Breast cancer and aging: Standing on the shoulders of a giant

Abstract

With the aging of the US population, the number of individuals age 65 or older who will be diagnosed with breast cancer is expected to rise. Despite this, older adults with breast cancer remain severely under-represented in cancer clinical trials. Numerous studies have highlighted disparites in care experienced by older patients with breast cancer. Dr. Arti Hurria was one of the most influential leaders in oncology to shed light on this vunerable and growing population. By uniting the fields of geriatrics and oncology, she brought together a powerful community of like-minded individuals and, through collaborative research, pioneered the current day approach and care of older patients with cancer. In this review, we highlight Dr. Hurria’s contribution in breast oncology. Specifically, we describe her work on functional and cognitive effects of breast cancer therapy, shared-decision making, toxicity risk prediction, and breast cancer therapeutics.

1. Introduction

Despite her numerous achievements and accolades on the academic stage, Dr. Arti Hurria credited her time spent with patients as her greatest professional reward. She once stated that “time with my patients is the most precious and satisfying time of the week.” Her research was driven by questions that directly pertained to patients she saw in clinic. “I recognized how important it was for geriatricians to be immersed in and contribute to clinical oncology practice.” To that end, she built a network of investigators in geriatric oncology through the formation of the Cancer and Aging Research Group (CARG). With partnership and collaborative research, she bridged the two worlds of geriatrics and oncology to find answers to clinically meaningful questions she had in the clinic. In particular, as a breast cancer specialist, Dr. Hurria’s scientific contributions have informed the care of the growing number of older patients with breast cancer, including: understanding the functional and cognitive effects of cancer therapy; highlighting the importance of shared-decision making by incorporating patient preferences; identifying risk factors that predict chemotherapy toxicity; and evaluating the efficacy and safety of breast cancer therapeutics.

2. Understanding the functional and cognitive effects of cancer therapy in older patients with breast cancer

Early in her career, Dr. Hurria recognized that older patients with breast cancer represent a vulnerable population. Patient with early stage breast cancer, in particular, are vulnerable because of the delicate balance that exists between breast cancer treatment and side-effects that potentially impact both short- and long-term quality-of-life. Dr. Hurria’s research has contributed significant knowledge regarding the functional and cognitive effects of cancer treatment in this population.

2.1. Functional status

In a prospective longitudinal cohort study (N = 50), Dr. Hurria evaluated chemotherapy toxicity, quality-of-life, and functional status experienced by older women (age > 65) with Stage I-III breast cancer receiving adjuvant chemotherapy [1]. A geriatric assessment was performed before the start of chemotherapy, upon completion, and 6 months after completion. In addition, chemotherapy toxicity was recorded and quality-of-life testing, measured utilizing the validated Functional Assessment of Cancer Therapy in breast cancer patient (FACT-B) scale, was performed during these same time periods. The mean age of participants was 68, with a majority of patients (69%) receiving cyclophosphamide/methotrexate/5-FU (CMF) regimen, and the remainder anthracycline-based therapy. The rate of grade 3–4 toxicities in this cohort was 53%, with a 23% risk and 31% risk of hematologic and non-hematologic grade 3–4 toxicities respectively. However, despite these toxicities, no significant longitudinal change in functional status as measured by geriatric assessment or quality-of-life was noted from the time period prior to chemotherapy to 6 months after. This study was amongst the earliest to integrate a geriatric assessment in patients receiving chemotherapy. It showed that this tool can provide helpful information to treating physicians. Dr. Hurria’s seminal work here was the foundation of a large body of evidence that would ultimately lead to the establishment of guideline based recommendations for the routine integration of a geriatric assessement into clinical practice.

Dr. Hurria expanded this work by exploring the impact of chemotherapy on functional status in secondary analyses of CALGB 49907 study – a multi-center randomized trial comparing the efficacy of standard chemotherapy (either CMF or anthracycline-based) with the oral flurouracil prodrug, capecitabine, in women with Stage I-III breast cancer aged 65 and older [2]. She sought to understand risk factors for functional decline in older women with breast cancer receiving adjuvat chemotherapy as well as the degree of resilience, or ability to return to pre-chemotherapy fuctional status, in this population. Dr. Hurria analyzed self-reported changes in physical function, comparing the results of the physical function subscale of the European Organization of Research and Treatment of Cancer Quality and life (EORTC) questionnaire pre-chemotherapy, post-chemotherapy, and 12 months after chemotherapy initiation. Functional decline was defined as a >10-point decrease from baseline at each time point. Resilience was defined as a return to within 10 points of baseline. Association of pretreatment characteristics with physical function change were examined through a multivariable regression analysis. This study revealed that nearly one-third of patients experienced functional decline from baseline (pre-chemotherapy) to 12 months after. Of the 42% of participants who had physical function decline from pre-chemotherapy to the post-chemotherapy, only 47% recovered by 12 months. Risk factors for functional decline prior to chemotherapy were pre-treatment fatigue (p = 0.02), pre-treatment dyspnea (p = 0.007) and being unmarried (p = 0.001). Dr. Hurria’s work highlighted the critical need for new strategies to identify and prevent functional decline in older adults receiving chemotherapy. Furthermore, this study underscored the need for more research to better understand the patient population coined as being “resilient,” and why some patients recover their physical function after treatment while others do not.

2.2. Cognitive status

Furthermore, Dr. Hurria was amongst a few researchers who recognized the potentially negative impact of both chemotherapy and endocrine therapy on the cognitive function in older patients with breast cancer. She published a systematic review in 2007, highlighting the existing but limited literature on cognitive impairment associated with chemotherapy treatment in patients with breast cancer and identified older adult breast cancer patients to be at particular risk [7]. In her review, she noted that there were 4 methodological areas that were barriers to the proper assessment of chemotherapy associated cognitive dysfunction in older patients receiving adjuvant systemic therapy including: (1)lack of representation of older adults on therapeutic trials in this setting and need for a longitudinal study design; (2)challenges of adequate screening of neuropsychological function on account of cumbersome assessments; (3)need for a consensus in defining a decline in cognitive function; (4)the determination of the degree of cognitive decline that is clinically relevant in regard to imparting downstream effects on functional, psychological and quality-of-life outcomes.

During her time at Memorial Sloan Keterring Cancer Center, Dr. Hurria and colleagues conducted an early longitudinal pilot study evaluating the effect of chemotherapy on cognitive function. Neuropsychologic and functional assessments were collected before and 6 months after chemotherapy [8]. Of the 31 patients recruited, 28 patients were evaluable with testing that measured attention, verbal memory, visual memory, verbal, spatial, psychomotor and executive function. The mean age of participants was 71 years old, with a majority having Stage II/III breast cancer. Of the women who participated, 39% experienced a decline in scores 2 standard deviations below the normal, with 50% experiencing no change and 11% having improved. Exploratory analysis revealed no significant difference between functional status, comorbidity and depression scale scores, or change in overall quality-of-life scores before or after chemotherapy. She performed a separate study of 45 patients in this same group to determine perceptions of older patients with breast cancer regarding the impact of adjuvant chemotherapy on cognitive function [9]. The squire-memory self-rating questionnaire was administered before and 6 months after chemotherapy to measure their perceptions on the ability to learn new information, working memory and remote learning abilities; 51% of participants perceived a decline in memory from before to 6 months after the completion of chemotherapy. Those who perceived having a poorer memory than average prior to chemotherapy were more likely to report further memory deterioration after chemotherapy as compared to women who perceived that their memory was average or better than average prior to chemotherapy. The domain of memory that was the most likely to be affected was the ability to learn new information (in 49% of participants), compared to remote memory (20%) and working memory (29%). Both studies illustrated an appreciable impact on subjective and objective cognition, which was acknowledged by Dr. Hurria as requiring prospective validation, with the ultimate goals of identifying particular subgroups at risk and ultimately devising interventions to target this population.

Another impactful line of Dr. Hurria’s research examined the potential use of neuroimaging to evaluate longitudinal changes in cognition. Along with Dr. Bihong Chen at City of Hope, Dr. Hurria conducted a study looking at the longitudinal changes in cognition in older women receiving adjuvant chemotherapy as they correlated with brain magnetic resonance imaging (MRI) [10]. They enrolled 16 patients with breast cancer (mean age of 67) and 14 age/sex-matched healthy controls (mean age 67.8). Patients had stage I-III breast cancer and received standard-chemotherapy regimens, including docetaxel and cyclophosphamide (TC, n = 7) and other non-TC regimens (n = 9). All participants underwent neuropsychological testing and brain MRI prior to chemotherapy, and again one month after the last infusion. As compared to healthy controls, no significant differences in brain volumes were observed in the chemotherapy-treated patients (p > 0.05). However, analysis did reveal a greater volume reduction in the temporal lobe in those treated with TC as compared to non-TC chemotherapy and healthy controls (p = 0.0004). Similarly, the TC group had a decrease in oral reading recognition scores compared to the non-TC group (p = 0.07) and healthy controls (p = 0.09), supporting the need for larger studies to focus on the differential impact of adjuvant regimens in this setting. In a separate analysis of this same study, Dr. Hurria and colleagues also demonstrated that there were appreciable and significant changes in brain gray matter density before and after adjuvant chemotherapy [11].

Dr. Hurria also performed a similar study utilizing neuroimaging looking the impact of endocrine therapy on cognitive function [12]. This specific study evaluated the effect of endocrine therapy with aromatase inhibitors on cognitive function over a 6-month period in a cohort of patients aged 60 and older compared to age-matched healthy controls, also evaluating changes in regional cerebral metabolism as measured by positron emission tomography (PET) scans of the brain done in a subset of the cohort. As compared to the healthy controls, no significant decline in cognition measured by neuropsychological battery was seen breast cancer patients treated with ndcorine therapy between baseline assessment and 6-month follow-up. However, in the patients receiving PET scans during this period, regionally specific changes in cerebral metabolic activity were detected that could potentially have clinical implications over time, and raised an opportunity for further study.

3. Treatment preferences and shared-decision making in older adults with breast cancer

Interactions with patients in the clinic regarding the complex, shared-decision about adjuvant systemic therapy led Dr. Hurria to another path of research. She realized that the decision about adjuvant systemic therapy was particularly complex in the older patient because healthcare providers may have specific biases. She also understood that older patients’ personal values and preferences differed from those of younger patients.

One study on this topic highlighted that, despite the lack of evidence-based guidelines for the treatment of older patients, physicians had specific opinions about treatment of early-stage breast cancer in older patients. Dr. Hurria and colleagues utilized an on-line survey with questions pertaining to hypothetical patients of varying ages (age 70, 75 and 80) and health status (good, average and poor) with Stage II-III breast cancer [3]. The method of generalized estimating equations was used to determine the effect of patient age and health status on the survey participants’ adjuvant treatment recommendations. 151 oncologist and 158 primary-care providers completed the survey, with several noteworthy findings. For one, they found that a majority of both oncologist and primary care providers recommended some form of adjuvant therapy for all patients of any health status, though the recommendation for adjuvant chemotherapy was less likely as age increased or health status declined (p < 0.0001). In a specific scenario involving patients with Stage III, hormone-receptor negative, HER2 amplified breast cancer, oncologists were less likely to recommend the combination of chemotherapy and trastuzumab overall, and more likely to recommend either trastuzumab alone or no therapy in patients with advanced age and deteriorating health status [4]. Similar trends were seen in patients with Stage III hormone-receptor positive, HER-2 negative breast cancer, where oncologists were less likely to recommend the combination of chemotherapy and endocrine therapy (p < 0.0001) and more likely to recommend endocrine therapy alone in patients with advanced age (p < 0.0001) and deteriorating health status (p < 0.0001) [5]. In regard to endocrine therapy choice, aromatase inhibitors were more likely to be recommended over tamoxifen (p < 0.01) irrespective of age or health status. This study provided valuable insights into the practices patterns of systemic therapy in older adults with breast cancer, underscoring the need for older adult-specific clinical trials that would provide healthcare providers with needed evidence-based guidance for this population.

Furthermore, Dr. Hurria focused on incorporating the patient preference as part of the shared-decision making process. In a substudy of CALGB 49907, Dr. Hurria and her colleagues analyzed the role of patient preference on quality-of-life and clinical outcomes in older patients with breast cancer receiving adjuvant chemotherapy [6]. In this study, a subset of 145 women completed questionnaires to look at the association of pre-treatment preferences with patients’ perception of self-health, reduced and actual quality-of-life, patient and professional reported toxicity, mental health, self-rated function and survival during and after treatment. They found that low preference for chemotherapy was associated with lower quality-of-life mid-treatment, worse social, emotional and physical function (p < 0.02) and higher rates of grade 3–5 adverse events (p < 0.02), financial worries (p < 0.05). Interestingly, all changes resolved after treatment, aside from financial worries that persisted at 24 months. Chemotherapy preference, was not, however, associated with worse survival. Data from this study suggested that considering patient preference in treatment may help providers identify patients at greater risk for complications and distress during treatment.

4. Identifying risk factors for chemotherapy toxicity in older adults with breast cancer

With the support of her collaborators, Dr. Hurria made a major contribution to the field of geriatric oncology through the development of the CARG chemotherapy toxicity model [13]. The CARG chemotherapy risk model is a tool that predicts severe (grade 3–5) chemotherapy toxicity in older adults with cancer, and was prospectively developed and validated based on participation of a heterogenous group of adults with various solids tumors receiving treatment in many different settings. As a breast cancer physician treating a vast population of patients with curative intent, she realized a tool formulated to this specific population was necessary, which would then better inform the decision-making process regarding chemotherapy, whether used in the adjuvant or palliative setting.

Dr. Hurria and colleagues successfully completed a multi-center study with the objective of building upon the CARG score by developing and validating a CARG-Breast cancer (BC) chemotherapy toxicity prediction model, with the additional plan to evaluate its association with dose-modifications, dose reductions and hospitalization [18]. Ultimately, they enrolled 501 patients aged 65 and older with Stage I-III breast cancer from 16 sites (300 patients in the development cohort, and 201 in the validation cohort). The assessments and information captured prior to chemotherapy initiation included the CARG chemotherapy toxicity score, breast cancer tumor/treatment variables, and additional geriatric assessments items. During treatment, grade 3–5 chemotherapy toxicities were captured utilizing the NCI CTCAE v. 4.0 criteria.

In this study, patients were well represented across stages and subtypes, mirroring what is seen in the general breast cancer patient population. The rate of grade 3–5 toxicities was 46%, and the baseline CARG score was found to be significantly associated with grade 3–5 toxicities (p < 0.001; AUC 0.64). The addition of certain breast cancer tumor and treatment variables (e.g. planned duration of treatment, stage of disease, anthracycline-containing vs. alternate regimen, liver function) and geriatric assessment variables (e.g. availability of social support, ability to walk a mile) improved the AUC to 0.76. Scores ranged from 0 to 19 (low risk 0–5, mid risk 6–9, high risk 10+) and were significantly associated with grade 3–5 toxicities (p < 0.001) while Karnofsky performance score was not (p = 0.20). Furthermore, a higher CARG-BC score was associated with dose delay/reduction, chemo discontinuation, hospitalization, and reduced-dose intensity of b85% (all p-values < 0.001). The development of such a tool for older patients with breast cancer can embolden cancer providers to anticipate which older patients are at increased risk of toxicity, improve patient-provider decision making, and help identify interventions to decrease toxicity during treatment.

5. Therapeutic trials in older adults with breast cancer

Aside from being an empathetic clinician devoted to the needs of her patients and innovator in the field of clinical research, Dr. Hurria was a tireless advocate towards the cause of expanding clinical trial enrollment in older adults. She led the U13 conference breast cancer panel, a collaboration between CARG and the National Institute on Aging and the National Cancer Institute with the objective of summarizing recommendations regarding therapeutic clinical trials in the older breast cancer patient population that would fill the vast knowledge gap. In their published report, they emphasized the need to enhance accrual of fit older adults to phase III trials, but also the need to develop dedicated trials for those who were considered more frail or vulnerable [14]. They also stressed that all studies should integrate a geriatric assessment to identify those at particular risk for treatment-related side-effects, and subsequent modifications. Along with colleagues in the Alliance for Clinical Trials in Oncology, Dr. Hurria also authored a publication with Dr. Rachel Freedman describing the experience of the Alliance in the accrual of older adults to breast-cancer specific clinical trials form 1985–2012 [15]. They reported that 17% of participants in these studies were aged 65 and older, ranging from 15 to 24% in the neo/adjuvant to metastatic setting with a smaller representation in those patients who were ≥70 years old. They also noted that the odds of a patient ≥65 years enrolling significantly increased over time for adjuvant trials (odds ratio [OR] per year, 1.04; 95% CI, 1.04 to 1.05) but decreased significantly for neoadjuvant and metastatic trials (OR, 0.62; 95% CI, 0.58 to 0.67 and OR, 0.98, 95% CI, 0.97 to 1.00). Similar trends were seen for those age ≥70 years but these were only statistically significant for adjuvant and neoadjuvant trials (OR, 1.05, 95% CI, 1.04 to 1.07; and OR, 0.57, 95% CI, 0.52 to 0.62). Finally, they showed that older patients enrolled in adjuvant studies tended to have higher-risk disease (more lymph-node involvement and more hormone-receptor negative tumors) in addition to higher rates of early protocol termination (50% in those ≥65 years as compared to 35% in those <65 years). Through their study, they provided succinct evidence for underrepresentation of older adults in clinical trials, highlighting the need for novel strategies to increase accrual.

In line with this mission, Dr. Hurria spear-headed a number of clinical trials evaluating the treatment of older patients with breast cancer in the metastatic setting, which incorporated validated geriatric focused measures and outcomes. One such study was a phase II trial of nab-paclitaxel in older adults with metastatic breast cancer [16,17]. Forty patients aged 65 and older were enrolled in this particular trial, in which they received nab-paclitaxel in the second-line setting (100 mg/m2 IV administered on a 3 week-on, 1 week-off schedule). A geriatric assessment as completed prior to initiating chemotherapy and the validated CARG chemotherapy -toxicity risk score was calculated. The objective was to not only assess clinical response, pharmaco-dynamic and pharmacokinetics, but also the relationship between tolerability (number of courses, hospitalization, dose-reductions and toxicity) and the CARG toxicity score. 31% of patients were noted to have a partial response and 38% stable disease, with a median progress-free survival (PFS) rate of 6.5 months (95%. CI, 5.5 months to undefined). 58% (n = 23) had treatment-related ≥grade 3 toxicities, and 30% (n = 12) were hospitalized owing to toxicity. No differences was seen in the grade 3 toxicity rate on the basis of age (p = 0.75), dose-reductions (p-0.38) and dose omissions (p = 0.39). Patients with intermediate/high CARG toxicity score had higher risk of grade ≥3 toxicity than those with low risk scores (odds ratio, 5.8; 95% confidence interval, 1.3–33.1; P = 0.01). Furthermore, they found that a higher mean risk score was associated with a greater likelihood of requiring dose reductions and undergoing hospitalizations.

In the era of targeted therapy, Dr. Hurria also sought to evaluate the combination of lapatinib and trastuzumab in a phase II trial of older patients with HER2/neu amplified breast cancer [19]. This combination represents a novel strategy to treat patients with a chemotherapy-sparing regimen, yet the seminal studies enrolled very few older patients (only 17% were >/=65, and 1% aged 75 and older). In Dr. Hurria’s study, 40 patients were accrued from 4/2011–5/2015, satisfying the eligibility criteria of an age of >/= 60 years old, and receipt of any number of prior lines of treatment. A standard regimen of lapatinib/trastuzumab was utilized, and pre-treatment assessments were performed that included measures of function, comorbidity, cognition, nutrition and psychosocial status. The overall response rate in this group was 23%, with 23% achieving stable disease, amounting to a PFS of 2.7 months (95% CI 2.5–12). Overall, the combination was found to be well-tolerated in older patients with only 20% experiencing grade >/= 3 toxicities. In terms of toxicity risk score, no significant association was found with treatment toxicity, which was thought explainable by the very low incidence of grade 3 or higher events. However, patients with high toxicity scores as compared to those with low scores were more likely to require a dose reduction of trastuzumab/lapatinib.

Finally, shortly prior to her passing, Dr. Hurria led the design and development and initiation of an ongoing clinical trial in the Alliance (A171601, NCT03633331) that serves as a prototype trial for learning how to design therapeutic, geriatric oncology studies within the National Clinical Trials Network (NCTN). This phase II trial aims to examine the tolerability of palbociclib in combination with letrozole or fulvestrant in patients age 70 and older with estrogen receptor-positive, HER2-negative metastatic breast cancer. This trial will help establish how to test new cancer therapies in a group of older patients across multiple centers, to acquire the data necessary to inform that new drugs will yield an acceptable adverse event profile in this vulnerable population. It serves as a first-step to allow the study of new cancer agents in older patients with cancer within cooperative groups and to help fill in critical knowledge gaps about the safety and efficacy of cancer therapeutics in older adults.

6. Conclusion

Dr. Hurria left an indelible impact on the lives of older adults with breast cancer, starting with the patients she directly cared for, and extending to a larger community who benefitted from her contributions to clinical research. On the larger stage, Dr. Hurria was a dynamic leader at the vanguard of the movement of geriatric oncology. However, she maintained a steadfast dedication to her first role as a physician, ensuring that all her efforts were aligned with her commitment to improve the care of her patients. Her own words are the embodiment of this focus and mission, as she once stated “Love your patients as much as you can. They are in a vulnerable place, and kindness and compassion go such a long way.”