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The article discusses research being done on the efficacy of zolendronic acid in preventing bone loss associated with cancer treatment. It references a study by M. F. X. Gnant and colleagues, published in the 2007 issue of the "Journal of Clinical Oncology." The study included breast cancer patients who developed bone loss following adjuvant endocrine therapy. It found that zoledronic acid is effective in inhibiting bone loss. A comment on the study is also offered.

Background: In an open-label, randomized, phase 3 trial, we compared the efficacy and safety of paclitaxel with that of paclitaxel plus bevacizumab, a monoclonal antibody against vascular endothelial growth factor, as initial treatment for metastatic breast cancer.Methods: We randomly assigned patients to receive 90 mg of paclitaxel per square meter of body-surface area on days 1, 8, and 15 every 4 weeks, either alone or with 10 mg of bevacizumab per kilogram of body weight on days 1 and 15. The primary end point was progression-free survival; overall survival was a secondary end point.Results: From December 2001 through May 2004, a total of 722 patients were enrolled. Paclitaxel plus bevacizumab significantly prolonged progression-free survival as compared with paclitaxel alone (median, 11.8 vs. 5.9 months; hazard ratio for progression, 0.60; P<0.001) and increased the objective response rate (36.9% vs. 21.2%, P<0.001). The overall survival rate, however, was similar in the two groups (median, 26.7 vs. 25.2 months; hazard ratio, 0.88; P=0.16). Grade 3 or 4 hypertension (14.8% vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001), headache (2.2% vs. 0.0%, P=0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P=0.02) were more frequent in patients receiving paclitaxel plus bevacizumab. Infection was more common in patients receiving paclitaxel plus bevacizumab (9.3% vs. 2.9%, P<0.001), but febrile neutropenia was uncommon (<1% overall).Conclusions: Initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with paclitaxel alone. (ClinicalTrials.gov number, NCT00028990 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor-positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence.Methods: We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival.Results: We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life.Conclusions: The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.). [ABSTRACT FROM AUTHOR]

Background: Epidermal Growth Factor Receptor (EGFR, HER1) is known to heterodimerize with HER2 and may impact the effectiveness of trastuzumab. Historically, EGFR has been difficult to measure; thus there is no evidence regarding its effects on trastuzumab clinical therapy. Here we use a new, standardized, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in a cohort from the North Central Cancer Treatment Group (NCCTG, Alliance) N9831 trial. Methods: Of the 3505 women in the N9831 trial, tissue microarrays were constructed that allowed analysis of 1,444 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) or concurrent trastuzumab with chemotherapy (Arm C). Fluorescence-based, standardized measurement of EGFR was done using the rabbit monoclonal EGFR antibody D38B1 on the AQUA platform (HistoRx). EGFR expression levels were analyzed as a continuous variable and dichotomized using recursive partitioning to define an optimal cut point. The cut point was validated on an independent retrospective cohort comprised of 130 patients with HER2-positive metastatic breast cancer who received trastuzumab. Results: EGFR assessed as a continuous variable shows an association with disease free survival (DFS) in Arm C (p = 0.002) but not in Arms A or B. Dichotomizing EGFR expression shows that high level expression is associated with worse outcome (HR = 2.2; 95% CI 1.33-3.59, p = 0.002) in arm C. Five year DFS within the low level EGFR expression group was 71%, 74% and 90% for Arms A, B and C, respectively (log-rank p-value=0.02) and within the high level EGFR expression (n = 213) group was 62%, 76% and 74% respectively (log-rank p- value 0.22). As validation, the same cut-point was used to define high EGFR expression in a retrospective metastatic breast cancer cohort. The median progression free survival difference between EGFR high group and EGFR low group was 6.1 months (p = 0.0063) and the hazard ratio of high EGFR was 1.92 (p = 0.0073). Conclusions: High expression of EGFR by the AQUA platform appears to be associated with decreased benefit from adjuvant concurrent (not sequential) trastuzumab and shorter PFS in the metastatic setting. The biological underpinning for these observations is being considered. Since there are other treatment options for HER2-driven tumors, this marker, once validated, could help select patients for alternative or additive therapy. [ABSTRACT FROM AUTHOR]

Background: Randomized studies investigating adjuvant bisphosphonates in women with breast cancer are ongoing. While bisphosphonates would be expected to prevent the deterioration of bone microarchitecture that accompanies hormone or chemotherapy, complete suppression of osteoclast activity for prolonged periods of time can decrease repair of micro-cracks, and possibly lead to decreased bone strength. While bone strength is governed by the amount of bone present, trabecular and cortical components of bone microarchitecture also contribute independently to bone strength. We aimed to characterize the effects of long-term bisphosphonates on bone microarchitecture in women with breast cancer using high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal radius and tibia. Methods: We conducted a cross-sectional study involving early stage breast cancer patients treated with bisphosphonates on the S0307 clinical trial. Women were randomized to receive zoledronic acid, oral clodronate or oral ibandronate in doses far higher than those used in osteoporosis treatment as per protocol. After 18-36 months of bisphosphonate therapy, participates underwent a one-time evaluation of areal bone mineral density (aBMD) of the 1/3 radius, lumbar spine, and hip by dual energy x-ray absorptiometry (DXA), and cortical and trabecular volumetric BMD (vBMD) and trabecular microarchitecture of the radius and tibia by HR-pQCT. HR-pQCT measurements were compared to healthy young premenopausal women and age-matched Caucasian women. Results: Baseline characteristics of the 12 enrolled patients: median age of 53 (range 40- 67); white/Hispanics 7/5; pre/postmenopausal 4/8; mean body mass index 28.7 kg/m2 (20.9-34.8); average time on bisphosphonates 20 months (18-30); zoledronic acid/clodronate/ibandronate 5/6/1. The median aBMD DXA T-score of the 1/3 radius, lumbar spine and total hip were normal at +0.3, +0.1, and +0.2, respectively. Mean total, cortical, and trabecular vBMD of the radius as measured by HR-pQCT were 330±71, 905±55, and 146±35 mg hydroxyapatite/cm3, respectively. Mean cortical thickness was 0.803±0.170 mm, and mean trabecular number was 1.9±0.2. Mean total, cortical, and trabecular vBMD of the tibia were 285±54, 880±54, and 150±38 mg hydroxyapatite/cm3, respectively. Mean cortical thickness was 1.135±0.264 mm, and mean trabecular number was 1.7±0.3. There were no statistically significant differences between study group and each control. However, results were more similar to healthy young premenopausal control than the age-matched control. Conclusion: Women on long-term bisphosphonate therapy for breast cancer had normal aBMD by DXA and normal cortical and trabecular vBMD, cortical thickness and trabecular number at the peripheral skeleton compared to healthy young women and age-matched women. This preliminary data is reassuring for cancer survivors if benefits from this therapy are established in the adjuvant setting. [ABSTRACT FROM AUTHOR]

Background: Some estrogen receptor-positive (ER+) metastatic breast cancers are bone and soft tissue dominant, indolent, and controlled by endocrine therapy. However, these tumors eventually become refractory to endocrine therapy and need a mechanism to reset the "estrogen-dependence" to allow continued benefit upon progression. Histone deacetylase inhibitors (HDACi) act as modulators of gene expression that are promising therapeutic agents for this group of tumors (Huang 2000, Sabnis 2011). Preclinical and clinical data demonstrate in ER-poor tumors and cell lines ER up-regulation and consequently enhanced lethality to endocrine agents. The optimal dose and schedule are not known, but two promising phase II studies show benefit in a continuous schedule (Yardley 2011, Munster 2011). FES PET is a promising imaging agent used as a biomarker to determine which patients will benefit from endocrine therapy, and to monitor estradiol binding during therapy (Mortimer 2001, Linden 2011). Methods: Patients with ER+ HER2- metastatic breast cancer with prior aromatase inhibitor (AI) exposure and clinical benefit of endocrine therapy were eligible for a phase II study of HDACi therapy to restore sensitivity to AI therapy. Following baseline FDG PET, FES PET and standard imaging (CT, MRI, ultrasound and/or bone scan as indicated by tumor location), patients received 2 weeks of vorinostat therapy (400 mg po daily). FES PET was performed at 2 weeks while on HDACi therapy. Patients then received 6 weeks of AI monotherapy. FDG PET, FES PET and response assessment were performed at 8 weeks. Patients with clinical benefit (stable disease or response) continued on the regimen, 2 weeks of vorinostat followed by 6 weeks of AI. Results: To date, 8 patients have been enrolled of whom 6 have completed the first 8 weeks of treatment and all correlative imaging studies. FES biomarker imaging results are mixed, with some patients showing an increase in tumor estradiol concentrating ability by FES PET on HDACi therapy, and decline in metabolic activity by FDG. Two patients continue on treatment with clinical benefit. Results will be updated as accrual continues. Conclusions: Changes in estradiol binding are measured by serial FES PET in patients on HDACi therapy support preclinical concept of HDACi modulation of ER expression in metastatic breast cancer. Molecular imaging is a promising tool to monitor Estradiol binding pharmacodynamics, and Vorinostat HDACi therapy is a promising novel approach to allow patients to avoid toxicities of traditional chemotherapy once their tumor has progressed on endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: Preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and North Central Cancer Treatment Group (NCCTG) (Alliance) N9831 Trial compared adjuvant chemotherapy with or without trastuzumab in women with HER2-positive breast cancer . The initial results were reported in 2005 and updated in early 2011 Methods: 4045 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The definitive analysis for OS will occur when 710 events have been reported. Results: Median time on study is 8 years. The required number of events have occurred for the definitive analysis for OS to be conducted by the end of September 2012. Updated analyses of disease free survival and related subgroups will also be presented. [ABSTRACT FROM AUTHOR]

Background: Adding adjuvant trastuzumab to chemotherapy for patients (pts) with resected HER2+ breast cancer (BC) improves disease free and overall survival (Perez EA, et al. J Clin Oncol 2011). Understanding which pts are most likely to benefit from these therapies is a goal of our team. Methods: Baseline 1639 annotated tumor specimens from pts enrolled in the phase III N9831 adjuvant trastuzumab trial (NCT00005970 ) were processed via the >29,000 gene probe DASL technology (Illumina) to identify genomic predictors of pt outcome to Arm A chemotherapy or Arm C chemotherapy plus concurrent trastuzumab. Samples were spotted in 96 well plates, with appropriate replicates. Extensive quality control and internal validation were performed. The association of each gene with recurrence-free survival (RFS) was determined for each treatment arm separately using CoxPH models adjusted for clinical and tumor risk factors. A p < 0.0001 was used to define significance. A geneset analysis (using 408 Kegg/BioCarta genesets) was performed to determine pathways associated with RFS. Results: PRPF4B, EWSR1, BMI1, CNNM1, FOXO4, CLIP2, MCCC1, CHRM2 were found to be significantly associated with RFS for Arm A and AAK1, DAZAP2, TP53INP1, MACF1 and ADHFE1 were associated with RFS for Arm C. The most significant pathway associated with RFS in Arm A was the KEGG hypertrophic cardiomyopathy pathway and for Arm C, the BioCarta pertussis toxin-insensitive CCR5 signaling in macrophage pathway. Conclusions: We have identified 8 genes associated with RFS for pts treated with adjuvant chemotherapy, and 5 genes associated with RFS for pts treated with concurrent trastuzumab and chemotherapy in pts with HER2 early stage BC. In addition, geneset analysis identified BioCarta and Kegg pathways associated with RFS for each arm. Validation in an independent cohort is expected to be completed by the end of 2012. [ABSTRACT FROM AUTHOR]

Competing Interests: We declare no competing interests.

Purpose: There is an urgent need to improve access to cancer therapy globally. Several independent initiatives have been undertaken to improve access to cancer medicines, and additional new initiatives are in development. Improved sharing of experiences and increased collaboration are needed to achieve substantial improvements in global access to essential oncology medicines., Methods: The inaugural Access to Essential Cancer Medicines Stakeholder Meeting was organized by ASCO and convened at the June 2022 ASCO Annual Meeting in Chicago, IL, with two subsequent meetings, Union for International Cancer Control World Cancer Congress held in Geneva, Switzerland, in October 2022 and at the ASCO Annual Meeting in June of 2023. Invited stakeholders included representatives from cancer institutes, physicians, researchers, professional societies, the pharmaceutical industry, patient advocacy organizations, funders, cancer organizations and foundations, policy makers, and regulatory bodies. The session was moderated by ASCO. Past efforts and current and upcoming initiatives were initially discussed (2022), updates on progress were provided (2023), and broad agreement on resulting action steps was achieved with participants., Results: Summit participants recognized that while much work was ongoing to enhance access to cancer therapeutics globally, communication and synergy across projects and organizations could be enhanced by providing a platform for collaboration and shared expertise., Conclusion: The summit resulted in new cross-stakeholder insights and planned collaboration addressing barriers to accessing cancer medications. Specific actions and timelines for implementation and reporting were established.

This Policy Review sourced opinions from experts in cancer care across low-income and middle-income countries (LMICs) to build consensus around high-priority measures of care quality. A comprehensive list of quality indicators in medical, radiation, and surgical oncology was identified from systematic literature reviews. A modified Delphi study consisting of three 90-min workshops and two international electronic surveys integrating a global range of key clinical, policy, and research leaders was used to derive consensus on cancer quality indicators that would be both feasible to collect and were high priority for cancer care systems in LMICs. Workshop participants narrowed the list of 216 quality indicators from the literature review to 34 for inclusion in the subsequent surveys. Experts' responses to the surveys showed consensus around nine high-priority quality indicators for measuring the quality of hospital-based cancer care in LMICs. These quality indicators focus on important processes of care delivery from accurate diagnosis (eg, histologic diagnosis via biopsy and TNM staging) to adequate, timely, and appropriate treatment (eg, completion of radiotherapy and appropriate surgical intervention). The core indicators selected could be used to implement systems of feedback and quality improvement., Competing Interests: Declaration of interests JC received a partnership grant from Bristol Meyers Squibb to support City Cancer Challenge Foundation (C/Can) missions, including contribution to the development and validation of the Quality Cancer Care Indicators. JG is a participant on the Roche/Genentech Independent Data Safety and Monitoring Committee for which she receives no compensation. JJ received payment or honoraria for lectures or other educational events from Merck Sharp and Dohme, Roche, Pfizer, Bristol Myers Squibb, and Novartis, and received support for attending the American Society of Clinical Oncology meeting from Takeda. AA has received an advanced fellowship from the National Institute for Health Research since July, 2020. All other authors declare no competing interests. The sponsor C/Can was not involved in the collection, analysis, or interpretation of data. JC and MM-L are members of the study sponsor team and were involved in the writing of the manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)

Anticancer agents can impair ovarian function, resulting in premature menopause and associated long-term health effects. Ovarian toxicity is not usually adequately assessed in trials of anticancer agents, leaving an important information gap for patients facing therapy choices. This American Society of Clinical Oncology (ASCO) statement provides information about the incorporation of ovarian toxicity measures in trial design. ASCO recommends: (1) measurement of ovarian toxicity in relevant clinical trials of anticancer agents that enrol post-pubertal, pre-menopausal patients; (2) collection of ovarian function measures at baseline and at 12-24 months after anticancer agent cessation, as a minimum, and later in line with the trial schedule; and (3) assessment of both clinical measures and biomarkers of ovarian function. ASCO recognises that routine measurement of ovarian toxicity and function in cancer clinical trials will add additional complexity and burden to trial resources but asserts that this issue is of such importance to patients that it cannot continue to be overlooked., Competing Interests: Declaration of interests WC reports honoraria from AstraZeneca, Pfizer, Merck Serono, and Eisai. RAA reports grants or contracts (research funding) and consulting fees from Roche Diagnostics. ND reports employment by AstraZeneca; grants or contracts (research funding) from Amgen, Novartis, Genentech, Lilly, Pfizer, Daiichi Sankyo, and Immunomedics; and travel, accommodations, expenses, and stock options from AstraZeneca. DS reports grants or contracts (research funding) from Janssen; consulting fees (advisory role) from Janssen Oncology, AstraZeneca, Boston Scientific, Bayer, Blue Earth, Varian Medical Systems, Pfizer, and Myovant Sciences; and honoraria from Varian Medical Systems. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: There is strong interest from patients, researchers, the pharmaceutical industry, medical journal editors, funders of research, and regulators in sharing clinical trial data for secondary analysis. However, data access remains a challenge because of concerns about patient privacy. It has been argued that synthetic data generation (SDG) is an effective way to address these privacy concerns. There is a dearth of evidence supporting this on oncology clinical trial data sets, and on the utility of privacy-preserving synthetic data. The objective of the proposed study is to validate the utility and privacy risks of synthetic clinical trial data sets across multiple SDG techniques., Methods: We synthesized data sets from eight breast cancer clinical trial data sets using three types of generative models: sequential synthesis, conditional generative adversarial network, and variational autoencoder. Synthetic data utility was evaluated by replicating the published analyses on the synthetic data and assessing concordance of effect estimates and CIs between real and synthetic data. Privacy was evaluated by measuring attribution disclosure risk and membership disclosure risk., Results: Utility was highest using the sequential synthesis method where all results were replicable and the CI overlap most similar or higher for seven of eight data sets. Both types of privacy risks were low across all three types of generative models., Discussion: Synthetic data using sequential synthesis methods can act as a proxy for real clinical trial data sets, and simultaneously have low privacy risks. This type of generative model can be one way to enable broader sharing of clinical trial data.

Introduction: Research is a critical pillar in national cancer control planning. However, there is a dearth of evidence for countries to implement affordable strategies. The WHO and various Commissions have recommended developing stakeholder-based needs assessments based on objective data to generate evidence to inform national and regional prioritisation of cancer research needs and goals., Methodology: Bibliometric algorithms (macros) were developed and validated to assess cancer research outputs of all 54 African countries over a 12-year period (2009-2020). Subanalysis included collaboration patterns, site and domain-specific focus of research and understanding authorship dynamics by both position and sex. Detailed subanalysis was performed to understand multiple impact metrics and context relative outputs in comparison with the disease burden as well as the application of a funding thesaurus to determine funding resources., Results: African countries in total published 23 679 cancer research papers over the 12-year period (2009-2020) with the fractional African contribution totalling 16 201 papers and the remaining 7478 from authors from out with the continent. The total number of papers increased rapidly with time, with an annual growth rate of 15%. The 49 sub-Saharan African (SSA) countries together published just 5281 papers, of which South Africa's contribution was 2206 (42% of the SSA total, 14% of all Africa) and Nigeria's contribution was 997 (19% of the SSA total, 4% of all Africa). Cancer research accounted for 7.9% of all African biomedical research outputs (African research in infectious diseases was 5.1 times than that of cancer research). Research outputs that are proportionally low relative to their burden across Africa are paediatric, cervical, oesophageal and prostate cancer. African research mirrored that of Western countries in terms of its focus on discovery science and pharmaceutical research. The percentages of female researchers in Africa were comparable with those elsewhere, but only in North African and some Anglophone countries., Conclusions: There is an imbalance in relevant local research generation on the continent and cancer control efforts. The recommendations articulated in our five-point plan arising from these data are broadly focused on structural changes, for example, overt inclusion of research into national cancer control planning and financial, for example, for countries to spend 10% of a notional 1% gross domestic expenditure on research and development on cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Patients of African ancestry are not well-represented in cancer clinical trials despite bearing a disproportionate share of mortality both in United States and Africa. We describe key stakeholder perspectives and priorities related to bringing early-stage cancer clinical trials to Africa and outline essential action steps. Increasing Diversity, Market Access, and Capacity in Oncology Registration Trials-Is Africa the Answer? satellite session was organized at 2021 Accelerating Anti-Cancer Agent Development and Validation Workshop. Panelists included representatives of African Organization for Research and Training in Cancer, Uganda Cancer Institute, Uganda Women's Cancer Support Organization, BIO Ventures for Global Health, Bill & Melinda Gates Foundation, the US Food and Drug Administration, Nigeria's National Agency for Food and Drug Administration and Control, Bayer, and Genentech, with moderators from ASCO and American Cancer Society. Key discussion themes and resulting action steps were agreed upon by all participants. Panelists agreed that increasing diversity in cancer clinical trials by including African patients is key to ensuring novel drugs are safe and effective across populations. They underscored the importance of equity in clinical trial access for patients in Africa. Panelists discussed their values related to access and barriers to opening clinical trials in Africa and described innovative solutions from their work aimed at overcoming these obstacles. Multisectoral collaboration efforts that allow leveraging of limited resources and result in sustainable capacity building and mutually beneficial long-term partnerships were discussed as key to outlined action steps. The panel discussion resulted in valuable insights about key stakeholder values and priorities related to bringing early-stage clinical trials to Africa, as well as specific actions for each stakeholder group.

Introduction: Sacituzumab govitecan-hziy, approved in 2020 for treatment of metastatic triple-negative breast cancer, provides a new option for a population with a historically poor prognosis with standard chemotherapy. Uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers are at increased risk for profound neutropenia. This case discusses clinical implications of the uridine diphosphate glucuronosyltransferase family 1 member A1*28/*28 genotype in patients receiving sacituzumab govitecan-hziy., Case Report: A 38-year-old otherwise healthy pre-menopausal female of South Asian descent was diagnosed with non-metastatic, hormone receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer. This was treated with neoadjuvant chemotherapy and multiple lines of subsequent therapies. Upon finding bone metastasis, an additional six lines of therapy ensued. In total, 3.5 years post-diagnosis, sacituzumab govitecan-hziy was started for disease transformation to triple-negative status., Management and Outcome: Sacituzumab govitecan-hziy was initiated at the Food and Drug Administration-approved 10 mg/kg/dose on days 1 and 8 of a 21-day cycle. Grade 4 neutropenia occurred after one dose. Pharmacogenomics testing identified the patient as a uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressor. Sacituzumab govitecan-hziy was dose-reduced, and granulocyte colony-stimulating factor was administered due to the severity of neutropenia. The patient continued on sacituzumab govitecan-hziy until disease progression., Discussion: Sacituzumab govitecan-hziy's propensity to cause neutropenia is multifactorial. Although incidence of all-grade neutropenia from sacituzumab govitecan-hziy is elevated for uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressors, this does not translate to increased risk for febrile neutropenia. Detailed guidance is lacking regarding empiric dose adjustments or prophylactic granulocyte colony-stimulating factor for these patients. 1 Currently, pre-sacituzumab govitecan-hziy pharmacogenomics testing to identify uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers is not recommended, and the cost-effectiveness of this approach is unclear.

Purpose: We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1)., Methods: The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing., Results: The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80)., Conclusion: The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC., Competing Interests: Ian E. KropEmployment: Freeline Therapeutics (I), PureTech (I)Leadership: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Stock and Other Ownership Interests: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Honoraria: Genentech/Roche, AstraZeneca¸ CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, MacroGenics, Novartis, Merck, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech (Inst), Pfizer (Inst) Seock-Ah ImConsulting or Advisory Role: AstraZeneca, Novartis, Roche/Genentech, Eisai, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, MSD, Daiichi SankyoResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Roche/Genentech (Inst), Daewoong Pharmaceutical (Inst), Eisai (Inst)Other Relationship: Roche Carlos BarriosStock and Other Ownership Interests: Biomarker, MedSIR, TummiHonoraria: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai¸ MSD, Bayer, Lilly, AstraZeneca, Zodiac PharmaConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Novartis, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Medical, LillyResearch Funding: Pfizer (Inst), Novartis (Inst), Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Roche/Genentech (Inst), Lilly (Inst), Sanofi (Inst), Taiho Pharmaceutical (Inst), Mylan (Inst), Merrimack (Inst), Merck (Inst), AbbVie (Inst), Astellas Pharma (Inst), BioMarin (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Abraxis BioScience (Inst), AB Science (Inst), Asana Biosciences (Inst), Medivation (Inst), Exelixis (Inst), ImClone Systems (Inst), LEO Pharma (Inst), Millennium (Inst), Janssen (Inst), Clinica Atlantis (Inst), INC Research (Inst), Halozyme (Inst), Covance (Inst), Celgene (Inst), inVentiv Health (Inst), Merck KGaA (Inst), Shanghai Henlius Biotech (Inst), Polyphor (Inst), PharmaMar (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, Lilly Hervé BonnefoiTravel, Accommodations, Expenses: Roche, Pfizer Julie GralowConsulting or Advisory Role: Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seattle Genetics, Genomic Health Masakazu ToiHonoraria: Novartis, Takeda, Eisai, AstraZeneca, Chugai Pharma, Taiho Pharmaceutical, Yakult Pharmaceutical, Shimadzu, Pfizer, Lilly, Kyowa Kirin, Devicor Medical Products, Exact Sciences, Nippon KayakuConsulting or Advisory Role: Daiichi Sankyo, Kyowa Kirin, Bertis, Athenex, BMS, Kansai Medical, Terumo, Lux Biosciences, AstraZeneca¸ LillySpeakers' Bureau: Pfizer, AstraZeneca, Lilly, Daiichi SankyoResearch Funding: Taiho Pharmaceutical, Chugai Pharma, Shimadzu, Astellas Pharma, AFI technology, Japan Breast Cancer Research Group, Pfizer, Eisai, Daiichi Sankyo, AstraZeneca, Nippon Kayaku, Kyoto Breast Cancer Research Network, Shionogi, Lilly, Yakult Pharmaceutical, Lux Biosciences (Inst), GL Science (Inst)Patents, Royalties, Other Intellectual Property: JP 2017-143763 WO2017/131162A1, PCT/JP2016/004374Travel, Accommodations, Expenses: EisaiOther Relationship: Japan Breast Cancer Research Group, Kyoto Breast Cancer Research Network, Organization for Oncology and Translational Research, Breast Cancer research and Treatment, Frontier in Women's Cancer, Scientific Reports, International Journal of Clinical Oncology, Cancer Science, Asian Journal of Surgery, Asian Journal of Breast Surgery, British Journal of Cancer Luca GianniConsulting or Advisory Role: Roche, Pfizer, AstraZeneca, Genomic Health, Merck Sharp & Dohme, Synaffix, Celgene, Lilly, ADC Therapeutics, Odonate Therapeutics, Oncolytics, Genenta Science, Sandoz, METIS Precision Medicine, Novartis, Revolution Medicines, Zymeworks, G1 Therapeutics, Genentech, Onkaido Therapeutics, Taiho Pharmaceutical, Seattle Genetics, Synthon, Forty Seven, Sanofi, Amgen, Menarini, BioMedical Insights, Artemida Pharma LtdSpeakers' Bureau: Roche Product, Zymeworks, Revolution MedicinesPatents, Royalties, Other Intellectual Property: RocheTravel, Accommodations, Expenses: Celgene, Roche, Chugai Pharma, Pfizer Sandra M. SwainConsulting or Advisory Role: Inivata, Genentech/Roche, Daiichi Sankyo, Molecular Templates, Athenex, Silverback Therapeutics, AstraZeneca, Exact Sciences, Natera, Beijing Medical Award Foundation, Lilly, MerckResearch Funding: Genentech (Inst), Kailos Genetics (Inst)Travel, Accommodations, Expenses: Caris Life Sciences, Daiichi Sankyo, Genentech/RocheOther Relationship: AstraZeneca, RocheOpen Payments Link: https://openpaymentsdata.cms.gov/physician/801195/associated-research-funding Michelino De LaurentiisHonoraria: Roche, Novartis, Pfizer, Lilly, Amgen, Pierre Fabre, AstraZeneca, MSD, Seattle Genetics, Gilead Sciences, Takeda, IpsenConsulting or Advisory Role: Roche, Novartis, Pfizer, Lilly, Amgen, AstraZeneca, MSD, Pierre Fabre, Seattle Genetics, Gilead Sciences, Ipsen, TakedaSpeakers' Bureau: NovartisResearch Funding: Novartis, Roche, Lilly, Puma Biotechnology, Pfizer, Daiichi Sankyo, MSD, MacroGenics, Bristol Myers Squibb Zbigniew NoweckiTravel, Accommodations, Expenses: Roche/Genentech Chiun-Sheng HuangHonoraria: Roche, Novartis, Pfizer, AstraZenecaConsulting or Advisory Role: Amgen, Pfizer, Roche, Lilly, AstraZeneca, NovartisSpeakers' Bureau: Amgen, Pfizer, Roche, Novartis, AstraZenecaResearch Funding: AstraZeneca (Inst), Lilly (Inst), MSD (Inst), Novartis (Inst)¸ Pfizer (Inst), Roche (Inst), OBI Pharma (Inst), EirGenix (Inst), Daiichi Sankyo (Inst)Travel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Yoshinori ItoResearch Funding: Daiichi Sankyo (Inst), Chugai Pharma (Inst), Novartis (Inst), Parexel (Inst), EPS Associates Co, Ltd (Inst), MSD (Inst), AstraZeneca (Inst), Lilly (Inst) Jigna ShahEmployment: GenentechStock and Other Ownership Interests: GenentechTravel, Accommodations, Expenses: GenentechOther Relationship: Genentech Thomas BouletEmployment: Roche/Genentech Haiying LiuEmployment: GenentechStock and Other Ownership Interests: Roche/GenentechTravel, Accommodations, Expenses: Roche/Genentech Harrison MachariaEmployment: Roche/Genentech Peter TraskEmployment: Roche/GenentechStock and Other Ownership Interests: Genentech, Pfizer Chunyan SongEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/Genentech Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other Relationship: InfiniteMD Nadia HarbeckStock and Other Ownership Interests: West German Study GroupHonoraria: Roche, Novartis, Amgen, Pfizer, AstraZeneca¸ Pierre Fabre, Daiichi-Sankyo, Exact Sciences, MSD, Seattle GeneticsConsulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, Sandoz, Daiichi Sankyo, AstraZeneca, West German Study Group (Inst), Pierre Fabre, Seattle Genetics, MSDResearch Funding: Roche/Genentech, Lilly, MSD¸ AstraZenecaNo other potential conflicts of interest were reported.

Cancer and its treatment pose challenges that affect not only patients but also their significant others, including intimate partners. Accumulating evidence suggests that couples' ability to communicate effectively plays a major role in the psychological adjustment of both individuals and the quality of their relationship. Two key conceptual models have been proposed to account for how couple communication impacts psychological and relationship adjustment: the social-cognitive processing (SCP) model and the relationship intimacy (RI) model. These models posit different mechanisms and outcomes, and thus have different implications for intervention. The purpose of this project is to test and compare the utility of these models using comprehensive and methodologically rigorous methods. Aims are: (1) to examine the overall fit of the SCP and RI models in explaining patient and partner psychological and relationship adjustment as they occur on a day-to-day basis and over the course of 1 year; (2) to examine the fit of the models for different subgroups (males vs. females, and patients vs. partners); and (3) to examine the utility of various methods of assessing communication by examining the degree to which baseline indices from different measurement strategies predict self-reported adjustment at 1-year follow up. The study employs a longitudinal, multi-method approach to examining communication processes including: standard self-report questionnaires assessing process and outcome variables collected quarterly over the course of 1 year; smartphone-based ecological momentary assessments to sample participant reports in real time; and laboratory-based couple conversations from which we derive observational measures of communicative behavior and affective expression, as well as vocal indices of emotional arousal. Participants are patients with stage II-IV breast, colon, rectal, or lung cancer and their spouses/partners, recruited from two NCI-designated comprehensive cancer centers. Results will be published in scientific journals, presented at scientific conferences, and conveyed to a larger audience through infographics and social media outlets. Findings will inform theory, measurement, and the design and implementation of efficacious interventions aimed at optimizing both patient and partner well-being., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Langer, Romano, Keefe, Baucom, Strauman, Syrjala, Bolger, Burns, Bricker, Todd, Baucom, Fischer, Ghosh, Gralow, Shankaran, Zafar, Westbrook, Leo, Ramos, Weber and Porter.)

Purpose: Breast cancer civil society organizations have emerged in Eastern Europe and Central Asia to raise awareness about cancer as a survivable disease and provide patient support. We explored the experiences and priorities of these organizations with the goal of making recommendations to advance cancer advocacy and improve cancer care., Methods: We conducted in-depth interviews and focus group discussions with representatives of civil society organizations attending the 7th Women's Empowerment Cancer Advocacy Network Summit in Romania in 2015. Interviews were audiorecorded, transcribed, coded, and analyzed for key themes. Findings were discussed at the 8th Women's Empowerment Cancer Advocacy Network Summit in Ukraine in 2017 to ensure accuracy., Results: We conducted nine in-depth interviews and three focus group discussions with a total of 36 participants. Survivor- and oncologist-led organizations played an important role in filling existing gaps in public health care systems through awareness raising, patient support, and advocacy to improve early detection and access to treatment. Barriers to these efforts included persistent stigma, mistrust of patients toward the public health care system, limited access to evidence-based guidelines, difficulty adapting existing best practices to their setting, and insufficient involvement of policymakers. Key facilitators of advocacy efforts included effective local and international partnerships with physicians, like-minded organizations, and policymakers to facilitate access to educational resources, improve breast cancer early detection and care, and catalyze meaningful policy change., Conclusion: Our findings highlight the value of providing opportunities for advocates to connect and share experiences. To advance cancer advocacy and improve cancer care, the following needs were identified: dissemination of resource-adapted information for improving outcomes; needs assessments; improved program-monitoring practices; and fostering and promotion of collaboration between advocates, medical professionals, and local governments., Competing Interests: Nicoleta AntoneTravel, Accommodations, Expenses: Pfizer Romania, Roche/Genentech Julie GralowConsulting or Advisory Role: Genentech, Sandoz, AstraZeneca, Immunomedics Jo Anne ZujewskiStock and Other Ownership Interests: Olema PharmaceuticalsConsulting or Advisory Role: Leidos Biomedical Research, PMK Bioresearch, BeyondSpring Pharmaceuticals, Olema PharmaceuticalsNo other potential conflicts of interest were reported.

Importance: Osteonecrosis of the jaw (ONJ) affects patients with cancer and metastatic bone disease (MBD) treated with bone-modifying agents (BMAs), yet the true incidence is unknown., Objective: To define the cumulative incidence of ONJ at 3 years in patients receiving zoledronic acid for MBD from any malignant neoplasm., Design, Setting, and Participants: This multicenter, prospective observational cohort study (SWOG Cancer Research Network S0702) included patients with MBD with either limited or no prior exposure to BMAs and a clinical care plan that included use of zoledronic acid within 30 days of registration. Medical, dental, and patient-reported outcome forms were submitted at baseline and every 6 months. Follow-up was 3 years. Osteonecrosis of the jaw was defined using established criteria. Data were collected from January 30, 2009, to December 13, 2013, and analyzed from August 24, 2018, to August 6, 2020., Interventions/exposures: Cancer treatments, BMAs, and dental care were administered as clinically indicated., Main Outcomes and Measures: Cumulative incidence of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region present for more than 8 weeks with no concurrent radiotherapy to the craniofacial region. Risk factors for ONJ were also examined., Results: The SWOG S0702 trial enrolled 3491 evaluable patients (1806 women [51.7%]; median age, 63.1 [range, 2.24-93.9] years), of whom 1120 had breast cancer; 580, myeloma; 702, prostate cancer; 666, lung cancer; and 423, other neoplasm. A baseline dental examination was performed in 2263 patients (64.8%). Overall, 90 patients developed confirmed ONJ, with cumulative incidence of 0.8% (95% CI, 0.5%-1.1%) at year 1, 2.0% (95% CI, 1.5%-2.5%) at year 2, and 2.8% (95% CI, 2.3%-3.5%) at year 3; 3-year cumulative incidence was highest in patients with myeloma (4.3%; 95% CI, 2.8%-6.4%). Patients with planned zoledronic acid dosing intervals of less than 5 weeks were more likely to experience ONJ than patients with planned dosing intervals of 5 weeks or more (hazard ratio [HR], 4.65; 95% CI, 1.46-14.81; P = .009). A higher rate of ONJ was associated with fewer total number of teeth (HR, 0.51; 95% CI, 0.31-0.83; P = .006), the presence of dentures (HR, 1.83; 95% CI, 1.10-3.03; P = .02), and current smoking (HR, 2.12; 95% CI, 1.12-4.02; P = .02)., Conclusions and Relevance: As the findings show, the cumulative incidence of ONJ after 3 years was 2.8% in patients receiving zoledronic acid for MBD. Cancer type, oral health, and frequency of dosing were associated with the risk of ONJ. These data provide information to guide stratification of risk for developing ONJ in patients with MBD receiving zoledronic acid.

The Uganda Cancer Institute, the sole national comprehensive cancer center in Uganda, has a long and rich history of clinical investigation and locally relevant cancer research. Given the increasing burden of breast cancer in Uganda and elsewhere in sub-Saharan Africa (SSA) and driven by the limited availability of immunohistochemistry (IHC), we launched a clinical trial aimed at evaluating locally available diagnostics to detect the presence of hormone receptors (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2. Preliminary data from 32 women in the diagnostic component of the study reveal high sensitivity and specificity for estrogen receptor and progesterone receptor and high specificity for human epidermal growth factor receptor 2 when comparing reverse transcriptase polymerase chain reaction with the gold standard (IHC). Innovative diagnostic and treatment strategies are required to address the burden of breast cancer that is increasing throughout SSA. Given the costs, infrastructure, and trained personnel associated with IHC, alternative testing options (including reverse transcriptase polymerase chain reaction as tested in our study) may provide an expedited and cost-effective method to determine receptor testing in breast cancer. Clinical trials conducted in the local setting are critical to determining optimal strategies for effective breast cancer management in SSA.

Purpose: Brain drain is the migration of educated and skilled individuals from a less developed region or country to a more economically established one. The Trump administration proposed a merit-based immigration plan. This article addresses its potential impact on health care delivery in low- and middle-income countries (LMICs) and their preparedness to deal with it., Materials and Methods: Data on immigration policies, numbers of international medical graduates practicing in high-income countries (HICs), various scientific exchange methods, and efforts for capacity building in LMICs., Results: Talented individuals seek to advance their knowledge and skills, and may stay in HICs because of greater rewards and opportunities. HICs also rely on immigrant international medical graduates to supplement their physician workforces., Conclusion: Ambitious individuals from LMICs need and should have opportunities to advance their education and training in more advanced countries. LMICs should increase their educational efforts, research capabilities, infrastructures, and living conditions to better serve their own populations and reduce their brain drain phenomenon.

Metastatic breast cancer frequently leads to brain metastases and, less commonly, leptomeningeal carcinomatosis (LC). Once cerebrospinal fluid involvement occurs, the prognosis is poor. There are limited treatment options available, but none offer significant survival benefit. Methotrexate, given systemically at high doses (3.5-8 gm/m 2 ), achieves cytotoxic concentrations in the CSF and has been shown to prolong survival in patients with LC. Intrathecal liposomal cytarabine has been shown to increase time to neurologic progression in patients with breast cancer and LC. The combination of these 2 agents in LC has not been studied extensively. Here, we present the results of the phase II study with this combination showing promising efficacy and very good tolerability., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To analyze self-reported changes in physical function in older women with breast cancer receiving adjuvant chemotherapy., Design: Secondary analysis of the Cancer and Leukemia Group B (CALGB) 49907 prospective randomized clinical trial., Setting: CALGB institutions in the United States., Participants: Women aged 65 and older with Stage I to III breast cancer enrolled in CALGB 49907 who had physical function data from before and after receipt of adjuvant chemotherapy (N=256; mean age 71.5, range 65-85)., Measurements: Participants were administered the physical function subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire before chemotherapy, at the end of chemotherapy, and 12 months after chemotherapy initiation. Functional decline was defined as a more than 10-point decrease from baseline at each time point. Resilience was defined as return to within 10 points of baseline. Multivariable regression was used to examine pretreatment characteristics associated with physical function changes., Results: Of 42% of participants who had physical function decline from before to the end of chemotherapy, 47% recovered by 12 months (were resilient). Almost one-third experienced functional decline from before chemotherapy to 12 months later. Pretreatment fatigue was a risk factor for functional decline from before to the end of chemotherapy (P=.02). Risk factors for functional decline at 12 months included pretreatment dyspnea (P=.007) and being unmarried (P=.01)., Conclusion: Functional decline was common in older women receiving adjuvant chemotherapy for breast cancer in a clinical trial. Although half recovered their physical function, one-third had a clinically meaningful decline at 12 months. Strategies are needed to prevent functional decline in older adults receiving chemotherapy. J Am Geriatr Soc 67:920-927, 2019., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Introduction: Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC., Patients and Methods: We conducted a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC. During induction, the patients received nab-paclitaxel 100 mg/m 2 intravenously (days 1, 8, and 15) and bevacizumab 10 mg/kg intravenously (days 1 and 15) every 28 days for 6 cycles. Patients free of progression at 24 weeks received maintenance therapy with bevacizumab 10 mg/kg intravenously every 2 weeks and oral erlotinib 150 mg/d until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were best overall response, overall survival (OS), and adverse events. We explored the measurement of circulating tumor cells as a prognostic marker., Results: A total of 55 evaluable patients were enrolled. The median PFS and OS for the cohort was 9.1 months (95% confidence interval, 7.2-11.1) and 18.1 months (95% confidence interval, 15.6-21.7), respectively. Of the 53 patients with measurable disease, 39 (74%) had experienced a partial response and 10 (19%) had stable disease using the Response Evaluation Criteria In Solid Tumors. The most common toxicities were uncomplicated neutropenia, fatigue, and neuropathy. Decreased circulating tumor cells from baseline to the first assessment correlated with longer PFS and OS., Conclusion: Nab-paclitaxel and bevacizumab, followed by maintenance targeted therapy with bevacizumab and erlotinib, resulted in PFS similar to that of other trials. Most patients experienced a partial response (74%). Most patients received maintenance therapy (55%), providing a break from cytotoxic chemotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Progress toward improvement in cancer therapy relies on clinical trials. Yet, only a minority of eligible patients with cancer enroll as a result of multiple barriers at the patient, investigator, center, and national level. However, the rise of the Internet and mobile technology has created a slew of tools with medical applications, from Web sites to apps to social media platforms, all of which may aide clinicians in our quest to improve the clinical research enterprise. SWOG is one of five members in the National Cancer Institute's National Clinical Trials Network-the nation's oldest and largest publicly funded cancer research network-and is taking a leadership role in exploring and testing the promise of digital engagement through the empaneling of the Digital Engagement Committee. This article outlines the mission, principles, and priorities of the Digital Engagement Committee and proposes how this work may inform the use of digital tools for the cancer research community and, hopefully, translate to improved outcomes for our patients.

Purpose: Although aromatase inhibitors (AIs) prolong survival in post-menopausal breast cancer (BC) patients, AI-associated arthralgia can lead to discontinuation. Obese patients have higher rates of AI arthralgia than non-obese patients, but treatment options are limited. Omega-3 fatty acid (O3-FA) treatment for AI arthralgia has produced mixed results., Methods: We performed an exploratory analysis of SWOG S0927, a multicenter randomized placebo-controlled trial of O3-FA use for AI arthralgia. Post-menopausal women with stage I-III BC taking an AI were randomized to 24 weeks of O3-FAs or placebo. Brief Pain Inventory (BPI) questionnaires and fasting serum were collected at baseline, 12, and 24 weeks. The BPI assessment included worst pain, average pain, and pain interference scores (range 0-10)., Results: Among the 249 participants, 139 had BMI < 30 kg/m 2 (56%) and 110 had BMI ≥ 30 kg/m 2 (44%). Among obese patients, O3-FA use was associated with significantly lower BPI worst pain scores at 24 weeks compared with placebo (4.36 vs. 5.70, p = 0.02), whereas among non-obese patients, there was no significant difference in scores between treatment arms (5.27 vs. 4.58, p = 0.28; interaction p = 0.05). Similarly, O3-FA use was associated with lower BPI average pain and pain interference scores at 24 weeks compared with placebo among obese patients, but no significant difference between treatment arms in non-obese patients (interaction p = 0.005 and p = 0.01, respectively)., Conclusions: In obese BC patients, O3-FA use was associated with significantly reduced AI arthralgia compared to placebo.

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18 F-FDG PET was predictive of time to skeletal-related events (tSRE) and time to progression (TTP). 18 F-NaF PET improves bone metastasis detection compared with bone scanning. We prospectively tested 18 F-FDG PET and 18 F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (MBC). Methods: Patients with bone-dominant MBC were imaged with 18 F-FDG PET and 18 F-NaF PET before starting new therapy (scan1) and again at a range of times centered around approximately 4 mo later (scan2). Maximum standardized uptake value (SUV max ) and lean body mass adjusted standardized uptake (SUL peak ) were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18 F-FDG PET and 18 F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) were also applied. Survival curves for mPERCIST compared response categories of complete response+partial response+stable disease versus progressive disease for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher 18 F-FDG SUL peak at scan2 predicted shorter time to tSRE ( P = <0.001) and TTP ( P = 0.044). Higher 18 F-FDG SUV max at scan2 predicted a shorter time to tSRE ( P = <0.001). A multivariable model using 18 F-FDG SUV max of the index lesion at scan1 plus the difference in SUV max of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18 F-FDG PET mPERCIST, tSRE and TTP were longer in responders (complete response, partial response, or stable disease) than in nonresponders (progressive disease) ( P = 0.007, 0.028, respectively), with a trend toward improved survival ( P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18 F-NaF PET was associated with longer OS ( P = 0.027). Conclusion: Changes in 18 F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18 F-NaF PET was associated with OS but was not useful for predicting TTP or tSRE in bone-dominant MBC., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: This study aimed to test the feasibility of a 12-month weight loss intervention using telephone-based counseling plus community-situated physical activity (PA) in female breast cancer (BC) and colorectal cancer (CRC) survivors., Methods: This multisite cooperative group study enrolled sedentary, female, postmenopausal BC and CRC survivors with BMI ≥ 25 kg/m 2 to receive 12-month fitness center memberships and telephone counseling encouraging 150 min/wk of PA and a 500-kcal/ddecrease in energy intake. Feasibility criteria included accrual, adherence, and retention. Target weight loss was ≥ 5%., Results: Among 25 BC survivors, median baseline BMI was 37.2 (range: 27.7-54.6), accrual occurred in 10 months, 60% and 28% met diet and exercise goals, 80% provided 12-month measures, and average weight loss was 7.6% (95% CI: -3.9%, 19.2%). Among 23 CRC survivors, median BMI was 31.8 (range: 26.4-48.7), accrual occurred in 24 months, 61% and 17% met diet and exercise goals, 87% provided measures, and average weight loss was 2.5% (95% CI: -8.2%, 13.3%)., Conclusions: It is feasible to recruit and retain BC survivors in a cooperative group diet and PA weight loss trial. BC survivors achieved clinically meaningful weight loss but did not meet a priori adherence goals. In CRC survivors, recruitment was more difficult, and the intervention was less effective., (© 2018 The Obesity Society.)

Many studies have sought to optimize the dosing schedule of adjuvant chemotherapy in early-stage breast cancer. Here, we assessed the use of continuous metronomic weekly doxorubicin plus daily oral cyclophosphamide (AC) with continuous G-CSF growth factor support for 12 weeks followed by weekly nab-paclitaxel (nP) for 12 weeks. A nonrandomized phase II clinical trial was designed to assess (1) DFS at 2 years, (2) dose delivered, (3) use of nP in the adjuvant setting, and (4) toxicities. The dosing of A was 24 mg/m2 IV weekly and C was 60 mg/m2 oral daily (with scheduled filgrastim 5mcg/kg 6 days/week); nP, 100 mg/m2 IV weekly. For patients with HER2 + disease, trastuzumab was started during the nP portion of therapy and continued for 12 months. Sixty patients enrolled with a median follow-up of 6 years. Node-positive disease was present in 58% of patients. Receptor categories included hormone receptor positive/HER2 negative (n = 25; 42%); triple negative (n = 19; 32%); or HER2 positive (n = 16; 27%). DFS at 2 years was 93%. Mean dose delivered was greater than 90% for metronomic AC and 88% for nP. Treatment was well tolerated with a 2% incidence of febrile neutropenia. Continuous metronomic AC followed by nP was well tolerated in our patients with comparable DFS to historical controls., (© 2018 Wiley Periodicals, Inc.)

The objectives of this article are to describe the ASCO Resource-Stratified Guidelines and to provide background within the context of ASCO Guidelines and efforts to address the global cancer burden.

Our aim was to examine the association of pretreatment tumor-infiltrating lymphocyte (TIL) count and PD-L1 levels with pathologic complete response (pCR) and assess immune marker changes following treatment in tumor specimens from the S0800 clinical trial, which randomized patients to bevacizumab + nab-paclitaxel, followed by doxorubicin/cyclophosphamide (AC) versus two control arms without bevacizumab (varying sequence of AC and nab-paclitaxel). TILs were assessed in 124 pre- and 62 posttreatment tissues (including 59 pairs). PD-L1 was assessed in 120 pre- and 43 posttreatment tissues (including 39 pairs) using the 22C3 antibody. Baseline and treatment-induced immune changes were correlated with pCR and survival using estrogen receptor (ER) and treatment-adjusted logistic and Cox regressions, respectively. At baseline, the mean TIL count was 17.4% (17% had zero TILs, 9% had ≥50% TILs). Posttreatment, mean TIL count decreased to 11% (5% had no TILs, 2% had >50% TILs). In paired samples, the mean TIL change was 15% decrease. Baseline PD-L1 was detected in 43% of cases ( n = 5 in tumor cells, n = 29 stroma, n = 18 tumor + stroma). Posttreatment, PD-L1 expression was not significantly lower (33%). Higher baseline TIL count and PD-L1 positivity rate were associated with higher pCR rate even after adjustment for treatment and ER status ( P = 0.018). There was no association between TIL counts, PD-L1 expression, and survival due to few events. In conclusion, TIL counts, but not PD-L1 expression, decreased significantly after treatment. Continued PD-L1 expression in some residual cancers raises the possibility that adjuvant immune checkpoint inhibitor therapy could improve survival in this patient population. Mol Cancer Ther; 17(6); 1324-31. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Approximately 0.5 million people worldwide die from metastatic breast cancer (mBC) every year. This manuscript provides an overview on the status of mBC in several regions of the world, highlighting the gaps in care, resources, and support available for patients with mBC. Primary research was conducted in 2015 and 2016, comprising four global qualitative and quantitative surveys of approximately 15,000 individuals in 34 countries. Secondary research was conducted using literature reviews of peer-reviewed publications, patient survey reports, and media or online articles. There have been modest improvements in mBC outcomes over the past decade. Patients are not provided with adequate information about mBC. There is a need for open discussion with patients and caregivers about realistic goals; however, physicians are not trained in communicating with patients about their disease. Maintaining patients' quality of life is a crucial goal; however, this has not improved, and in some cases, may have declined in the past decade. Public awareness and understanding of mBC is limited, with damaging consequences for patients and caregivers. Issues affecting employment remain relevant to patients with mBC and their caregivers. Globally, mBC is associated with a substantial economic burden. Relationships with caregivers are crucial to patients with mBC, and caregiver support needs are often overlooked. A strong and united global effort among healthcare professionals, including clinicians, oncologists, pharmaceutical manufacturers, payers, and policy makers, and with advocates, families, and patients, is necessary to improve the outcome and quality of life for patients with mBC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose MA.17R was a Canadian Cancer Trials Group-led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor as adjuvant therapy for hormone receptor-positive breast cancer. Quality of life (QOL) was a secondary outcome measure of the study, and here, we report the results of these analyses. Methods QOL was measured using the Short Form-36 (SF-36; two summary scores and eight domains) and menopause-specific QOL (MENQOL; four symptom domains) at baseline and every 12 months up to 60 months. QOL assessment was mandatory for Canadian Cancer Trials Group centers but optional for centers in other groups. Mean change scores from baseline were calculated. Results One thousand nine hundred eighteen women were randomly assigned, and 1,428 women completed the baseline QOL assessment. Compliance with QOL measures was > 85%. Baseline summary scores for the SF-36 physical component summary (47.5 for letrozole and 47.9 for placebo) and mental component summary (55.5 for letrozole and 54.8 for placebo) were close to the population norms of 50. No differences were seen between groups in mean change scores for the SF-36 physical and mental component summaries and the other eight QOL domains except for the role-physical subscale. No difference was found in any of the four domains of the MENQOL Conclusion No clinically significant differences were seen in overall QOL measured by the SF-36 summary measures and MENQOL between the letrozole and placebo groups. The data indicate that continuation of aromatase inhibitor therapy after 5 years of prior treatment in the trial population was not associated with a deterioration of overall QOL.

Background: This study evaluated the efficacy of an intervention combining the Valencia model of waking hypnosis with cognitive-behavioral therapy (VMWH-CBT) in managing cancer-related pain, fatigue, and sleep problems in individuals with active cancer or who were post-treatment survivors. We hypothesized that four sessions of VMWH-CBT would result in greater improvement in participants' symptoms than four sessions of an education control intervention. Additionally, we examined the effects on several secondary outcome domains that are associated with increases in these symptoms (depression, pain interference, pain catastrophizing, and cancer treatment distress)., Methods: The study design was a randomized controlled crossover clinical trial comparing the VMWH-CBT intervention with education control. Participants (N = 44) received four sessions of both treatments, in a counterbalanced order (n = 22 per order condition)., Results: Participants were 89% female (N = 39) with mean age of 61 years (SD = 12.2). They reported significantly greater improvement after receiving the active treatment relative to the control condition in all the outcome measures. Treatment gains were maintained at 3-month follow-up., Conclusions: This study supports the beneficial effects of the VMWH-CBT intervention relative to a control condition and that treatment gains remain stable. VMWH-CBT-trained clinicians should be accessible for managing symptoms both during and after cancer treatment, though the findings need to be replicated in larger samples of cancer survivors., (Copyright © 2016 John Wiley & Sons, Ltd.)

Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor-positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.

Every year, more than 2 million women worldwide are diagnosed with breast or cervical cancer, yet where a woman lives, her socioeconomic status, and agency largely determines whether she will develop one of these cancers and will ultimately survive. In regions with scarce resources, fragile or fragmented health systems, cancer contributes to the cycle of poverty. Proven and cost-effective interventions are available for both these common cancers, yet for so many women access to these is beyond reach. These inequities highlight the urgent need in low-income and middle-income countries for sustainable investments in the entire continuum of cancer control, from prevention to palliative care, and in the development of high-quality population-based cancer registries. In this first paper of the Series on health, equity, and women's cancers, we describe the burden of breast and cervical cancer, with an emphasis on global and regional trends in incidence, mortality, and survival, and the consequences, especially in socioeconomically disadvantaged women in different settings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n = 349) was superior to anastrozole alone (n = 345) in hormone receptor (HR)-positive metastatic breast cancer. Here we report a pharmacokinetic subset analysis investigating a possible drug interaction between anastrozole and fulvestrant., Methods: Post-menopausal patients with HR-positive metastatic breast cancer were randomized to anastrozole with or without concurrent fulvestrant. Blood samples were collected at 2, 4, 6 and 8 months, just prior to receiving the next dose of anastrozole and fulvestrant. Drug concentrations were measured via LC/MS-MS. Anastrozole concentration was compared in patients on anastrozole alone vs. patients on concomitant fulvestrant. Comparisons were made at each time point using parametric tests and over time using a linear mixed effects model., Results: A total of 483 anastrozole concentration measurements were included, 224 samples from 64 patients on the anastrozole alone arm and 259 from 73 patients on the combination arm. The mean anastrozole concentration in the combination arm was significantly lower than that in the anastrozole alone arm at each sample collection time (all P < 0.01) and in the mixed effects model (an estimated difference of 9.85 ng ml(-1) (95% CI 5.69, 14.00 ng ml(-1) ), P < 0.001)., Conclusion: A significant pharmacokinetic drug interaction was detected, in which the addition of fulvestrant to anastrozole treatment decreased the trough anastrozole concentration. Further research is needed to verify whether this interaction affects treatment efficacy and to determine the pharmacological mechanism by which this interaction occurs., (© 2016 The British Pharmacological Society.)

Purposes: To (1) determine the frequency and severity of hot flashes, (2) examine the associations between hot flash frequency and severity and quality of life, and (3) identify the predictors of hot flash activity in breast cancer survivors., Methods: The study used a cross-sectional design and mailed survey of 253 breast cancer survivors recruited from a cancer wellness clinic. Participants provided information regarding cancer history, hot flashes, pain intensity, sleep problems, physical functioning, and psychological functioning., Results: About half of the survivors reported at least one hot flash in the past 24 h (45%) or past week (52%). The average frequency of hot flashes was 1.9 in the past 24 h and 1.8 in the past week. Hot flash severity was usually mild or asymptomatic. However, participants with hot flashes reported significantly more sleep problems and higher pain severity than those reporting no hot flashes. Moreover, the severity of hot flashes was associated with more sleep problems, higher pain severity, and more psychological dysfunction. History of hormonal suppression therapy and younger age predicted hot flash activity in the study sample., Conclusions: In breast cancer survivors, hot flashes are common and are associated with unpleasant symptoms and poor quality of life. Research is needed to determine if treatments that reduce the frequency and severity of hot flashes in breast cancer survivors also result in improvements in symptoms such as sleep problems, pain, and psychological dysfunction., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Studies point to a direct association between social support and better cancer outcomes. This study examined whether baseline social support is associated with better survival and fewer chemotherapy-related adverse events in older, early-stage breast cancer patients., Methods: This study is a pre-planned secondary analysis of CALGB 49907/Alliance A171301, a randomized trial that compared standard adjuvant chemotherapy versus capecitabine in breast cancer patients 65 years of age or older. A subset reported on the extent of their social support with questionnaires that were completed 6 times over 2 years., Results: The median age of this 331-patient cohort was 72 years (range: 65, 90); 179 (55%) were married, and 210 (65%) lived with someone. One hundred forty-five patients (46%) described a social network of 0-10 people; 110 (35%) of 11-25; and 58 (19%) of 26 or more. The Medical Outcomes Study (MOS) social support survey revealed that the median scores (range) for emotional/informational, tangible, positive social interaction, and affectionate social support were 94 (3, 100), 94 (0, 100), 96 (0, 100), and 100 (8, 100), respectively. Social support scores appeared stable over 2 years and higher (more support) than in other cancer settings. No statistically significant associations were observed between social support and survival and adverse events in multivariate analyses. However, married patients had smaller tumors, and those with arthritis reported less social support., Conclusion: Although social support did not predict survival and adverse events, the exploratory but plausible inverse associations with larger tumors and arthritis suggest that social support merits further study., (Copyright © 2015 John Wiley & Sons, Ltd.)

Purpose: CALGB 49907 showed the superiority of standard therapy, which included either cyclophosphamide/doxorubicin (AC) or cyclophosphamide/methotrexate/fluorouracil over single-agent capecitabine in the treatment of patients age ≥ 65 with early-stage breast cancer. The treatment allowed dosing adjustments of methotrexate and capecitabine for pretreatment renal function. The purpose of the current analysis was to assess the relationship between pretreatment renal function and five end points: toxicity, dose modification, therapy completion, relapse-free survival, and overall survival., Methods: Pretreatment renal function was defined as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Multivariable logistic and proportional hazards regression were used to model separately for each regimen the relationship between CrCl and the first three binary end points and the last two time-to-event end points, respectively, after adjusting for variables of prognostic importance., Results: Six hundred nineteen assessable patients were analyzed. The incidence of stage III (moderate) or stage IV (severe) renal dysfunction was 72%, 64%, and 75% for treatment with cyclophosphamide/methotrexate/fluorouracil, AC, and capecitabine, respectively. There was no relationship for any regimen between pretreatment renal function and the five end points. For AC, as CrCl increased, the odds of nonhematologic toxicity decreased (P = .008), whereas for capecitabine, as CrCl increased, the odds of experiencing toxicity of any type also increased (P = .035). Patients with renal insufficiency who received dose modifications were not at increased risk for complications compared with those who did not have renal insufficiency and received a full dose., Conclusion: Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients., (© 2016 by American Society of Clinical Oncology.)

Background: Screening MRI is recommended for individuals at high risk for breast cancer, based on genetic risk or family history (GFH); however, there is insufficient evidence to support screening MRI for women with a personal history (PH) of breast cancer. We compared screening MRI performance in women with PH vs GFH of breast cancer., Methods: We analyzed case-series registry data, collected at time of MRI and at 12-month follow-up, from our regional Clinical Oncology Data Integration project. MRI performance was compared in women with PH with those with GFH. Chi-square testing was used to identify associations between age, prior history of MRI, and clinical indication with MRI performance; logistic regression was used to determine the combined contribution of these variables in predicting risk of a false-positive exam. All statistical tests were two-sided., Results: Of 1521 women who underwent screening MRI from July 2004 to November 2011, 915 had PH and 606 had GFH of breast cancer. Overall, MRI sensitivity was 79.4% for all cancers and 88.5% for invasive cancers. False-positive exams were lower in the PH vs GFH groups (12.3% vs 21.6%, P < .001), specificity was higher (94.0% vs 86.0%, P < .001), and sensitivity and cancer detection rate were not statistically different (P > .99). Age (P < .001), prior MRI (P < .001), and clinical indication (P < .001) were individually associated with initial false-positive rate; age and prior MRI remained statistically significant in multivariable modeling (P = .001 and P < .001, respectively)., Conclusion: MRI performance is superior in women with PH compared with women with GFH. Screening MRI warrants consideration as an adjunct to mammography in women with a PH of breast cancer., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab., Methods: N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative <10.7, equivocal 10.7 to <11.5, and positive ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence., Results: Median follow-up was 7.4 years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14 %), equivocal in 85 (9 %), and positive in 686 (76 %) patients. Concordance between HER2 assessments was 95 % for RT-PCR versus central immunohistochemistry (IHC) (>10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels., Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays., Trial Registration: Clinicaltrials.gov NCT00005970 . Registered 5 July 2000.

Purpose: Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Omega-3 fatty acids (O3-FAs) can be effective in decreasing arthralgia resulting from rheumatologic conditions and reducing serum triglycerides., Patients and Methods: Women with early-stage breast cancer receiving an AI who had a worst joint pain/stiffness score ≥ 5 of 10 using the Brief Pain Inventory-Short Form (BPI-SF) were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. Clinically significant change was defined as ≥ 2-point drop from baseline. Patients also completed quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Symptoms) and additional pain/stiffness assessments at baseline and weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis., Results: Among 262 patients registered, 249 were evaluable, with 122 women in the O3-FA arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein., Conclusion: We found a substantial (> 50%) and sustained improvement in AI arthralgia for both O3-FAs and placebo but found no meaningful difference between the groups., (© 2015 by American Society of Clinical Oncology.)