, breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA 295:2492-2502, 2006.

3. Anders CK, Hsu D, Broadwater G, et al: Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancer with shared patterns of gene expression. J Clin Oncol 26:3324-3330, 2008.

4. Partridge AH, Gelber S, Piccart-Gebhart MJ, et al: Effect of age on breast cancer outcomes in women with human epidermal growth factor receptor 2-positive breast cancer: Results from a Herceptin adjuvant trial. J Clin Oncol. June 10, 2013.

5. Anders CK, Fan C, Parker JS, et al: Breast carcinomas arising at a younger age: Unique biology or a surrogate for aggressive intrinsic subtypes? J Clin Oncol 29:e18-e20, 2011.

6. Azim H, Michiels S, Bedard PL, et al: Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res 18:1341-1351, 2012.

7. Howlader N, Noone AM, Krapcho M, et al: SEER Cancer Statistics Review, 1975-2010, National Cancer Institute, Bethesda, Maryland. Based on November 2012 SEER data submission, posted to the SEER website April 2013. Available at http://seer.cancer.gov/csr/1975_2010. Accessed July 17, 2013.


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