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There are three US FDA–approved CDK4/6 inhibitors: palbociclib, ribociclib and abemaciclib for patients with HR-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). They are all equally effective, so the question becomes how to choose among these agents and how to sequence them. Other areas with active investigation include identifying predictive biomarkers for the selection of patients whom may benefit more from CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitors after disease progression on CDK4/6 inhibitors, creating novel treatment combinations and expanding use beyond HR+/HER2- MBC. Here, we review the current use of and potential next directions for CDK4/6 inhibitors in the treatment of patients with HR+/HER2- MBC.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer patients. Cancer patients have a four to sevenfold increased risk of VTE compared with non-cancer patients and approximately 20% -30% of all VTE occurs in patients with cancer. Incidence of VTE varies with cancer type and is the highest among patients with metastatic-stage disease. Assessing risk of VTE in the patients with cancer and risk stratification tools as the Khorana score may predict VTE. The highest risk is associated with cancers of the pancreas, stomach, brain, and lung and some hematologic malignancies, whereas lower risks are associated with breast and prostate cancer. The incidence rate ratio (IRR) for prostate cancer is 3.25(2,56 - 4,13) and for pancreas 15.56 (10.50-23.0). We give a case report with a quite perplexing undertaking, where a submassive acute pulmonary embolism (PE) originated from an asymptomatic calf vein thrombosis or intertwined with the Trousseau´s syndrome. Essential Section: One of the authors (A.T) was unexpected faced with the diagnosis of poorly differentiated prostate cancer. There were no signs of the disease, the PSA level was normal. As a retired medical oncologist, he had to care for many patients with prostate cancer and had now to cope with this cancer. To make the matter worse he suffered after the radical prostatectomy a submassive asymptomatic pulmonary embolism. Clinically there were no signs if a deep venous thrombosis. The coincidence of both events without clinical signs of a thrombosis could be caused by the Trousseau´s syndrome. Prostasomes extracellular vesicles synthesizes by prostate cancer cells and secreted into body fluids are prothrombotic by virtue of the expression of polyphosphate-activated coagulation factor XII.

Neratinib is an irreversible, pan-human epidermal growth factor inhibitor that has shown efficacy across human epidermal growth factor receptor 2 (HER2)-positive breast cancer settings. Neratinib is indicated for use as extended adjuvant therapy for HER2-positive early-stage breast cancer or, in combination with capecitabine, in the treatment of HER2-positive metastatic breast cancer. The primary tolerability concern with neratinib is diarrhea, and severe diarrhea early in treatment can lead to a substantial proportion of patients discontinuing neratinib, which may lead to reduced or nonexistent efficacy. In order to establish a set of treatment recommendations for use of neratinib, on May 12, 2020, an expert panel of oncologists and gastroenterologists met virtually to discuss the role of neratinib in the treatment of patients with HER2-positive breast cancer. The panel reviewed the current data on neratinib, including efficacy across settings and diarrhea management strategies. Based on these data and their clinical experience, the panelists developed a set of recommendations to guide selection of patients for neratinib, implement weekly dose escalation at initiation of therapy, and prophylactically manage diarrhea.

Background The US Food and Drug Administration and European Medicines Agency have published guidance for industry on the use of pathologic complete response (pCR) as a surrogate endpoint to accelerate the regulatory approval of neoadjuvant agents in high-risk early-stage breast cancer (EBC). Three meta-analyses, the CTNeoBC consortium (Cortazar 2014), Berruti (2014), and Korn (2016), evaluated the association between the pCR odds ratio and the event hazards ratio but did not identify strong trial-level associations. Thus, uncertainties remain with respect to whether the magnitude of effect-size increase in pCR reasonably predicts long-term clinical benefit. Findings Trial-level data from CTNeoBC were used as the training data set to derive an empirical nonlinear model for predicting long-term outcomes based on pCR results. A Cox regression model was used to evaluate the relationship among treatments, event hazards, and pCR as joint covariates. The trial-level association between treatment and event hazard was derived and then linked with pCR rates. Magnitude of the patient-level association was also included in the analysis. Additional published trials were used to validate the predictive model. Numerical differences between the perfect surrogate prediction and observed effect followed normal distribution based on the Kolmogorov-Smirnov test. For event-free survival (EFS), the Student t- test P value of 0.02 suggested a statistically significant nonzero difference, with a mean value of −0.163 (SE 0.058). For overall survival (OS), the Student t- test P value of 0.0027 suggested a statistically significant nonzero difference, with a mean value of −0.153 (SE 0.038). Three studies, including GeparSixto, BOOG, and Neo-tAnGo, were used for validation. The F test suggested the model fit the test data well. Implications The observed hazard ratios fit well with the predicted hazard ratios for both EFS and OS and suggest plausible trial-level associations with the new predictor. Major findings Our model predicted the correlation between pCR and EFS as well as OS. This model could be used as a supporting tool to help interpret positive pCR results in neoadjuvant clinical studies in patients with high-risk EBC.

Background: nab-Paclitaxel (nab-P)–containing regimens have demonstrated efficacy and safety in triple-negative breast cancer (TNBC). In the absence of a standard of care for metastatic (m) TNBC, tnAcity evaluated the efficacy and safety of 3 common chemotherapy combination regimens: nab-P + carboplatin (nab-P/C) or gemcitabine (nab-P/G) vs G/C as first-line treatment (Tx) for patients (pts) with mTNBC based on a ranking algorithm of efficacy and safety. Results of the phase 2 portion are reported here. Methods: Pts with pathologically confirmed mTNBC, no prior cytotoxic chemotherapy for metastatic disease, and no brain metastases were enrolled. Pts received (1:1:1) nab-P 125 mg/m2 + C AUC 2, nab-P 125 mg/m2 + G 1000 mg/m2, or G 1000 mg/m2 + C AUC 2, all given on d 1 and 8 every 3 weeks. The phase 2 primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), percentage of pts initiating cycle 6 receiving doublet therapy, and safety. Results: 191 pts were included in the phase 2 portion. Median age was 55, 53, and 59 years in the nab-P/C, nab-P/G, and G/C groups, respectively. Overall, 98% of pts had an ECOG PS of 0 - 1, 83% were white, and 48% were treated in North America. Most pts (81%) had relapsed disease. Median Tx duration was 25, 18, and 20 weeks, and 47%, 33%, and 52% of pts had ≥ 1 dose reduction for both agents in the nab-P/C, nab-P/G, and G/C groups, respectively. Key efficacy and safety results are summarized in the table. PFS was significantly longer with nab-P/C vs either nab-P/G or G/C (median, 7.4 vs 5.4 mo, P = 0.03 and 7.4 vs 6.0 mo, P = 0.02). Overall, 179 pts discontinued Tx; of these, 55% discontinued due to progression and 16% due to adverse events (AEs). Grade ≥ 3 AEs in ≥ 10% of pts were mainly hematologic. The rank sum of the algorithm for 5 key weighted efficacy and safety endpoints favored nab-P/C. Table 1 nab-P/Cnab-P/GG/CEfficacyn = 64n = 61n = 66PFS, median, mo7.4a5.4b6.0ORR, %71.937.743.9OS, median, mo16.411.913.7Pts initiating cycle 6 with a doublet, %64.155.750.0Safetyn = 64n = 60n= 64Myelosuppression-related events, %c53.141.767.2Pts discontinuing all Tx due to AE, %18.820.021.9Serious TEAEs, %29.736.737.5Grade ≥ 3 AEs, %Neutropenia40.633.348.4Anemia7.88.315.6Thrombocytopenia4.73.314.1Peripheral neuropathy4.75.01.6Deaths due to TEAE, n (%)1 (2)2 (3)2 (3)a P = 0.03 vs nab-P/G; P = 0.02 vs G/C; b P = 0.85 vs G/C; c Including grade ≥ 3 neutropenia, thrombocytopenia, anemia, bleeding, febrile neutropenia, or red blood cell/platelet transfusion. Conclusions: In this phase 2 study, nab-P/C demonstrated a statistically significant longer PFS and a better risk/benefit profile vs nab-P/G or G/C as first-line Tx in pts with mTNBC. These data demonstrate nab-P/C efficacy in mTNBC and address a relevant question around a nab-P/C chemotherapy backbone for this difficult-to-treat tumor type. Further studies are warranted in the context of immunotherapies and targeted agents. NCT01881230. Citation Format: Yardley D, Coleman R, Conte P, Cortes J, Brufsky A, Shtivelband M, Young R, Bengala C, Ali H, Eakel J, Schneeweiss A, de la Cruz Merino L, Wilks S, O'Shaugnessy J, Glück S, Li H, Beck R, Barton D, Harbeck N. nab-paclitaxel + carboplatin or gemcitabine vs gemcitabine/carboplatin as first-line treatment for patients with triple-negative metastatic breast cancer: Results from the randomized phase 2 portion of the tnAcity trial [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 P5-15-03.

Background Mild to moderate depressive symptoms are common during treatment for non-metastatic breast cancer. The goal of this secondary analysis was to determine if depressive symptoms predict clinical outcomes at long-term follow-up. Methods From 1998 to 2005, we interviewed 231 women with the Hamilton Rating Scale for Depression who were participating in a psychosocial study 2–10weeks post-surgery for non-metastatic breast cancer (Stage 0-IIIb). We conducted Kaplan Meier (K-M) curves and Cox proportional hazards (PH) models to examine associations between depressive symptoms, overall survival, and disease-free survival at 8–15-year follow-up. Results A total of 95 women (41.1%) scored in the mild-moderately depressed range. Non-depressed women had longer overall survival ( M =13.56years; SE =0.26) than those in the mild/moderate depressed group ( M =11.45years; SE =0.40), Log-rank χ 2 (1)=4.41, p =0.036. Cox PH models, adjusting for covariates, showed comparable results: mild/moderate depressive symptoms hazard ratio=2.56, [95% CI, 1.11 to 5.91], p =0.027. Similar results were observed in a subsample with invasive disease (n=191). Depression category did not predict disease-free survival in the overall or invasive sample. Conclusions Screening and referrals for treatment of depressive symptoms, even at subclinical levels, is important early in treatment. A randomized trial is warranted to determine effects of depressive symptoms on clinical outcomes.

With the introduction of anthracycline-based regimens, 5-year survival rates have significantly improved in patients with early-stage breast cancer. With the addition of trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), improvements in overall survival have been observed among patients with advanced HER2-positive disease. Subsequently, lapatinib, an orally bioavailable small molecule dual HER2- and EGFR/HER1-specific tyrosine kinase inhibitor, received Food and Drug Administration (FDA) approval in combination with capecitabine for patients with advanced HER2+ breast cancer. Then, pertuzumab in 2012 and ado-trastuzumab emtansine in 2013 were approved in the US and elsewhere based on evidence showing an improvement in survival outcomes in patients with mostly trastuzumab naïve or trastuzumab-exposed metastatic disease. The FDA also approved 1 year of extended adjuvant neratinib after chemotherapy and a year of trastuzumab for HER2-positive breast cancer on the basis of the ExteNET trial. The clinical benefit demonstrated by those drugs in advanced disease has triggered several adjuvant and neoadjuvant trials testing them in combination with chemotherapy, but also without conventional chemotherapy, using single or dual HER2-targeting drugs. In this article, we review the current data on the therapeutic management of HER2-positive early-stage breast cancer in the adjuvant and neoadjuvant setting. We also review the data the efficacy and safety of anthracycline-based and nonanthracycline-based adjuvant chemotherapy regimens combined with trastuzumab, and optimum chemotherapy regimens in small HER2-positive tumors.

We integrate for the first time, to our knowledge, a dynamic transit assignment model into the tactical planning phase. The settings of service frequencies and vehicle capacities determine line capacity and have significant consequences for level-of-service and operational costs. The objective of this study is to determine frequency and vehicle capacity at the network level while accounting for the impact of service variations on users and operator costs. To this end, we propose a simulation-based optimization approach. The proposed model allows accounting for variations in service headways and crowding as well as their consequences for passenger flows distribution, all of which have not been accounted for in the tactical planning so far. Practical benefits of the model are demonstrated by an application to a bus network in the Amsterdam metropolitan area. This study contributes to the development of a new generation of methods that integrate reliability into the tactical planning phase to improve service quality.

Objective Depression and inflammation may independently promote breast cancer (BCa) disease progression and poorer clinical outcomes. Depression has been associated with increased levels of inflammatory markers in medically healthy individuals and patients with cancer. However, inconsistencies in study time frames complicate interpretation of results within specific cancer types. This study examined relationships between depressive symptoms and inflammation in women with early-stage BCa before beginning adjuvant treatment. Methods Women with Stage 0-III BCa were recruited approximately 4 to 8 weeks after surgery. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression, and blood samples were collected to quantify circulating levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α) by enzyme-linked immunosorbent assay. Analyses of covariance were used to test for group differences (elevated versus low depressive symptoms) in levels of cytokines. Multiple regression analyses were used to examine relationships between continuous severity of depressive symptoms and levels of cytokines adjusting for relevant biobehavioral covariates. Results Thirty-six (40%) of 89 patients showed elevated levels of depressive symptoms and, in adjusted models, had marginally higher levels of IL-1β (mean [M] = 14.49 [95% confidence interval {CI} = 6.11-32.65] versus M = 4.68 [95% CI = 1.96-9.86] and IL-6 [M = 88.74 {95% CI = 33.28-233.96} versus M = 61.52 {95% CI = 27.44-136.40}]) significantly higher levels of TNF-α (M = 17.07 [95% CI = 8.27-34.32] versus M = 6.94 [95% CI = 3.58-12.80]) than did women with low depressive symptoms. Across the spectrum of depressive symptoms, greater magnitude of depressive symptoms was related to greater levels of IL-1β (β = 0.06, p = .006, R = 0.25) and TNF-α (β = 0.06, p = .003, R = 0.27). Conclusions Postsurgery and preadjuvant treatment for early-stage BCa, depressive symptoms covary with elevated levels of multiple proinflammatory cytokines. Findings have implications for psychosocial and biological interventions concurrently focusing on depression and inflammation. Trial registration NCT01422551.

Background Real-world analyses of treatments for patients with metastatic breast cancer are limited. We evaluated the comparative effectiveness of nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer using data from an electronic medical record database from community practices across the USA. Methods We performed a retrospective cohort study using fully de-identified data from an independent US electronic medical record platform of patients with metastatic breast cancer initiating single-agent nab-paclitaxel or paclitaxel as a first- or second-line treatment from December 1, 2010 to October 6, 2014. The clinical efficacy objectives were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Subgroup analyses were performed in patients with 2 types of metastatic breast cancer as follows: 1) hormone receptor-positive and human epidermal growth factor receptor 2 negative, and 2) triple-negative disease. Results This analysis included 925 patients. Patients receiving nab-paclitaxel vs. paclitaxel had significantly longer TTD (median 4.2 vs. 2.8 months, P

Non-metastatic breast cancer patients often experience psychological distress which may influence disease progression and survival. Cognitive-behavioral stress management (CBSM) improves psychological adaptation and lowers distress during breast cancer treatment and long-term follow-ups. We examined whether breast cancer patients randomized to CBSM had improved survival and recurrence 8–15 years post-enrollment. From 1998 to 2005, women (N = 240) 2–10 weeks post-surgery for non-metastatic Stage 0–IIIb breast cancer were randomized to a 10-week, group-based CBSM intervention (n = 120) or a 1-day psychoeducational seminar control (n = 120). In 2013, 8–15 years post-study enrollment (11-year median), recurrence and survival data were collected. Cox Proportional Hazards Models and Weibull Accelerated Failure Time tests were used to assess group differences in all-cause mortality, breast cancer-specific mortality, and disease-free interval, controlling for biomedical confounders. Relative to the control, the CBSM group was found to have a reduced risk of all-cause mortality (HR = 0.21; 95 % CI [0.05, 0.93]; p = .040). Restricting analyses to women with invasive disease revealed significant effects of CBSM on breast cancer-related mortality (p = .006) and disease-free interval (p = .011). CBSM intervention delivered post-surgery may provide long-term clinical benefit for non-metastatic breast cancer patients in addition to previously established psychological benefits. Results should be interpreted with caution; however, the findings contribute to the limited evidence regarding physical benefits of psychosocial intervention post-surgery for non-metastatic breast cancer. Additional research is necessary to confirm these results and investigate potential explanatory mechanisms, including physiological pathways, health behaviors, and treatment adherence changes.

Introduction The objective of the study was to assess the cost-effectiveness of EVE+EXE versus endocrine monotherapies in the treatment of postmenopausal women with HR + , HER2 − ABC after failure of treatment with nonsteroidal aromatase inhibitors from a US third-party payer perspective. Materials and Methods A Markov model was developed to evaluate the costs and effectiveness associated with EVE+EXE, exemestane (EXE), fulvestrant (FUL), and tamoxifen (TAM) over a 10-year time horizon. The model included 3 health states: responsive/stable disease, progression, or death. Monthly transition probabilities were estimated based on the BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) data and network meta-analyses. Costs included drug acquisition and administration costs, medical costs associated health states, and costs for managing adverse events (AEs). Utilities for each health state and disutilities for AEs were derived from the literature. Incremental costs per quality-adjusted life year (QALY) were estimated by comparing EVE+EXE with each endocrine monotherapy. One-way and probabilistic sensitivity analyses were performed. Results In the base case, EVE+EXE was associated with 1.99 QALYs and total direct costs of $258,648 over 10 years. The incremental cost per QALY of EVE+EXE was $139,740 compared with EXE, $157,749 compared with FUL, and $115,624 compared with TAM. At a willingness-to-pay threshold of $130,000/QALY or above, EVE+EXE appeared to be the most cost-effective treatment among all drugs. Conclusions Everolimus with EXE demonstrated QALY improvements compared with 3 other endocrine monotherapies. Benchmarked by the economic value of other novel cancer therapies, EVE+EXE might be considered a cost-effective option compared with endocrine therapies for HR + /HER2 − ABC.

Diagnosis of and treatment for breast cancer (BCa) may require psychological adaptation and often involve heightened distress. Several types of social support positively relate to psychological adaptation to BCa, and negative support is associated with poorer adaptation. Although Hispanic women report greater distress than non-Hispanic White (NHW) women after diagnosis of BCa, no studies have examined ethnic differences in types of social support received from varying sources after surgery for BCa.Hispanic (N = 61) and NHW (N = 150) women diagnosed with early-stage BCa self-reported emotional, informational, instrumental, and negative support from five sources. Ethnic differences in levels of social support were compared using multiple regression analysis.When controlling for age, income, days since surgery, and stage of disease in multivariable models there were no ethnic differences in levels of emotional support from any source. Hispanic women reported greater informational support from adult women family members and children and male adult family members than did NHW women. Instrumental support from adult women family members was also greater among Hispanic than NHW women. Hispanic women reported higher negative support from husbands/partners and from children and male adult family members. When the number of years in the USA was controlled, Hispanic women showed greater informational support from adult women family members, children and male adult family members, and friends. Instrumental support from adult women family members remained greater in Hispanic women, but negative support no longer differed.Family is a greater source of informational and instrumental support for Hispanic than NHW women. Hispanic women reported higher negative support from male sources than did NHW women. Level of support from different sources may also depend on time spent in the USA. Longitudinal studies are needed to determine whether patterns and sources of social support shift over the course of BCa treatment.

Introduction: Eribulin mesylate is a nontaxane microtubule inhibitor approved to treat MBC in patients (pts) who previously received ≥2 chemotherapeutic regimens for MBC. A phase 2 study of first-line eribulin for HER2-negative (HER2-) MBC showed an overall response rate of 29%, median 6.8 m progression-free survival, and tolerability consistent with earlier studies. We present prespecified quality of life (QoL) results for this trial. Methods: Pts (N=56) received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-wk cycle (median: 7 cycles). QoL was assessed using the EORTC QoL assessment (QLQ-C30) and a breast-cancer specific questionnaire (QLQ-BR23) pretreatment (baseline) and on day 1 of every other cycle during treatment. Percentage of pts with at least ±10-point change from baseline was summarized descriptively. Linear mixed-effects models were used to evaluate changes over time and compare responders vs nonresponders controlling for baseline score and time effect. Time-to-event analysis was performed on time to deterioration, defined as time from 1st dose to 1st occurrence of worsening in QoL score that reached minimally clinically important difference (MID; eg, 10 points in global health status in QLQ-C30) from baseline without further improvement of at least MID. Results: For QLQ-C30 at cycle 6 (n=29), more pts had at least a 10-point improvement from baseline in role, emotional, and social functioning; fatigue, nausea/vomiting, pain, dyspnea, and insomnia item scores, than had worsening. More pts had worsening in global health status/QoL, cognitive functioning, and diarrhea (Table). Category, n (%) ImprovedStableWorsenedGlobal health status/QoL2 (7)16 (55)11 (38)Physical functioning9 (31)13 (45)7 (24)Role functioning14 (48)10 (35)5 (17)Emotional functioning9 (31)14 (48)6 (21)Cognitive functioning2 (7)13 (45)14 (48)Social functioning10 (35)13 (45)6 (21)Fatigue16 (55)5 (17)8 (28)Nausea and vomiting8 (28)16 (55)5 (17)Pain15 (52)8 (28)6 (21)Dyspnea9 (31)18 (62)2 (7)Insomnia12 (41)15 (52)2 (7)Appetite loss7 (24)16 (55)6 (21)Constipation5 (17)18 (62)6 (21)Diarrhea2 (7)21 (72)6 (21) Median time to deterioration in global health status/QoL was 5.06 m (responders, 8.54 m; nonresponders, 3.71 m; hazard ratio=0.60, P=0.22). In linear mixed models, responders (n=16) performed better than nonresponders (n=40) in role functioning (P=0.011), emotional functioning (P=0.031), fatigue (P=0.007), pain (P=0.047), insomnia (P=0.018), and appetite loss (P=0.032). Mean symptom scores were significantly correlated with corresponding adverse event rates for nausea and vomiting, dyspnea, appetite loss, constipation, and diarrhea; Spearman rank correlation coefficients ranged from 0.31 to 0.54. For QLQ-BR23 at cycle 6, symptom scores were mostly stable; more pts had worsening in body image and systemic therapy side effects than had improvement and more pts had improvement in breast and arm symptoms than had worsening. Responders also had longer time to symptom deterioration. Conclusions: In this study of first-line eribulin treatment for HER2- MBC, a majority of pts had stable or improvement in QoL scales. Responders to eribulin were more likely than nonresponders to have stable or improved QoL. Citation Format: Lee Schwartzberg, Kristi McIntyre, Joyce O'Shaughnessy, Stefan Glück, Erhan Berrak, James Song, David Cox, Linda Vahdat. Quality of life in patients receiving first-line eribulin mesylate for HER2- locally recurrent or MBC [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-17-02.

BACKGROUND Breast cancer survivors experience long-term physical and psychological sequelae after their primary treatment that negatively influence their quality of life (QOL) and increase depressive symptoms. Group-based cognitive-behavioral stress management (CBSM) delivered after surgery for early-stage breast cancer was previously associated with better QOL over a 12-month follow-up and with fewer depressive symptoms up to 5 years after study enrollment. This 8- to 15-year follow-up (median, 11 years) of a previously conducted trial (NCT01422551) evaluated whether women in this cohort receiving CBSM had fewer depressive symptoms and better QOL than controls at an 8- to 15-year follow-up. METHODS Women with stage 0 to IIIb breast cancer were initially recruited 2 to 10 weeks after surgery and randomized to a 10-week CBSM intervention or a 1-day psychoeducational control group. One hundred women (51 CBSM patients and 49 controls) were recontacted 8 to 15 years after study enrollment to participate in a follow-up assessment. The Center for Epidemiologic Studies–Depression (CES-D) scale and the Functional Assessment of Cancer Therapy–Breast (FACT-B) were self-administered. Multiple regression was employed to evaluate group differences on the CES-D scale and FACT-B over and above effects of confounding variables. RESULTS Participants assigned to CBSM reported significantly lower depressive symptoms (d, 0.63; 95% confidence interval [CI], 0.56-0.70) and better QOL (d, 0.58; 95% CI, 0.52-0.65) above the effects of the covariates. CONCLUSIONS Women who received CBSM after surgery for early-stage breast cancer reported lower depressive symptoms and better QOL than the control group up to 15 years later. Early implementation of cognitive-behavioral interventions may influence long-term psychosocial functioning in breast cancer survivors. Cancer 2015;121:1873–1881. © 2015 American Cancer Society.

Vitamin D (VD) supplementation has pleiotropic effects that extend beyond their impact on bone health, including the disruption of human epidermal growth factor receptor 2 (HER2) signaling through the ErbB2/AKT/ ERK pathway. We performed a retrospective review of patients who received VD supplementation during neoadjuvant chemotherapy (n [ 134) and those who did not (n [ 112). In our final multivariate model, VD use was associated with improved disease-free survival (DFS) (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.15-0.88); P [ .026). To the best of our knowledge, our study is the first to report a significant improvement in DFS for patients who received VD supplementation concurrently with trastuzumab-based chemotherapy for HER2-positive (HER2 D ) nonmetastatic breast cancer. Background: Vitamin D (VD) supplementation has pleiotropic effects that extend beyond their impact on bone health, including the disruption of downstream VD receptor signaling and human epidermal growth factor receptor 2 (HER2) signaling through the ErbB2/AKT/ERK pathway. In the present study, we examined our institutional experience with patients having nonmetastatic HER2-positive (HER þ ) breast cancer and hypothesized that those patients who received VD supplementation during neoadjuvant chemotherapy would have improved long-term outcomes. Patients and Methods: We performed a retrospective review of all patients (n ¼ 308) given trastuzumab-based chemotherapy between 2006 and 2012 at the University of Miami/Sylvester Comprehensive Cancer Center (UM/SCCC). We identified 2 groups of patients for comparison—those who received VD supplementation during neoadjuvant chemotherapy (n ¼ 134) and those who did not (n ¼ 112). Univariate and multivariate Cox proportional hazard regression models were fitted to overall survival (OS) and disease-free survival (DFS). Results: More than half of the patients received VD during neoadjuvant chemotherapy (54.5%), with 60% receiving a dose < 10,000 units/wk and 33.3% having aV D deficiency at the start of therapy. In our final multivariate model, VD use was associated with improved DFS (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.15-0.88; P ¼ .026], whereas larger tumor size was associated with worse DFS (HR, 3.52; 95% CI, 1.06-11.66; P ¼ .04). There were no differences in OS based on any of

There has been considerable progress in the treatment of metastatic breast cancer. However, the identification of optimal cytotoxic agents in patients with triple-negative breast cancer (TNBC) (negative for hormone receptors and human epidermal growth factor receptor 2) remains a therapeutic challenge. We conducted a comparative effectiveness analysis of 4 cytotoxic agents in patients with TNBC.We retrospectively identified patients who received single-agent chemotherapy with eribulin, capecitabine, gemcitabine, or vinorelbine from 19 community oncology clinics across the United States. Data collection included baseline patient and disease characteristics, prior therapies, performance status, duration of current therapy, growth-factor use and other supportive care, and dose-limiting toxicities and associated dose reductions or delays or skipped doses. Time to treatment failure (TTF) was measured from the first cycle of chemotherapy until disease progression, discontinuation due to toxicity, or death. TTF was estimated using the Kaplan-Meier method and Cox proportional hazards modeling adjusted for clustering on the practice site. To control for selection bias, which is inherent in observational studies, a propensity score-weighted TTF analysis was also conducted.Data from 225 patients were included in the analysis (eribulin, 47 patients; capecitabine, 69; gemcitabine, 56; and vinorelbine, 53). The median age of each group was60 years, with the exception of the gemcitabine group (63 years). The 4 groups were comparable with respect to age, performance status, duration of disease-free survival, presence of comorbidities, and hemoglobin level before the start of chemotherapy. Median lines of therapy of eribulin, capecitabine, gemcitabine, and vinorelbine and were 4th, 2nd, 3rd, and 3rd, respectively. The median durations of treatment were ~2 months with eribulin, capecitabine, and gemcitabine compared with 1.6 months with vinorelbine. Using eribulin as the reference drug, and with adjustment for line of therapy and associated prognostic factors, the propensity score-weighted Cox regression analysis did not identify significant between-treatment differences in TTF (hazard ratios [95% CI] vs eribulin: capecitabine, 1.15 [0.75-1.76]; gemcitabine, 0.62 [0.34-1.13]; and vinorelbine, 1.0 [0.67-1.67]).In this assessment of patients with TNBC treated in a community oncology setting, eribulin was utilized in later lines compared with the other agents. However, comparable drug activity was reported among the 4 agents.

The idea of using the immune system to fight cancer is over 100 years old. A new molecular approach led to a better understanding of the immune system. Checkpoint regulation, understanding the roles of Tregs, Th1, and Th2, development of Chimeric antigen receptor (CAR) T cells, as well as regulation of dendritic cells and macrophages, are just a few examples of our understating that has also led to the discovery of immune checkpoint inhibitors (ICIs) and modulators. This led the Nobel Prize committee in 2018, to award Dr. James P. Allison the Nobel Prize in medicine for the discovery of Cytotoxic T lymphocyte associated antigen 4, and Dr. Tasuku Honjo for the discovery of programmed cell death 1 (PD 1)/PD 1 ligand (PDL 1). Several ICIs are already approved by the regulatory authorities, and many more are currently used in studies of several solid tumors and hematologic malignancies. Positive studies have led to the US Food and Drug Administration (FDA) and European Medicines Agency approval of a number of these compounds, but none to date are approved in breast cancer (BC). Moreover, PD 1/PDL 1, MSI high (and dMMR), and tumor mutational burden are the currently “best” predictive markers for benefit from immunotherapy. BCs have some of these markers positive only in subsets but less frequently expressed than most other solid tumors, for example, malignant melanoma or non small cell lung cancer. To improve the potential efficacy of ICI in BC, the addition of chemotherapy was one of the strategies. Many early and large clinical trials in all phases are underway in BC. We will discuss the role of immune system in BC editing, and the potential impact of immunotherapy in BC outcomes.

AIM For early-stage breast cancer, four cycles of docetaxel and cyclophosphamide (TC) was proven superior to doxorubicin plus cyclophosphamide in the US Oncology 9375 trial. Given primary prophylactic antibiotics, 5% febrile neutropenia was recorded in a population comprising 75.5% Caucasians. Smaller trials and retrospective studies reviewing TC use in Asian patients did not produce similar incidence rates. This study aims to discover the variable hematological toxicities with TC use in Caucasian and Asian patients. METHODS Breast cancer data was retrospectively reviewed for patients receiving adjuvant docetaxel 60-75 mg/m2 plus cyclophosphamide 600 mg/m2 from six countries (China, Hong Kong, Japan, Taiwan, Italy, and United States). Similar number of patients with relatively balanced baseline characteristics were chosen for analysis of hematological and nonhematological toxicities and survival data. RESULTS From March 2004 to July 2013, data of 227 patients (127 Asians and 100 Caucasian) patients were analyzed for treatment-related toxicities. During the four cycles of TC, Asians had a significantly higher rate of grade ≥2 neutropenia than Caucasians (45.7% vs 6.0%; P

Racial disparities in breast cancer incidence and outcome are a major health care challenge. Patients in the black race group more likely present with an early onset and more aggressive disease. The occurrence of high numbers of macrophages is associated with tumor progression and poor prognosis in solid malignancies. Macrophages are observed in adipose tissues surrounding dead adipocytes in "crown-like structures" (CLS). Here we investigated whether the numbers of CD163+ tumor-associated macrophages (TAMs) and/or CD163+ CLS are associated with patient survival and whether there are significant differences across blacks, non-black Latinas, and Caucasians. Our findings confirm that race is statistically significantly associated with the numbers of TAMs and CLS in breast cancer, and demonstrate that the highest numbers of CD163+ TAM/CLS are found in black breast cancer patients. Our results reveal that the density of CD206 (M2) macrophages is a significant predictor of progression-free survival univariately and is also significant after adjusting for race and for HER2, respectively. We examined whether the high numbers of TAMs detected in tumors from black women were associated with macrophage proliferation, using the Ki-67 nuclear proliferation marker. Our results reveal that TAMs actively divide when in contact with tumor cells. There is a higher ratio of proliferating macrophages in tumors from black patients. These findings suggest that interventions based on targeting TAMs may not only benefit breast cancer patients in general but also serve as an approach to remedy racial disparity resulting in better prognosis patients from minority racial groups.

A breast cancer (BCa) diagnosis is a major life stressor compounded by surgery, chemotherapy, radiation, and hormonal treatments that impose significant physical and psychological challenges (Carlson et al., 2004). Women with BCa are among the most distressed of cancer subgroups, and those with non-metastatic BCa report distress related to fear of disease progression and recurrence (Herschbach et al., 2004). This distress can be manifested as depressed mood and elevated anxiety (Montanzer, 2008), disrupted quality of life and emotional well-being (Reich et al., 2008), and withdrawal from social activities during BCa treatment (Carver, Lehman, & Antoni, 2003). Further, cancer-specific distress in the form of cognitive intrusions about illness, prognosis, recurrence, death, and disability may occur (Tatrow & Montgomery, 2006) and are associated with worse quality of life (QOL) later in treatment (Golden-Kruetz et al., 2005). Conversely, stress management interventions have the potential to ameliorate many of the negative psychosocial effects of cancer. Despite controversy regarding their effectiveness for all cancer patients (Coyne, Lepore, & Palmer, 2006), stress management interventions have been shown to improve QOL and decrease distress during cancer treatment (Jacobsen & Jim, 2008). The components of these interventions that generate improvements are underexplored (Phillips et al., 2012) and may provide insight into the ways to fine-tune interventions to maximize benefit. One such intervention is group-based cognitive-behavioral stress management (CBSM), which combines cognitive-behavioral techniques and relaxation training. This intervention improves psychological adaptation during active treatment among women with non-metastatic BCa (Antoni et al., 2006b). Correlational evidence points to the role of perceived efficacy in using cognitive-behavioral processes and relaxation skills to explain its effects in women with BCa (Antoni et al., 2006a), and recent work has tested the effects of focused CBT interventions (Schnur et al., 2009), but no study has tested CBSM processes in a dismantling design. Prior CBT-oriented interventions during primary treatment for breast cancer have ranged from 9–20 weeks, with 1.5–2 hour sessions each week (Fors et al., 2011), but this intensity may not be feasible in clinical oncology services. Studies of brief “clinic ready” interventions are needed in view of the limited time and resources for providing psychological support in the oncology setting (Stanton, Lueken, MacKinnon, & Thompson, 2013). Prior work suggests that the effects of a 10-week CBSM intervention may be observed in persons who attend as few as 5 weekly sessions (Antoni et al., 2006a), and 5-week CBSM interventions have also shown some positive effects in women with BCa (Groarke, Curtis, & Kerin, 2013). However, prior trials have not employed an attention-time matched control design to rule out the possibility that effects were driven by non-CBSM-specific group intervention processes (Cohen & Fried, 2007). The current randomized controlled trial (RCT) addressed these limitations. It explored specific components of traditional CBSM by dismantling the intervention into two active 5-week treatment groups (i.e., Cognitive-Behavioral Training [CBT] and Relaxation Training [RT]) and examining changes in primary indicators of psychological adaptation and intermediary stress management resources as compared to an attention-matched Health Education (HE) control condition. We hypothesized that women assigned to the active intervention conditions would show improvements in psychological adaptation indicators, including general affect, cancer-specific distress, interpersonal disruption, and emotional well-being/QOL compared to the control condition at post-intervention follow-up. We further hypothesized that the CBT group, which focused on cognitive-behavioral and interpersonal skills training, would show differential increases in perceived social support resources, while the RT group would show differential increases in perceived efficacy for using relaxation skills to deal with stress at post-intervention follow-up. Although true mediation tests could not be conducted because the present study involves concurrent outcome measures, intervention-specific stress management resources were further examined as provisional mediators of intervention effects on psychological adaptation.

Sleep disruption and fatigue are ubiquitous among cancer patients and are sources of stress that may compromise treatment outcomes. Previously, we showed that a cognitive behavioral stress management (CBSM) intervention reduced anxiety and other stress-related processes in women undergoing primary treatment for breast cancer.This study examined secondary outcomes from a CBSM intervention trial for women with early-stage breast cancer to test if CBSM would improve sleep quality and fatigue among these patients at a single site in southern Florida. CBSM-related effects have already been demonstrated for indicators of psychosocial adaptation (e.g., general and cancer-related anxiety).Patients were randomized to CBSM (n= 120) or a 1-day psychoeducation control group (n= 120). The Pittsburgh Sleep Quality Index (PSQI) and Fatigue Symptom Inventory were completed prior to randomization and 6 and 12 months after the baseline assignment.In latent growth analyses, women in CBSM reported greater improvements in PSQI sleep quality scores than controls, although there were no significant differences between conditions on PSQI total scores. Women in CBSM also reported greater reductions in fatigue-related daytime interference than controls, though there were no significant differences in changes in fatigue intensity. Changes in sleep quality were associated with changes in fatigue.Future work may consider integrating sleep and fatigue content into stress management interventions for women with early-stage breast cancer.

Background: TNMBC has an aggressive clinical course and poor prognosis. In phase II trials, nab-P–based therapy has demonstrated efficacy and tolerability as first-line therapy, in patients with MBC. The international triple-negative Albumin-bound paclitaxel combination treatment study (tnAcity) will evaluate 2 nab-P regimens (with either Gem or Carbo) and compare the selected regimen with Gem/Carbo as first-line treatment for TNMBC. Trial design: All patients must have pathologically confirmed TNBC (TN defined as < 1% estrogen receptor and progesterone receptor expression by immunohistochemistry (IHC) and 0 - 1+ human epidermal growth factor receptor 2 expression by IHC or confirmed negative by fluorescence in situ hybridization) with measurable metastatic disease. Eligibility criteria include no prior cytotoxic therapy for MBC, prior adjuvant or neoadjuvant anthracycline use unless not indicated by physician or other appropriate regimens were administered, and no history or current evidence of brain metastasis. Prior neoadjuvant or adjuvant chemotherapy must have been completed ≥ 6 months before randomization (≥ 12 months if using taxane-, Gem-, or platinum-containing regimen). Patients will be enrolled internationally in North America, Europe, Latin America, and Australia. In the phase II portion, 240 patients will be randomized to receive nab-P 125 mg/m2 plus Gem 1000 mg/m2 (arm A), nab-P 125 mg/m2 plus Carbo area under the curve (AUC) 2 (arm B), or the control regimen of Gem 1000 mg/m2 plus Carbo AUC 2 (arm C), all given intravenously on days 1 and 8 of a 21-day cycle. The phase II portion will identify the nab-P combination to be evaluated in the phase III portion based on efficacy and safety (Table 1). In the phase III portion, 550 patients will receive the selected nab-P regimen (A or B) or Gem/Carbo. The primary endpoint of the phase III portion is progression-free survival (PFS) by independent radiological assessment; secondary endpoints include overall response rate (ORR), overall survival (OS), disease control rate, duration of response, and safety (Table 1). Monotherapy is allowed in the event of hypersensitivity or toxicity to 1 of the treatment components. The trial design provides ≈ 90% power to detect a hazard ratio of 0.70 for PFS with a 2-sided 5% significant level. Current enrollment is 52 patients. Clinical trial NCT01881230. Trial Design ParameterPhase IIPhase IIINn = 240n = 550Randomization1:1:11:1StratificationDisease-free interval (DFI): ≤ 1 y vs > 1 yDFI: ≤ 1 y vs > 1 y Prior neo/adjuvant taxane (yes vs no)Key EndpointsPrimaryPFS by investigator assessmentPFS by independent assessment SecondaryORR by investigator assessmentORR Percentage of patients to initiate cycle 6OS OSPFS by investigator assessment SafetyDisease control rate Duration of response Safety ExploratoryTime to second-line therapy or deathTime to second-line therapy or death Circulating tumor cellsQuality of life Tumor biomarkersHealthcare resource utilization Tumor biomarkers Citation Format: Denise A Yardley, Robert E Coleman, Pierfranco Conte, Joyce O'Shaughnessy, Javier Cortes, Stefan Glück, Adam Brufsky, Jean-Marc A Nabholtz, Li Li, JulieAnn Miller, Debora Barton, Nadia Harbeck, on bahalf of the tnAcity Investigators. tnAcity: A phase II/III trial of nab-paclitaxel (nab-P) plus either gemcitabine (Gem) or carboplatin (Carbo) vs Gem/Carbo as first-line treatment for patients with triple-negative metastatic breast cancer (TNMBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-01.