Phase 2 prospective open label study of neoadjuvant nab-paclitaxel, trastuzumab, and pertuzumab in patients with HER2-positive primary breast cancer.

BACKGROUND: The objective of this study was to evaluate the safety and efficacy of nab-paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy (NAT) in patients with human epidermal growth factor receptor 2 HER2+ breast cancer (HER2+ BC) to determine pathologic complete response (pCR), invasive disease-free survival (iDFS), and overall survival. METHODS: Forty-five patients with HER2+ BC Stages II-III were to be enrolled from 2013 to 2017. Patients were treated with weekly nab-paclitaxel (100 mg/m2 intravenously), weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg), and six cycles of pertuzumab (840 mg loading dose, then 420 mg intravenously day 1 every 21 days). RESULTS: Median follow-up was 60 months (95% CI, 32.3-55.6) and pCR was 29/45 (64%). The 5-year iDFS for patients who achieved pCR (N = 29) was 96.3% (95% CI, 76.5-99.5) and non-pCR patients (N = 16) was 74.3% (95% CI, 39.1-91.0). The 5-year overall survival (N = 45) was 94.1% (95% CI, 77.6-98.5). Based on hormonal status, the 5-year iDFS for HR+ pCR patients (N = 14) was 92.3% (95% CI, 56.6-98.9) and for HR- (N = 15) was 100% (p = .3). CONCLUSIONS: This anthracycline/carboplatin-free regimen with nab-paclitaxel achieved a pCR rate of 64% in patients with HER2+ BC. The 5-year iDFS in patients with and without pCR was 96.3% and 74.3%, respectively. The pCR rate is comparable with docetaxel, carboplatin, trastuzumab, and pertuzumab therapy in the NAT setting, but with fewer treatment-associated toxicities. This finding suggests the possibility of safe avoidance of anthracyclines and carboplatin as components of NAT in patients with HER2+ BC.

Phase II Study Combining Pembrolizumab with Aromatase Inhibitor in Patients with Metastatic Hormone Receptor Positive Breast Cancer.

This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2- MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3-46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone.

A Randomized Trial of Fulvestrant, Everolimus, and Anastrozole for the Front-line Treatment of Patients with Advanced Hormone Receptor-positive Breast Cancer, SWOG S1222.

PURPOSE: Metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is an important cause of cancer mortality. Endocrine treatment with or without additional targeted therapies has been the mainstay of treatment. This trial was designed to evaluate the combination of fulvestrant plus everolimus versus fulvestrant, everolimus, and anastrozole compared with fulvestrant alone in the first-line treatment of advanced HR-positive, HER2-negative breast cancer. PATIENTS AND METHODS: This randomized placebo-controlled trial included postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no prior systemic therapy for metastatic disease. Participants were randomized to one of three treatment arms and the primary outcome was progression-free survival (PFS), comparing combinations of fulvestrant and everolimus with or without anastrozole with fulvestrant alone. Circulating tumor cells (CTC), as measured with two different methods, and circulating tumor DNA (ctDNA) were evaluated serially prior to treatment and the beginning of the second cycle of therapy. RESULTS: Due in part to changes in clinical practice, the study was closed after accruing only 37 participants. There was no evidence that everolimus-containing combination treatment improved PFS or overall survival relative to fulvestrant alone. When modeled continuously, an association was observed of baseline CTC and ctDNA with poorer survival. CONCLUSIONS: Although power of the study was limited, the findings were unable to support the routine use of everolimus combination endocrine therapy in the first-line treatment of advanced hormone-sensitive breast cancer. Prognostic impact of baseline ctDNA and copy-number variations in CTC was demonstrated.

Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer.

BACKGROUND: CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with stage IV HR+ HER2- MBC were enrolled and treated with palbociclib, pembrolizumab and letrozole. Primary end-points were safety, tolerability and efficacy. RESULTS: Between November 2016 and July 2020, 23 patients were enrolled with 20 evaluable for response, including 4 patients in cohort 1 and 16 patients in cohort 2. Cohort 1 median age was 48 years (33-70) and cohort 2 median age was 55 (37-75). Cohort 1 closed early due to limited accrual. Grade III-IV adverse events were neutropenia (83%), leucopaenia (65%), thrombocytopenia (17%) and elevated liver enzymes (17%). In cohort 1, 50% achieved a partial response (PR) and 50% had stable disease (SD). In cohort 2, 31% achieved complete response (CR), 25% had PR and 31% had SD by Response Evaluation Criteria in Solid Tumours version 1.1. Median progression-free survival was 25.2 months (95% confidence interval [CI] 5.3, not reached) and median overall survival was 36.9 months (95% CI 36.9, not reached) in cohort 2 with a median follow-up of 24.8 months (95% CI 17.1, not reached). A correlative immune biomarker analysis was published separately. CONCLUSION: The combination of palbociclib, pembrolizumab and letrozole is well tolerated, and a complete response rate of 31% was identified in HR+ MBC patients who received this combination as front-line therapy. Confirmatory trials are required to better understand the immune-priming effects of CDK4/6 inhibitors.

Integrating Academic and Community Cancer Care and Research through Multidisciplinary Oncology Pathways for Value-Based Care: A Review and the City of Hope Experience.

As the US transitions from volume- to value-based cancer care, many cancer centers and community groups have joined to share resources to deliver measurable, high-quality cancer care and clinical research with the associated high patient satisfaction, provider satisfaction, and practice health at optimal costs that are the hallmarks of value-based care. Multidisciplinary oncology care pathways are essential components of value-based care and their payment metrics. Oncology pathways are evidence-based, standardized but personalizable care plans to guide cancer care. Pathways have been developed and studied for the major medical, surgical, radiation, and supportive oncology disciplines to support decision-making, streamline care, and optimize outcomes. Implementing multidisciplinary oncology pathways can facilitate comprehensive care plans for each cancer patient throughout their cancer journey and across large multisite delivery systems. Outcomes from the delivered pathway-based care can then be evaluated against individual and population benchmarks. The complexity of adoption, implementation, and assessment of multidisciplinary oncology pathways, however, presents many challenges. We review the development and components of value-based cancer care and detail City of Hope's (COH) academic and community-team-based approaches for implementing multidisciplinary pathways. We also describe supportive components with available results towards enterprise-wide value-based care delivery.

Phase II Trial of Neoadjuvant Carboplatin and Nab-Paclitaxel in Patients with Triple-Negative Breast Cancer.

BACKGROUND: In this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients with newly diagnosed stage II-III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m2 ) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS). RESULTS: Sixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune-hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune-hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01-25.68; p = .002) and 8.95 (95% CI, 2.09-38.23; p = .003), respectively. CONCLUSION: The combination of carboplatin and nab-paclitaxel for early stage high-risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune-hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: NCT01525966 IMPLICATIONS FOR PRACTICE: Platinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple-negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, "immune-hot" GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune-hot GSIS with higher pCR holds promise for de-escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.

Use of HER2-Directed Therapy in Metastatic Breast Cancer and How Community Physicians Collaborate to Improve Care.

The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Clinical trials can be completed more rapidly by expanding trial enrollment to community sites. In this article we review some of the challenges in treating metastatic breast cancer with HER2-directed therapies and our strategies for incorporating our community partners into the research network.

Strategies to Improve Participation of Older Adults in Cancer Research.

Cancer is a disease associated with aging. As the US population ages, the number of older adults with cancer is projected to dramatically increase. Despite this, older adults remain vastly underrepresented in research that sets the standards for cancer treatments and, consequently, clinicians struggle with how to interpret data from clinical trials and apply them to older adults in practice. A combination of system, clinician, and patient barriers bar opportunities for trial participation for many older patients, and strategies are needed to address these barriers at multiple fronts, five of which are offered here. This review highlights the need to (1) broaden eligibility criteria, (2) measure relevant end points, (3) expand standard trial designs, (4) increase resources (e.g., institutional support, interdisciplinary care, and telehealth), and (5) develop targeted interventions (e.g., behavioral interventions to promote patient enrollment). Implementing these solutions requires a substantial investment in engaging and collaborating with community-based practices, where the majority of older patients with cancer receive their care. Multifaceted strategies are needed to ensure that older patients with cancer, across diverse healthcare settings, receive the highest-quality, evidence-based care.

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

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.

Exploring characteristics, predictors, and consequences of fear of cancer recurrence among Asian-American breast cancer survivors.

BACKGROUND: To address the fear of cancer recurrence (FCR) research gap, we used prospective data to explore FCR predictors and FCR associations with health-related quality of life among Asian-American breast cancer survivors (BCS). METHODS: A total of 208 diverse Asian-American BCS completed T1 survey, and 137 completed T2 survey after 1 year. RESULTS: Fear of cancer recurrence scores (range = 0-4) were 2.01 at T1 and 1.99 at T2 reflecting low-to-moderate FCR. Scores of FCR were stable over the 1-year period (t(126) = .144, P = .886). Multiple regression analyses showed that Chinese women reported lower FCR both at T1 (t(193) = -2.92, P = .004) and T2 (t(128) = -2.56, P = .012) compared to other Asian women. Also, more positive health care experience at T1 predicted lower FCR at T2 (ß = -.18, P = .041). Controlling for other covariates, greater FCR at T1 predicted poorer outcomes 1 year later including lower physical (ß = -.31, P < .001), emotional (ß = -.37, P < .001) and functional (ß = -.16, P = .044) well-being and health-related quality of life specific to breast cancer at T2 (ß = -.31, P < .001). CONCLUSIONS: We found substantial consistencies and some divergences between our findings with Asian-American BCS and the existing literature. This prospective investigation reveals new information suggesting that Asian-American subgroup variation exists and health care system factors may influence FCR. Thus, FCR studies should consider Asian subgroupings, cultural aspects, ie, level of acculturation and health care system factors including provider-patient communication and treatment setting. Future research may benefit from contextualizing FCR within a broader distress framework to advance the science and practice of patient-centered and whole-person care.

Phase Ib Trial of mFOLFOX6 and Everolimus (NSC-733504) in Patients with Metastatic Gastroesophageal Adenocarcinoma.

OBJECTIVES: Based upon preclinical data showing synergy with mTOR inhibition and platinum chemotherapy, this study explores the safety and tolerability of combining everolimus with mFOLFOX6 for patients with metastatic gastroesophageal adenocarcinoma. METHODS: Eligible patients with metastatic gastroesophageal adenocarcinoma received standard-dose mFOLFOX6 chemotherapy in combination with escalating doses of everolimus. RESULTS: Six patients were accrued to the first dose level of 2.5 mg everolimus daily with mFOLFOX6. Overall, the toxicity profile was manageable with expected grade 3 toxicities of mucositis and neutropenia. The dose-limiting toxicity (DLT) included a week delay in therapy greater than 7 days as a result of the first 2 courses of mFOLFOX6. Two patients experienced DLTs at the first dose level due to delays in their treatment caused by prolonged grade 2 neutropenia and fever with fatigue. They were allowed to continue with a dose reduction of their chemotherapy. The median overall survival and progression-free survival were 20.3 and 14.5 months, respectively. CONCLUSIONS: The combination of mFOLFOX6 and everolimus is an active regimen with 83% of the patients experiencing a partial response. p53 mutations were found in the 5 samples analyzed.

Aromatase inhibitor-associated arthralgia and/ or bone pain: frequency and characterization in non-clinical trial patients.

BACKGROUND: The frequency of aromatase inhibitor (AI)-associated arthralgia and/or bone pain in clinical practice is not known. PATIENTS AND METHODS: Fifty-six consecutive patients with breast cancer not on clinical trials who were receiving AIs in a clinical practice were interviewed regarding occurrence of worsening or new arthralgia and/or bone pain after starting AI therapy. The occurrence, character, severity, and resolution of pain were evaluated. RESULTS: Arthralgia and/or bone pain was reported in 61% of patients. It was severe in 30%, continuous in 41%, central in 50%, peripheral in 79%, and resulted in discontinuation of the drug in 20% of patients. Effective therapies in controlling pain were acetaminophen, 29%; nonsteroidal anti-inflammatory drugs, 50%; opiates, 18%, and glucosamine in 15% of patients. Despite this, 20% of patients discontinued AI therapy because of pain. CONCLUSION: Aromatase inhibitor-associated pain is more frequent in patients not in clinical trials than previously appreciated in clinical trials. Improved patient education is needed, and prompt therapeutic management of pain is required to ensure continued drug treatment and improved quality of life.

Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer.

Human epidermal growth factor receptor-2 (HER2/erbB-2) is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival and differentiation via multiple signal transduction pathways. Amplification of the HER2 gene occurs in 20-25% of human breast cancers. This amplification event is an independent adverse prognostic factor as well as a predictive factor for increased response to doxorubicin-based combination chemotherapy, response to trastuzumab and decreased response to hormonal therapy. Methods for detecting protein overexpression or gene amplification in clinical tumor specimens include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques, with the latter considered by some to be more accurate. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody which targets an epitope in the extracellular domain of the HER2 protein. Preclinical models demonstrated that this antibody has significant anti-tumor activity as a single agent and has synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancer that overexpress HER2 have shown that trastuzumab has clinical activity when used as first-, second- or third-line monotherapy, and improves survival when used as first-line therapy in combination with chemotherapy. Newer combinations with numerous chemotherapeutic drugs have also shown significant clinical activity in phase II studies. In all of these trials, trastuzumab was generally well-tolerated, but cardiac toxicity (particularly when the antibody was combined with anthracyclines) was an unexpected adverse effect. Although trastuzumab is currently usually administered on a weekly intravenous schedule, evidence suggests that a triple dose of the drug given once every three weeks has a pharmacokinetic profile expected to be equally efficacious. Neither the optimal schedule nor the optimal duration of trastuzumab therapy has yet been clearly defined in controlled clinical trials. Current clinical investigations of trastuzumab include its use in both the adjuvant and neoadjuvant settings as well as in combination with other chemotherapy drugs or new biologic targeted agents.