At the recent San Antonio Breast Cancer Symposium (SABCS), there was exciting information about new drugs, but a lack of information about how they should be used in our older patients.
Among the high-profile oral presentations at San Antonio this year, there was little specific to older women, despite the fact that the majority of our patients with breast cancer are postmenopausal and many are age 65 and older. If anything, the need to expand evidence to include older patients in clinical trials or, alternatively, the need for clinical trials specifically for this population was emphasized. (1–3) For instance, on Wednesday morning at the first of the General Sessions, the scientific presentations were kicked off by two exciting presentations describing benefits of tucatinib (GS1-01) and margetuximab (GS1-02). The HER2CLIMB study showed that adding tucatinib, an oral tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of EGFR, to trastuzumab and capecitabine for treatment of HER2+ metastatic breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1, reduced death, progression, and brain metastases rates by about half. Unfortunately, the median age of women in this study was about 55 years and, in subgroup analysis, the benefit was not shown to be significant in women age 65 and older (probably because only 51 of the 275 participants in the trial were 65 or older). Likewise, the median age in the SOPHIA trial of chemotherapy combined with trastuzumab or margetuzimab, a monoclonal antibody similar to trastuzumab but with higher propensity to augment antibody-dependent cellular cytotoxicity and immune activation, was about 55 years. Margetuximab improved progression-free survival by about 25% compared to trastuzumab (p=0.033); the overall survival benefit of about 20% was not statistically significant (p=0.087). Subgroup analysis lacked breakdown of level of benefit by age. These ground-breaking studies will no doubt lead to the approval of new drugs to target HER2+ breast cancers, but with a lack of information about how they should be used in our older patients.
Cardiac Monitoring Even More Important For Older Patients
Cardiotoxicity risk increases with increasing age, for anthracyclines and for anti-HER2 therapies. This was reemphasized in a retrospective study presented by Rushton-Marovac et al (P5-14-11) from Ontario. Among 2,284 patients with HER2+ metastatic breast cancer treated with trastuzumab, cardiac events, defined as new diagnosis of heart failure, cardiomyopathy, or pulmonary edema, were more common in women age more than 60 years (OR 5.21, 95% CI 1.83-14.84, p=0.05).
There were two posters describing work to ameliorate cardiotoxicity during breast cancer treatment, one with statins and the other with beta blockers. These studies augment what is known from past work (4), but did not describe results with regard to age or preexisting heart disease or hypertension common in our older patients.
- Vo et al (P5-14-06) presented a systematic review and meta-analysis of statins to mitigate cardiotoxicity of anthracyclines and/or trastuzumab in adjuvant treatment of breast cancer. Among the five studies included, only one was prospective. Data were analyzed for 890 patients treated with anthracycline and/or trastuzumab. Cardiac toxicity, defined as incidence of heart failure or reduction in left ventricular ejection fraction of more than 10% from baseline to an absolute value of <50%, was significantly less likely in women taking statins (6.85% versus 13.89%; RR 0.49, 95% CI 0.31-0.79, p=0.003).
- Livi et al (P5-14-24) presented preliminary results of the SAFE trial (NCT2236805), a 2X2 randomized trial studying use of beta-blockers and/or ACE inhibitors in non-metastatic breast cancer patients treated with anthracyclines. Subclinical heart damage by traditional echocardiogram, pulsed tissue Doppler, global linear strain, or three-dimentional left ventricular ejection fraction, was analyzed in those receiving placebo, bisoprolol (5 mg), ramipril (5 mg), or both. Of the 191 patients enrolled thus far, 123 were available for analysis. The incidence of subclinical heart damage was decreased significantly with both beta blockers and ACE inhibitors and drop-out or dose reduction rates were low.
Caution in Omitting Key Therapy Components
According to guidelines, it is now standard of care to omit adjuvant radiation after breast conserving surgery in women who are age 65 and older who have hormone receptor positive, lymph node negative breast cancer.
Although we clearly acknowledge the prospective randomized trials that showed lack of survival benefit for adding radiation to the management plan of breast conserving surgery and adjuvant endocrine therapy, some of us are hesitant to recommend this approach for all of our patients.(5) This is primarily due to the fact that we realize the small benefit of systemic benefit of adjuvant endocrine therapy and that five, or even 10, years of adjuvant endocrine therapy is recommended, but not adhered to in many women, especially older women.(6, 7)
Wei and colleagues (Abstr P2-18-04) looked into this issue among a “real world” population in their patients at University of Utah.
In their retrospective cohort study of women age 65 and older with clinically node-negative breast cancer who underwent breast conserving surgery, there was 34.5 months follow-up for recurrence, defined as any local, regional, or distant recurrence, but excluding contralateral breast cancers. Among the 484 included patients, median age was 71.9 years, 81% had tumors that were <2 cm in size, 28% did not undergo axillary surgery, and 8% received adjuvant chemotherapy. With regard to endocrine and radiation therapies, 27.4% received endocrine therapy alone, 10.2% received radiation therapy alone, 12.8% received neither, and 47.9% received both. Use of adjuvant endocrine and radiation therapy decreased with age. Interestingly, among the 361 patients who initiated endocrine therapy, discontinuation was associated with not receiving radiation therapy. Among the 276 women treated with lumpectomy and adjuvant radiation, there was no difference in risk of recurrence by use of endocrine therapy, whether adherent to 5 years, initiated but not adherent, or not initiated. Among the 159 women treated with lumpectomy without adjuvant radiation, risk of recurrence was 4 times higher in those not taking adjuvant endocrine therapy and 9 times higher in those who started adjuvant endocrine therapy and stopped early.
So, what does this mean in practice? We can honestly tell our patients who are age 65 and older, who have breast cancer that is 2 cm or smaller and clinically negative nodes, who fit the eligibility criteria for the randomized prospective trials, that their survival will not be improved by adding radiation to adjuvant endocrine therapy after breast conserving surgery. If they do not take or must stop taking endocrine therapy early, however, the risk of recurrence is higher. The impact of this recurrence on survival in a “real world” setting has not yet been explored. In my practice, older women who are in good health after breast conserving surgery for T1 N0 hormone receptor positive breast cancer typically choose to proceed with radiation, particularly since the duration of adjuvant radiation is now about three weeks. After reviewing pros and cons of radiation versus endocrine therapies, they prefer the short inconvenience to the potential side effects of five years of adjuvant endocrine therapy.
1. Kimmick G. Clinical trial accrual in older cancer patients: The most important steps are the first ones. J Geriatr Oncol. 2016;7(3):158-61.
2. Hurria A, Dale W, Mooney M, Rowland JH, Ballman KV, Cohen HJ, et al. Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol. 2014;32(24):2587-94.
3. Wildiers H, Mauer M, Pallis A, Hurria A, Mohile SG, Luciani A, et al. End points and trial design in geriatric oncology research: a joint European organisation for research and treatment of cancer--Alliance for Clinical Trials in Oncology--International Society Of Geriatric Oncology position article. J Clin Oncol. 2013;31(29):3711-8.
4. Kimmick G, Dent S, Klem I. Risk of Cardiomyopathy in Breast Cancer: How Can We Attenuate the Risk of Heart Failure from Anthracyclines and Anti-HER2 Therapies? Current treatment options in cardiovascular medicine. 2019;21(6):30.
5. Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382-7.
6. He W, Fang F, Varnum C, Eriksson M, Hall P, Czene K. Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer. Journal of Clinical Oncology. 2015;33(20):2262-U59.
7. Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010;28(27):4120-8.