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Practical considerations must guide combination treatment for older patients with advanced hormone receptor-positive breast cancer
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An FDA-conducted meta-analysis of CDK4/6 inhibitor trials submitted for FDA registration showed no difference in the efficacy or tolerability of CDK4/6 inhibitors between elderly and younger patients with advanced breast cancer.
This meta-analysis and other articles suggest the PFS benefits of the CDK4/6 inhibitors palbociclib (Ibrance, Pfizer), ribociclib (Kisqali, Novartis) and abemaciclib (Verzenio, Eli Lilly) in combination with endocrine therapy for women with advanced hormone receptor-positive, HER-2-negative breast cancer can be achieved regardless of age.
However, these benefits are accompanied by adverse events not commonly observed with endocrine monotherapy. Examples include neutropenia with palbociclib and ribociclib, and diarrhea with abemaciclib.
Although these events typically are manageable with dose modifications — as evidenced by relatively low rates of discontinuation due to adverse events — the increased monitoring required for treatment with combination therapies may be more burdensome for elderly patients with poor performance status or low mobility.
This highlights the need for individualized decisions when determining the most appropriate therapy for older patients with advanced breast cancer.
Consistent benefits
In a review of clinical trials published last year in Breast Cancer Research and Treatment, we discussed in detail the efficacy and safety of combination treatment for older patients with hormone receptor-positive, HER-2-negative advanced breast cancer.
This review — which reported results in age-stratified subsets — showed consistent PFS benefits for patients who received endocrine therapy plus ribociclib, palbociclib, abemaciclib or the mTOR inhibitor everolimus, regardless of age (Table).
Further, the safety profiles of these agents appeared similar for older and younger patients.
However, higher rates of most adverse events were observed among the older patient subsets.
Despite higher adverse event rates for older patients, we observed similar rates of discontinuation due to adverse events for ribociclib or palbociclib plus letrozole, but not everolimus plus exemestane.
The FDA meta-analysis showed no difference in efficacy according to age using multiple cutoffs (eg, > 65 years, 70 years or > 75 years). Tolerability decreased with age, with results showing discontinuation rates of 8% among those aged younger than 65 years (n = 50 of 625), 16% among those aged 65 years or older (n = 76 of 479), and 17% among those aged 70 years or older (n = 48 of 280).
Although data from clinical trials suggest combination treatment generally is tolerable for older patients with hormone receptor-positive, HER-2-negative advanced breast cancer who met the criteria to enroll in these trials, the number of older patients in these trials was relatively small.
Dedicated trials for older patients likely are necessary to truly understand the efficacy and toxicity of combination treatment for patients with comorbidities or functional limitations.
However, the results from our review are reassuring. Treatment with these novel agents should be considered for older patients, with careful assessment of how any agent would affect quality of life, toxicity risk and efficacy.
Practical considerations
Primary considerations when determining treatment for older patients include their treatment goals, overall life expectancy and functional status.
Health care providers and their patients should consider functional status and other general treatment barriers that may disproportionately affect older patients before determining the most appropriate treatment.
For patients with a short life expectancy due to comorbid conditions, maintenance of quality of life may be more important than delaying breast cancer progression, and symptom management may be most appropriate. However, if delaying progression is a treatment goal, combination treatment including targeted therapies likely will provide greater PFS benefit with tolerable safety and similar quality of life compared with endocrine monotherapy.
When starting therapy for older patients — especially those with poor performance status — it is important to consider the challenges that may be posed by the increased monitoring needs associated with combination treatment relative to endocrine monotherapy, including toxicity assessments, laboratory evaluations and possible drug interactions in the setting of polypharmacy.
Older patients with poor functional status may need to be seen more frequently than patients with good performance status, particularly at the start of therapy for toxicity assessments and laboratory evaluations. If patients are doing well on treatment, it may be possible to reduce the frequency of follow-up visits to a schedule more typical of patients with advanced breast cancer. However, some patients may need to remain on a more frequent follow-up schedule throughout treatment.
In all cases, it is important to involve a patient’s primary care provider so that other conditions can be optimized while on therapy for breast cancer.
To determine the most appropriate treatment and follow-up visit schedule, health care providers should assess supportive care needs for older patients with cancer. Managing these needs may improve patient outcomes and quality of life by enabling patients to remain on therapy.
For example, it is important to ask patients about their social support networks, how they get around on a day-to-day basis, and what their transportation needs are for follow-up visits. If a patient’s functional status is of concern, it is important to ask about home care needs, including the need for assistance with medication or meals.
One tool proven helpful in evaluating a patient’s baseline functional status and risk of toxicity to treatment is the geriatric assessment, a set of validated measures that can be completed by the patient and provider as part of a routine clinical evaluation.
Although multiple studies have demonstrated usefulness of the geriatric assessment for predicting the likelihood of a patient experiencing toxicity on treatment, no standardized data-driven method exists for incorporating the results of these assessments into clinical practice.
Several forthcoming studies aim to address this issue, including an ongoing trial (NCT01472094) of more than 500 patients led by Arti Hurria, MD, vice provost for clinical faculty and director of the Center for Cancer and Aging at City of Hope, as well as a HemOnc Today Editorial Board Member.
The goal of this study is to determine associations between clinical and biological predictors of toxicity and relative dose intensity for patients receiving neoadjuvant chemotherapy, potentially identifying a patient population for whom an alternative treatment may be more appropriate. These results, and results from other trials, will provide guidance on how to optimally incorporate geriatric assessments into clinical practice for patients with cancer.
In conclusion, combination treatment with CDK4/6 or mTOR inhibitors plus endocrine therapy is effective for and generally well tolerated by older patients with advanced breast cancer.
Although there are challenges associated with interpreting clinical trial data from elderly patients with advanced breast cancer, the available data suggest health care providers should not treat patients differently solely because of age but should focus on functional status and frailty.
Treatment decisions must be individualized and unique supportive care needs must be considered for older patients with poor performance status or a high comorbidity burden.
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For more information:
Sara M. Tolaney, MD, MPH, is associate director of Susan F. Smith Center for Women’s Cancers and associate director for clinical research in breast oncology at Dana-Farber Cancer Institute. She can be reached at sara_tolaney@dfci.harvard.edu.
Rachel A. Freedman, MD, MPH, is associate clinical director of the breast oncology center at Susan F. Smith Center for Women’s Cancers, as well as senior physician at Dana-Farber Cancer Institute. She can be reached at rachel_freedman@dfci.harvard.edu.
Disclosures: Tolaney reports institutional research funding from AstraZeneca, Bristol-Myers Squibb, Cyclacel, Eisai, Eli Lilly, Exelixis, Genentech, Merck, Nektar Therapeutics, Novartis and Pfizer, as well as consultant roles with AstraZeneca, Eisai, Eli Lilly, Merck, Nektar Therapeutics, Novartis, Pfizer and Sanofi. Freedman reports grant funding from American Cancer Society and Susan G. Komen, as well as institutional research support from Eisai and Puma Biotechnology.