Daneng Li

Distress in Older Patients With Cancer

PURPOSE To determine the predictors of distress in older patients with cancer. PATIENTS AND METHODS Patients age >or= 65 years with a solid tumor or lymphoma completed a questionnaire that addressed these geriatric assessment domains: functional status, comorbidity, psychological state, nutritional status, and social support. Patients self-rated their level of distress on a scale of zero to 10 using a validated screening tool called the Distress Thermometer. The relationship between distress and geriatric assessment scores was examined. RESULTS The geriatric assessment questionnaire was completed by 245 patients (mean age, 76 years; standard deviation [SD], 7 years; range, 65 to 95 years) with cancer (36% stage IV; 71% female). Of these, 87% also completed the Distress Thermometer, with 41% (n = 87) reporting a distress score of >or= 4 on a scale of zero to 10 (mean score, 3; SD, 3; range, zero to 10). Bivariate analyses demonstrated an association between higher distress (>or= 4) and poorer physical function, increased comorbid medical conditions, poor eyesight, inability to complete the questionnaire alone, and requiring more time to complete the questionnaire. In a multivariate regression model based on the significant bivariate findings, poorer physical function (increased need for assistance with instrumental activities of daily living [P = .015] and lower physical function score on the Medical Outcomes Survey [P = .018]) correlated significantly with a higher distress score. CONCLUSION Significant distress was identified in 41% of older patients with cancer. Poorer physical function was the best predictor of distress. Further studies are needed to determine whether interventions that improve or assist with physical functioning can help to decrease distress in older adults with cancer.

Cancer and Aging: General Principles, Biology, and Geriatric Assessment.

Cancer is a disease of aging as older adults are much more likely to develop cancer compared with their younger counterparts. Understanding the biology of cancer and aging remains complex, and numerous theories regarding the relationship between the two have been proposed. Cancer treatment decisions in older patients are particularly challenging, because the evidence is scarce and the risk of toxicity increases with age. Determination of biologic age is essential due to heterogeneity of functional status, comorbidity, and physiologic reserves between patients of the same chronologic age.

Functional versus chronological age: geriatric assessments to guide decision making in older patients with cancer

As the worldwide population ages, oncologists are often required to make difficult and complex decisions regarding the treatment of older people (aged 65 years and older) with cancer. Chronological age alone is often a poor indicator of the physiological and functional status of older adults, and thus should not be the main factor guiding treatment decisions in oncology. By contrast, a geriatric assessment can provide a much more comprehensive understanding of the functional and physiological age of an older person with cancer. The geriatric assessment is a multidimensional tool that evaluates several domains, including physical function, cognition, nutrition, comorbidities, psychological status, and social support. In this Series paper, we discuss the use of a geriatric assessment-based approach to cancer care, and provide clinicians with tools to better assess the risks and benefits of treatment to engage in shared decision making and provide better personalised care for older people with cancer.

Subcortical brain iron deposition and cognitive performance in older women with breast cancer receiving adjuvant chemotherapy: A pilot MRI study

As the number of older adults in the U.S. increases, so too will the incidence of cancer and cancer-related cognitive impairment (CRCI). However, the exact underlying biological mechanism for CRCI is not yet well understood. We utilized susceptibility-weighted imaging with quantitative susceptibility mapping, a non-invasive MRI-based technique, to assess longitudinal iron deposition in subcortical gray matter structures and evaluate its association with cognitive performance in women age 60+ with breast cancer receiving adjuvant chemotherapy and age-matched women without breast cancer as controls. Brain MRI scans and neurocognitive scores from the NIH Toolbox for Cognition were obtained before chemotherapy (time point 1) and within one month after the last infusion of chemotherapy for the patients and at matched intervals for the controls (time point 2). There were 14 patients age 60+ with breast cancer (mean age 66.3 ± 5.3 years) and 13 controls (mean age 68.2 ± 6.1 years) included in this study. Brain iron increased as age increased. There were no significant between- or within- group differences in neurocognitive scores or iron deposition at time point 1 or between time points 1 and 2 (p > 0.01). However, there was a negative correlation between iron in the globus pallidus and the fluid cognition composite scores in the control group at time point 1 (r = -0.71; p < 0.01), but not in the chemotherapy group. Baseline iron in the putamen was negatively associated with changes in the oral reading recognition scores in the control group (r = 0.74, p < 0.01), but not in the chemotherapy group. Brain iron assessment did not indicate cancer or chemotherapy related short-term differences, yet some associations with cognition were observed. Studies with larger samples and longer follow-up intervals are warranted.

Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single-agent checkpoint blockade

Immune checkpoint inhibitors have demonstrated broad single-agent antitumor activity and a favorable safety profile that render them attractive agents to combine with other systemic anticancer therapies. Pancreatic cancer has been fairly resistant to monotherapy blockade of programmed cell death protein 1 receptor, programmed death ligand 1, and cytotoxic T-lymphocyte associated protein 4. However, there is a growing body of preclinical evidence to support the rational combination of checkpoint inhibitors and various systemic therapies in pancreatic cancer. Furthermore, early clinical evidence has begun to support the feasibility and efficacy of checkpoint inhibitor-based combination therapy in advanced pancreatic cancer. Despite accumulating preclinical and clinical data, there remains several questions as to the optimal dosing and timing of administration of respective agents, toxicity of combination strategies, and mechanisms by which immune resistance to single-agent checkpoint blockade are overcome. Further development of biomarkers is also important in the advancement of combination systemic therapies incorporating checkpoint blockade in pancreatic cancer. Results from an impressive number of ongoing prospective clinical trials are eagerly anticipated and will seek to validate the viability of combination immuno-oncology strategies in pancreatic cancer.

A Phase II Trial of Older Adults with Metastatic Breast Cancer Receiving nab-Paclitaxel: Melding the Fields of Geriatrics and Oncology

Micro‐Abstract nab‐Paclitaxel may be an attractive therapy for older adults because of its efficacy, the infrequency of allergic reactions, and the lack of need for steroid pre‐medications. We evaluated the tolerability and efficacy of nab‐paclitaxel in older adults with metastatic breast cancer, as well as the relationship between a geriatric assessment‐based toxicity risk score and chemotherapy toxicity, dose reductions, dose delays, and hospitalizations. Patients with intermediate/high toxicity risk scores had higher risk of grade ≥ 3 toxicity than those with low risk scores, and a higher mean risk score was associated with higher likelihood of dose reductions and hospitalizations. A geriatric assessment‐based risk score can help weigh the risks and benefits of chemotherapy in older adults, and should be incorporated into future trials testing new therapies in this population. Introduction: Phase II clinical trials including geriatric assessment (GA) measures are critical for improving the evidence base for older adults with cancer. We assessed the efficacy and tolerability of nab‐paclitaxel in older adults with metastatic breast cancer (MBC). Patients and Methods: Patients aged ≥ 65 years with MBC and ≤ 1 previous line of chemotherapy received 100 mg of nab‐paclitaxel on days 1, 8, and 15 of a 28‐day cycle. A GA was completed pre‐chemotherapy, and the validated Cancer and Aging Research Group (CARG) chemotherapy toxicity risk score was calculated. Relationships between tolerability (number of courses, hospitalizations, dose reductions, and toxicity) and risk score were assessed using general linear models, Student t tests, and the Fisher test. Response rate and progression‐free survival were evaluated using the Kaplan‐Meier method. Results: Forty patients (mean age, 73 years; range, 65‐87 years) were included. The median number of cycles was 6, 75% (n = 30) of patients had ≥ 1 dose hold, and 50% (n = 20) had ≥ 1 dose reduction. Fifty‐eight percent (n = 23) had treatment‐related ≥ grade 3 toxicities, and 30% (n = 12) were hospitalized owing to toxicity. Thirty‐five percent (n = 14) responded, and the median progression‐free survival was 6.5 months (95% confidence interval, 5.5 months to undefined). Patients with intermediate/high toxicity risk scores 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 = .01). A higher mean risk score was associated with higher likelihood of dose reductions and hospitalizations. Conclusions: Among older adults with MBC receiving weekly nab‐paclitaxel, more than one‐half experienced ≥ grade 3 chemotherapy toxicity. However, a GA‐based risk score could predict treatment tolerability.

Abstract OT1-02-05: Phase II clinical trial of neratinib in patients 60 and older with HER2 over-expressed or mutated breast cancer: Trial design considerations for older adults

Background: This study addresses a key knowledge gap identified by the Institute of Medicine report on quality cancer care. Although there has been a growth in the number of targeted agents approved for the treatment of breast cancer, there are limited data regarding the efficacy, toxicity, and management of side effects in older adults. Neratinib is a potent oral small molecule tyrosine kinase inhibitor. Early clinical data have demonstrated the activity of neratinib in patients who have already progressed through HER2 targeted therapies. This study is designed to evaluate the tolerability and toxicity profile of neratinib in older adults with metastatic breast cancer (MBC) incorporating geriatric oncology design considerations. Trial Design : This is an open label, single arm, phase II study of single agent neratinib in patients with HER2 positive MBC. Neratinib is given at 240mg orally in 28 day cycles. Unique factors of this geriatric oncology trial design include: 1) pre-treatment and on-treatment geriatric assessment; 2) additional nurse toxicity visits; 3) an algorithm for aggressive management of diarrhea; 4) measurements of the pharmacokinetics (PK) of neratinib; 5) inclusion of biomarkers of aging; 6) measurement of patient adherence; and 7) evaluation of quality of life. Eligibility Criteria: Patients must be age≥60 with histologically-proven HER2 positive MBC or MBC with HER2 receptor activating mutations. There is no limitation on the number of previous lines of therapy, but patients must have adequate organ and bone marrow functions, and a baseline LVEF ≥ 50%. Exclusion Criteria include: prior treatment with neratinib; major surgery within 28 days; uncontrolled cardiac disease; concurrent use of digoxin; or chronic diarrhea. Specific Aims: The primary objective of this study is to identify the rate of grade 2 or higher toxicities attributed to neratinib in adult age ≥60 with HER2 over-expressing breast cancer. The secondary objectives are to describe the full toxicity profile (including all grades of gastrointestinal toxicities); to estimate the rate of dose reduction, holds and hospitalizations; to describe the PK parameters; to estimate the adherence rate to neratinib; and to estimate the overall response, clinical benefit rate, progression-free and overall survival. Furthermore, we will explore the role of a cancer-specific geriatric assessment and serum biomarkers of aging (IL-6, CRP, and D-dimer) in predicting treatment toxicities and PK parameters. Statistical Design: We plan to enroll 40 patients age ≥60 (at least 5 patients age 75 years or older, and no more than 15 patients 60-70) in order to assure that our sample is representative of the entire age range of older adults. Given a sample size of 40 subjects, the widest half-width of the 95% confidence limits for the rate of grade 2 or higher toxicities will be less than or equal to 0.16. An interim analysis will be performed after 20 subjects have been on study for at least one cycle. Accrual goal: 40 Contact information: Yuan Yuan MD PhD, Email: yuyuan@coh.org. Citation Format: Yuan Y, Blanchard S, Li D, Mortimer J, Waisman J, Somlo G, Yost S, Katheria V, Hurria A. Phase II clinical trial of neratinib in patients 60 and older with HER2 over-expressed or mutated breast cancer: Trial design considerations for older adults [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-02-05.

Abstract P4-21-35: Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC)

Background: Pathologic complete response (pCR) to HER2-targeting neoadjuvant therapy (NT) predicts for improved survival (Cortazar et al, Lancet, 2014). The addition of pertuzumab to trastuzumab and docetaxel increased pCR rates, and, as first line treatment for MBC led to longer overall survival ([OS] Swain et al, NEJM 2015). Avoidance of anthracyclines in the adjuvant setting for HER2+ BC reduced the risk of secondary hematologic malignancies without a detriment to OS (Slamon et al, NEJM, 20111). Finally, nab-paclitaxel (nab) might provide an advantage over other taxanes via decreased use of steroids and may lead to increased response rates (RR). We designed a study of pertuzumab (pert), trastuzumab (trast), and nab, testing the feasibility and efficacy of this regimen in the LABC and metastatic breast cancer settings. Materials and Methods: Pts with Stages II-III LABC received six cycles of NT with pert (day 1 q 21 days), trast, and nab 100 mg/m2 (both given IV, weekly). Pts with untreated MBC received the same regimen until progression, toxicities, or patient or physician preference led to stopping therapy. Primary endpoints included pCR (LABC) and RR and progression-free survival (PFS) in MBC. Forty pts with LABC and 25 pts with MBC were to be accrued. The study was designed to test whether the pCR rate of Neosphere (Gianni et al, Lancet Oncol, 2012, > 45.8%) and the PFS rate of CLEOPATRA (median of > 18.5 months) can be matched or exceeded. Procurement of serial samples for assessment of tumor gene expression, circulating tumor cells, miRNA, and serum DNA profiling for exploratory biomarker analysis was carried out. Results:Twenty-two of 28 already enrolled pts with LABC (clinical stage II:15, stage III: 7) completed NT. The median age was 53 (34-77). The pCR rate was 86% (6/7) for hormone receptor negative (HR-) and 40% (6/15) for HR+ pts, with an overall pCR of 55%. Three pts without pCR following NT had residual BC with a HER2 negative phenotype. Eighteen of 22 pts required nab dose modifications. The most frequent toxicities following NT included elevated liver function tests:27%, peripheral neuropathy:23%, hematological toxicities:17%, diarrhea:18%, infusion reactions:18%. In the MBC cohort there were 13 of 16 enrolled pts with > 2 months of follow-up. The median age was 47 (31-65), 62% had HR+ disease. A CR rate of 4/13 (31%) and confirmed RR of 77% were observed. The median number of cycles with pert, trast, nab was 9 (3+ to 41); 11 of 13 pts required dose modifications or delays (3 of the delays were due to primary breast surgery performed upon response to treatment). At a median follow-up of 19 months, PFS and OS estimates are 63% (95% CI 0.09-0.93), and 89% (95% CI 0.61-1.0). Conclusion: The non-anthracycline-containing regimen of pertuzumab, trastuzumab, and nab-paclitaxel induced a high pCR rate in HER2+ BC. PFS is encouraging in MBC. Outcome of the fully accrued cohorts inclusive of residual cancer burden scores in the LABC cohort, and correlative data with exploratory biomarker analysis will be presented. Citation Format: Somlo G, Frankel P, Yeon C, Yuan Y, Yim J, Kruper L, Taylor L, Mortimer J, Waisman J, Jones V, Vito C, Paz B, Huria A, Li D, Gaal C, Tong T, Tumyan L. Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-35.

Age, hepatitis C virus infection, and the risk of cancer: Unlocking a complex puzzle of interactions: Age, HCV, and the Risk of Cancer

An estimated 70% of all cancer diagnoses will occur in patients aged>65 years by the year 2030 as the US population continues to age. Chronologic age has been identified as a risk factor for numerous malignancies. However, understanding the biology of cancer and aging remains complex and is an area of active investigation. Similarly, hepatitis C virus (HCV) infection is of particular concern for older adults. The “baby boomers” (individuals born between 1945 and 1965) currently represent 70% of the estimated 3 million individuals infected with HCV in the United States. Although the association between HCV and hepatocellular carcinoma (HCC) has been well established, the association between HCV and other malignancies is less well known. Furthermore, the mechanistic interactions between age, HCV infection, and the risk of cancer among older adults remain a mystery yet to be solved. In this issue of Cancer, the article by Mahale et al reports on the association between HCV infection and the risk of various malignancies among older adults in the United States. They performed a registry-based case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database in US adults aged 65 years from 1993 to 2011. The results revealed a strong association between HCV infection and cancers of the liver (adjusted odds ratio [aOR], 31.5) and weaker associations between HCV infection and intrahepatic (aOR, 3.40) and extrahepatic (aOR, 1.90) bile duct cancer, pancreatic cancer (aOR, 1.23), anal cancer (aOR, 1.97), nonmelanoma nonepithelial skin cancer (aOR, 1.53), myelodysplastic syndrome (aOR, 1.56), and diffuse large B-cell lymphoma (DLBCL) (aOR, 1.57). The authors concluded that HCV was associated with an increased risk for cancers other than HCC, raising the possibility of an etiologic role for HCV in an expanded group of cancers. The current study by Mahale et al adds to the growing knowledge base regarding potential cancer risks among HCV-infected individuals. In particular, 2 prior large US studies also reported increased incidence rates of various malignancies among all adults with chronic HCV infection. However, the current study is unique, in that it specifically focused on a population of older adults with HCV. This is of particular importance, because greater than 50% of older adults with HCV are either not aware of being infected with HCV or are not treated for HCV. Compared with earlier large US studies, Mahale et al observed similar positive associations between HCV infection and the risk of HCC and pancreatic cancer but no associations with other previously reported cancer types such, as colorectal, kidney or lung cancers. In contrast, associations of HCV infection with biliary cancers and DLBCL were reported in their study that were not previously reported in the 2 other large US studies. The inability to completely account for confounding variables could have contributed to the differences reported among associations between HCV and various nonliver cancers across these 3 large US studies. In addition, the complex biology of the aging process in the context of HCV infection could have played an additional role in the overall differences in cancer risk reported between the various studies. Therefore, understanding the underlying mechanism of how HCV could possibly contribute to carcinogenesis among older adults is essential. Although a definitive mechanism of how HCV-induced carcinogenesis has not been fully elucidated, studies aimed at understanding the link between HCV and HCC development may provide initial clues of the underlying biologic process. In general, it is thought that HCV contributes to HCC development through both direct viral factors as well as indirect induction of chronic inflammation pathways. For example, overexpression of HCV core protein results in inhibition of numerous tumor-suppressor genes, such as tumor protein 53 (TP53) and retinoblastoma 1 (RB1). In addition, it