老年患者：被乳腺癌临床研究遗忘的角落？
2016年7月18日，美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表北卡罗来纳大学莱恩伯格综合癌症中心、以色列瑞本医院、美国希望之城综合癌症中心的述评指出，乳腺癌临床研究必须纳入老年患者人群。
美国人口逐渐老龄化，75岁以上人群在半个世纪内增加了3倍，会导致乳腺癌老年人数量显著增加，但是这些人群在临床研究中经常被排除。
由于缺乏老年患者，临床研究导致对癌症患者群体结局和毒性相关知识的严重不足。这些临床研究数据导致1998～2016年美国食品药品管理局（FDA）批准6种乳腺癌靶向治疗药物上市，但是大多数注册临床研究均未纳入很多老年人，尤其是75岁以上的患者。
这些注册临床研究只纳入了8%的老年人，尽管该年龄组占了美国乳腺癌患者的20%。
在有关人类表皮生长因子受体2（HER2）阳性的注册临床研究中，这种差异更为显著，75岁以上患者只占了1%～2.5%，尽管该年龄组患者占HER2阳性患者的14%。
除了数量上的局限性，纳入临床研究的老年人也倾向于具有较好健康状况，这就限制了数据结果用于广泛的老年人群。
J Clin Oncol. 2016 Jul 18. [Epub ahead of print]
Targeted Therapies in Older Adults With Breast Cancer: What Do We Know?
Shlomit Strulov Shachar, Arti Hurria, Hyman B. Muss.
Lineberger Comprehensive Cancer Center, Department of Medicine, University of North Carolina, Chapel Hill, NC; Rambam Health Care Campus, Haifa, Israel; City of Hope Comprehensive Cancer Center, Duarte, CA.
Over the past decade, there has been a dramatic increase in Food and Drug Administration (FDA) -approved targeted therapies for breast cancer. In the Unites States, breast cancer incidence rises dramatically with age, with median ages at diagnosis and death of 62 and 68 years, respectively.[1] In addition, our population is aging rapidly, and the number of individuals 75 years of age and older will triple by 2050.[2] This will result in substantial growth in the number of older adults with breast cancer who are suitable for these new therapeutic options. But the older adult cancer population remains underrepresented in clinical trials, which has led to major gaps in knowledge regarding outcomes and toxicity in this ever-expanding group of cancer patients. Recently, ASCO, recognizing a critical need identified by the Institute of Medicine, developed recommendations for improving the evidence base for treating older adults with cancer.[3] As a group, older adults are more vulnerable to the adverse effects of cancer when compared with younger patients, in large part because of their higher incidence of comorbidities, their frequent use of many concomitant medications, and age-associated physiologic changes that may affect organ function. According to the Centers for Disease Control and Prevention, approximately 80% of older adults have one chronic condition, and half have two or more.[4] In a study that examined the enrollment of older adults in trials that led to the approval of new cancer agents (2007 to 2010), the representation of older patients was much lower than expected on the basis of the actual distribution of this population in the SEER database.[5] In this correspondence, we review the participation of older adults with breast cancer in registration trials of newer targeted agents.
Data that led to FDA approval of six targeted agents for breast cancer between 1998 and 2016 were reviewed, focusing on the patient population, agent, treatment arms, primary end point, number of participants, and participants older than 65 and 75 years of age on the basis of the FDA prescribing information.[6] These agents included trastuzumab (1998), lapatinib (2007), everolimus (2012), pertuzumab (2012), ado-trastuzumab emtansine (2013), and palbociclib (2015; Table 1). There was a significant underrepresentation of older adults in most of these FDA registration studies. This was particularly true for patients 75 years and older: only 8% were included in registration trials, whereas this age bracket comprises 20% of all patients with breast cancer in the US population[9] (Table 1). In most of the registration trials for human epidermal growth factor receptor 2-positive tumors, the percentage of patients 75 years and older was 1% to 2.5% (Appendix Fig A1B); however, patients with breast cancer who are 75 years of age and older comprise 14% of the human epidermal growth factor receptor 2-positive populaton.[9] In addition to lower numbers, older patients in these trials tended to have excellent performance status, which limits the generalizability of these data to the general population.
Table 1. Efficacy Trials for Targeted Therapy: Drug, Arms, Primary End Point Results, and Elderly Patients' Participation
Fig A1. Participation of patients ≥ 75 years old in registration trials by phenotype. (A) Patients ≥ 75 years old with HR positive/HER2 negative metastatic breast cancer registration trials and percent in phenotype population. (B) Patients ≥ 75 years old with HER2 positive metastatic breast cancer registration trials and percent in phenotype population. (*) The percentage of patients ≥ 75 years old for the same phenotype on the basis of SEER data; adapted from Howlader et al.[9] (+) Absolute number of patients in the intervention arm. HER2, human epidermal growth factor receptor 2; HR, hormone receptor; TDM-1, ado-trastuzumab emtansine.
One example that emphasizes the importance of an adequate sample of older patients is the study that led to the approval of everolimus for metastatic hormone receptor positive breast cancer, in which 40% of patients were 65 years and older (N = 290; Appendix Fig A1A). Here, older age was associated with greater toxicity data (higher discontinuation and death compared with patients younger than 65 years old), a major consideration for clinicians recommending this agent for older patients.[10] For pediatric patients, the FDA requires pharmaceutical companies to comply with the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act if they wish to label their drugs safe for children. In return, the pharmaceutical manufacturers receive an additional 6 months of exclusivity. This legislation has resulted in significant increases in toxicity and efficacy data for new treatments in the pediatric setting and it is estimated that in the past decade, more new drugs have been studied in children than in the preceding five.[11] Similar legislation for older patients would be a major step forward in filling the knowledge gap regarding the safety of new agents in older patients with cancer.
We strongly support the ASCO task force recommendations for filling the knowledge gaps for new agents in older patients with cancer. This includes expanding clinical trials to include adequate samples of older patients (this can be performed after efficacy data are obtained), increasing the authority of the US FDA to require or incentivize research in older patients, supporting legislation for geriatric patients similar to that for pediatric patients, and encouraging journals to specifically provide the outcomes for older patients taking part in therapeutic trials.[5] Moreover, new trials in older patients should include the effects of treatment on quality of life and functional status.
REFERENCES
SEER: SEER stat fact sheets: Female breast cancer. http://seer.cancer.gov/statfacts/html/breast.html
United Nations Department of Economic and Social Affairs: World population ageing 2015. http://www.un.org/en/development/desa/population/theme/ageing/WPA2015.shtml
Hurria A, Levit LA, Dale W, et al. Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement. J Clin Oncol. 2015;33:3826-3833.
Centers for Disease Control and Prevention Helping people to live long and productive lives and enjoy a good quality of life. http://stacks.cdc.gov/view/cdc/6114
Scher KS, Hurria AUnder-representation of older adults in cancer registration trials: Known problem, little progress. J Clin Oncol. 2012;30:2036-2038.
US Food and Drug Administration, Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.
Cristofanilli M, Turner NC, Bondarenko I, et al., Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425-439.
Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106:dju055.
Food and Drug Administration Everolimus prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s036lbl.pdf
Christensen ML Best pharmaceuticals for children act and pediatric research equity act: Time for permanent status. J Pediatr Pharmacol Ther. 2012;17:140-141.
DOI: 10.1200/JCO.2016.68.8242