Chemotherapy-induced weight gain in early-stage breast cancer: a prospective matched cohort study reveals associations with inflammation and gut dysbiosis.

BACKGROUND: Early-stage breast cancer patients treated with chemotherapy risk the development of metabolic disease and weight gain, which can result in increased morbidity and reduced quality of life in survivorship. We aimed to analyze changes within the gastrointestinal microbiome of early-stage breast cancer patients treated with and without chemotherapy to investigate a potential relationship between dysbiosis, a systemic inflammatory response, and resultant anthropomorphic changes. METHODS: We undertook an a priori analysis of serially collected stool and plasma samples from 40 patients with early-stage breast cancer who underwent adjuvant endocrine therapy only, adjuvant chemotherapy only, or both. Gut microbiota were assessed by metagenomic comparison of stool samples following deep sequencing. Inflammatory biomarkers were evaluated by proteomic analysis of plasma and measurement of fecal calprotectin. Body composition was investigated by dual-energy X-ray absorptiometry to determine biomass indices. RESULTS: As opposed to treatment with endocrine therapy only, chemotherapy resulted in statistically and clinically significant weight gain and an increase in the android to gynoid ratio of fat distribution. Patients treated with chemotherapy gained an average of 0.15% total mass per month, as opposed to a significantly different loss of 0.19% in those patients who received endocrine-only therapy. Concurrently, a twofold increase in fecal calprotectin occurred after chemotherapy that is indicative of interferon-dependent inflammation and evidence of colonic inflammation. These anthropomorphic and inflammatory changes occurred in concert with a chemotherapy-dependent effect on the gut microbiome as evidenced by a reduction in both the abundance and variety of microbial species. CONCLUSIONS: We confirm the association of chemotherapy treatment with weight gain and potential deleterious anthropometric changes and suggest that alterations of bacterial flora may contribute to these phenomena through the induction of systemic inflammation. Consequently, the gut microbiome may be a future target for intervention in preventing chemotherapy-dependent anthropometric changes.

Unwarranted imaging for distant metastases in patients with newly diagnosed ductal carcinoma in situ and stage I and II breast cancer

Background: In 2012, the American Society of Clinical Oncology (ASCO) released a Choosing Wisely Top Five list that included a recommendation against ordering advanced imaging tests to screen for metastases among asymptomatic patients with early breast cancer. Our provincial breast cancer staging guideline was subsequently updated. We report on the use of unwarranted bone scanning (BS), computed tomography (CT), nonbreast magnetic resonance imaging (MRI) and positron emission tomography (PET) among women diagnosed with stage 0­II breast cancer in Alberta in 2011­2015. Methods: The cohort was retrospectively ascertained from the Alberta Cancer Registry. We used additional provincial data sources to obtain information about diagnostic imaging tests completed from biopsy to surgical date plus 4 months. The reason for each BS, CT, MRI and PET was abstracted. We calculated the frequency of advanced imaging tests completed for routine metastatic screening. Results: Of 10 142 patients included, 2887 (28.5%) had at least 1 advanced imaging test completed for routine metastatic screening. Of these 2887 patients, 438 (15.2%) had a follow-up BS, CT, MRI or PET, and 28 patients (1.0%) had a nonbreast imageguided biopsy. Use of routine advanced imaging tests did not change clearly over time. Conclusion: Our results demonstrate persistent use of advanced imaging tests for routine metastatic screening among patients with stage 0­II breast cancer despite the release of the ASCO Choosing Wisely recommendations and the update of our provincial breast cancer staging guideline. Investigation of strategies for guideline translation to improve upon value-based care of patients with early breast cancer is warranted.

Contexte: En 2012, l'American Society of Clinical Oncology (ASCO) a publié sa liste de 5 interventions à « Choisir avec soin ¼, dans laquelle elle recommandait notamment de ne pas recourir aux techniques d'imagerie de pointe pour le dépistage des métastases chez les patientes atteintes d'un cancer du sein peu avancé et asymptomatique. Nos lignes directrices provinciales pour la stadification du cancer du sein ont été mises à jour en conséquence. Nous faisons aujourd'hui état de l'utilisation injustifiée de la scintigraphie osseuse (SO), de la tomodensitométrie (TDM), de l'imagerie par résonnance magnétique (IRM) non mammaire et de la tomographie par émission de positrons (TEP) chez les femmes ayant reçu un diagnostic de cancer du sein peu avancé (stade 0-II) en Alberta entre 2011 et 2015. Méthodes: La cohorte a été réunie de manière rétrospective à partir du registre albertain du cancer. Nous avons utilisé d'autres sources de données provinciales pour obtenir des renseignements sur les épreuves d'imagerie diagnostique effectuées entre les dates de la biopsie et les dates de la chirurgie plus 4 mois. Le motif invoqué pour recourir à chaque SO, TDM, IRM et TEP a été recueilli. Nous avons calculé la fréquence des épreuves d'imagerie de pointe effectuées pour un dépistage de routine des métastases. Résultats: Sur les 10 142 patientes incluses, 2887 (28,5 %) avaient subi au moins 1 épreuve d'imagerie de pointe pour le dépistage de routine des métastases. Parmi ces 2887 patientes, 438 (15,2 %) ont subi une SO, une TDM, une IRM ou une TEP de suivi et 28 patientes (1,0 %) ont subi une biopsie non mammaire guidée par l'imagerie. L'utilisation de routine des épreuves d'imagerie de pointe n'a pas nettement changé avec le temps. Conclusion: Selon nos résultats, l'utilisation des épreuves d'imagerie de pointe pour le dépistage de routine des métastases persiste chez les patientes atteintes d'un cancer du sein de stade 0­II, malgré la publication des recommandations Choisir avec soin de l'ASCO et la mise à jour de nos lignes directrices provinciales concernant la stadification du cancer du sein. Il faudra se pencher sur des stratégies pour améliorer l'adoption de lignes directrices relatives aux soins véritablement utiles pour les patientes atteintes d'un cancer du sein peu avancé.

Why "Reply All" Can Push All the Wrong Buttons.

Technology has changed the way medicine is practiced. This commentary considers the effect of digital communications and offers advice on e­mail etiquette.

Palbociclib with Letrozole in Postmenopausal Women with ER+/HER2- Advanced Breast Cancer: Hematologic Safety Analysis of the Randomized PALOMA-2 Trial.

BACKGROUND: PALOMA-2 confirmed that first-line palbociclib + letrozole improved progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.46-0.72) in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This analysis evaluated palbociclib-associated hematologic adverse events (AEs) and provides insight on managing these AEs. MATERIALS AND METHODS: Postmenopausal women with ER+/HER2- ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC). RESULTS: PALOMA-2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression-free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12-700) days (grade ≥ 3, 28.0 [12-854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001). CONCLUSION: Palbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2- ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427) IMPLICATIONS FOR PRACTICE: Palbociclib demonstrated an acceptable safety profile in PALOMA-2 in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) receiving first-line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib-related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first-line treatment for ER+/HER2- ABC.

Creating a pragmatic trials program for breast cancer patients: Rethinking Clinical Trials (REaCT).

BACKGROUND: The proportion of breast cancer patients enrolled in clinical trials is falling. The Rethinking Clinical Trials (REaCT) program was developed to challenge some of the contemporary barriers responsible for this fall in accrual. In this article, we review the successes and challenges our program has faced. METHODS: The REaCT program was created to improve care and outcomes for cancer patients through surveys of patients and healthcare providers, systematic reviews, economic evaluations, and the performance of pragmatic randomized trials with patient-centered outcomes. Likely, the greatest difference to conventional trial methodologies has been our widespread use of the integrated consent model (ICM) incorporating oral consent. RESULTS: Between 2014 and 2018, the program has recruited over 2000 patients to 15 randomized studies at 11 Canadian cancer centers. The REaCT program has completed and published five patient surveys, six healthcare provider surveys, ten systematic reviews, performed four economic evaluations, opened 15 clinical trials comparing standard of care interventions (two surgical, two adjuvant chemotherapy, five adjuvant supportive care, one radiology, two vascular devices, two palliative supportive care, and one molecular diagnostics). Patient surveys have shown high levels of satisfaction with the ICM. CONCLUSION: The REaCT program was developed to tackle important practice questions that will better guide optimal practice and to increase the availability of pragmatic clinical trials. While many challenges remain, future strategies will involve including more study sites and efforts to integrate novel information technology strategies.

Undiagnosed cardiac deficits in non-small cell carcinoma patients in the candidate population for anti-cachexia clinical trials.

PURPOSE: Currently, there is no approved therapy for cancer cachexia. According to European and American regulatory agencies, physical function improvements would be approvable co-primary endpoints of new anti-cachexia medications. As physical functioning is in part dependent on cardiac functioning, we aimed to explore the cardiac status of a group of patients meeting current criteria for inclusion in cachexia clinical trials. METHODS: Seventy treatment-naive patients with metastatic NSCLC [36 (51.4%) male; 96% ECOG 0-1; eligible for carboplatin-based therapy and meeting eligibility criteria for cachexia clinical trials] were recruited before the start of first-line carboplatin-based chemotherapy. Patients were evaluated by echocardiography, electrocardiography, and scales for fatigue and dyspnea. Computed tomography cross-sectional images were utilized for body composition analysis. RESULTS: In 9/70 patients (12.8%), echocardiography allowed discovery of clinically relevant cardiac disorders [seven patients with left ventricular ejection fraction (LVEF) 32%-47%; one patient with severe right ventricular dilation and severe pulmonary hypertension and one patient with severe pericardial effusion warranted hospitalization and drainage]. Another 10/70 (14.3%) patients had diastolic dysfunction with preserved LVEF. The cardiac conditions were associated with aggravated fatigue (p < 0.05), dyspnea (p < 0.05), and anemia (p = 0.06). Five out of seven patients with LVEF < 50% were sarcopenic and one was borderline sarcopenic. CONCLUSION: Baseline cardiac status of the metastatic NSCLC patients adds potential heterogeneity for anti-cachexia clinical trials. Detailed cardiac screening data might be useful for inclusion/exclusion criteria, randomization, and post hoc analysis.

The "Begin Exploring Fertility Options, Risks and Expectations" (BEFORE) decision aid: development and alpha testing of a fertility tool for premenopausal breast cancer patients.

BACKGROUND: Premenopausal breast cancer patients are at risk of treatment-related infertility. Many patients do not receive sufficient fertility information before treatment. As such, our team developed and alpha tested the Begin Exploring Fertility Options, Risks, and Expectations decision aid (BEFORE DA). METHODS: The BEFORE DA development process was guided by the International Patient Decision Aids Standards and the Ottawa Decision Support Framework. Our team used integrated knowledge translation by collaborating with multiple stakeholders throughout the development process including breast cancer survivors, multi-disciplinary health care providers (HCPs), advocates, and cancer organization representatives. Based on previously conducted literature reviews and a needs assessment by our team - we developed a paper prototype. The paper prototype was finalized at an engagement meeting with stakeholders and created into a graphically designed paper and mirrored online decision aid. Alpha testing was conducted with new and previously engaged stakeholders through a questionnaire, telephone interviews, or focus group. Iterative reviews followed each step in the development process to ensure a wide range of stakeholder input. RESULTS: Our team developed an 18-page paper prototype containing information deemed valuable by stakeholders for fertility decision-making. The engagement meeting brought together 28 stakeholders to finalize the prototype. Alpha testing of the paper and online BEFORE DA occurred with 17 participants. Participants found the BEFORE DA usable, acceptable, and most provided enthusiastic support for its use with premenopausal breast cancer patients facing a fertility decision. Participants also identified areas for improvement including clarifying content/messages and modifying the design/photos. The final BEFORE DA is a 32-page paper and mirrored online decision aid ( https://fertilityaid.rethinkbreastcancer.com ). The BEFORE DA includes information on fertility, fertility options before/after treatment, values clarification, question list, next steps, glossary and reference list, and tailored information on the cost of fertility preservation and additional resources by geographic location. CONCLUSION: The BEFORE DA, designed in collaboration with stakeholders, is a new tool for premenopausal breast cancer patients and HCPs to assist with fertility discussions and decision-making. The BEFORE DA helps to fill the information gap as it is a tool that HCPs can refer patients to for supplementary information surrounding fertility.

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Predatory Invitations from Journals: More Than Just a Nuisance?

Physicians and academic researchers are frequently targeted with spam invitations to submit manuscripts to predatory journals. This study was conducted to understand the nature and characteristics of these invitations. All spam e-mails received by an academic medical oncologist over a 3-month period were collected and categorized. Presumed predatory journal invitations were analyzed and cross-checked against Beall's list of "potential, probable, or possible predatory" journals and publishers. Invitations to submit to predatory journals were the most common single type of spam received. The Oncologist 2017;22:236-240.

Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm.

The results of the Phase III DESTINY-Breast04 trial of trastuzumab deruxtecan (T-DXd) are leading to a shift in both the classification and treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. In this trial, T-DXd was associated with a substantial survival benefit among patients with hormone receptor-positive and hormone receptor-negative disease and low expression of HER2, a biomarker previously considered unactionable in this treatment setting. Herein, we discuss the evolving therapeutic pathway for HER2-low disease, ongoing clinical trials, and the potential challenges and evidence gaps arising with treatment of this patient population.

Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial.

Importance: Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination. Objective: To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes. Design, Setting, and Participants: In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021. Interventions: All patients in phases 1b and 2 received avelumab plus talazoparib. Main Outcomes and Measures: The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers. Results: A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]). Conclusions and Relevance: This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations. Trial Registration: ClinicalTrials.gov Identifier: NCT03330405.

Novel Therapies for the Treatment of HER2-Positive Advanced Breast Cancer: A Canadian Perspective.

The advent of anti-HER2 targeted therapies has dramatically improved the outcome of HER2-positive breast cancer; however, resistance to treatment in the metastatic setting remains a challenge, highlighting the need for novel therapies. The arrival of new treatment options and clinical trials examining the efficacy of novel agents may improve outcomes in the metastatic setting, including in patients with brain metastases. In the first-line setting, we can potentially cure a selected number of patients treated with pertuzumab + trastuzumab + taxane. In the second-line setting, clinical trials show that trastuzumab deruxtecan (T-DXd) is a highly effective option, resulting in a shift from trastuzumab emtansine (T-DM1) as the previous standard of care. Moreover, we now have data for patients with brain metastases to show that tucatinib + trastuzumab + capecitabine can improve survival in this higher-risk group and be an effective regimen for all patients in the third-line setting. Finally, we have a number of effective anti-HER2 therapies that can be used in subsequent lines of therapy to improve patient outcomes. This review paper discusses the current treatment options and presents a practical treatment sequencing algorithm in the context of the Canadian landscape.

Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines.

BACKGROUND: Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available. METHODS: We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms 'breast cancer' AND 'HER2' AND 'advanced' AND ('phase II' OR 'phase III'). RESULTS: Eight clinical trials reporting efficacy outcomes on third-line or greater HER2-directed therapy for HER2-positive advanced breast cancer were identified. In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p < 0.001) and 0.1-month (HR = 0.76, p = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS). Tucatinib added to trastuzumab and capecitabine demonstrated a significant 2.7-month improvement in median PFS (HR = 0.57, p < 0.00001) and a 5.5-month improvement in median OS (HR = 0.73, p = 0.004) in a randomized phase II trial, including significant clinical benefit for patients with brain metastases. Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients. CONCLUSION: Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable.

Cost-Effectiveness Analysis of 12-Versus 4-Weekly Administration of Bone-Targeted Agents in Patients with Bone Metastases from Breast and Castration-Resistant Prostate Cancer.

A cost-utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) (n = 130) versus 4-weekly (once every 4 weeks) (n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer's perspective.

Optimising weight-loss interventions in cancer patients-A systematic review and network meta-analysis.

BACKGROUND: Excess weight has been associated with increased morbidity and a worse prognosis in adult patients with early-stage cancer. The optimal lifestyle interventions to optimize anthropometric measures amongst cancer patients and survivors remain inconsistent. OBJECTIVE: To conduct a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing the effects of exercise and dietary interventions alone or in combination on anthropometric measures of adult cancer patients and survivors. METHODS: A systematic search of Medline, Embase and the Cochrane Trials Registry was performed. Outcomes of interest included changes in weight, body mass index (BMI), and waist circumference. Screening and data collection were performed by two reviewers. Bayesian NMAs were performed. RESULTS: Overall, 98 RCTs were included; 75 were incorporated in NMAs (n = 12,199). Groups of intervention strategies included: 3 exercise interventions, 8 dietary interventions, 7 combination interventions of diet and exercise and standard care. Median intervention duration was 26 weeks. NMA suggested that diet alone (mean difference [MD] -2.25kg, 95% CrI -3.43 to -0.91kg) and combination strategies (MD -2.52kg, 95% CrI -3.54 to -1.62kg) were associated with more weight loss compared to standard care. All dietary interventions achieved a similar magnitude of weight loss (MD range from -2.03kg to -2.52kg). Both diet alone and combination strategies demonstrated greater BMI reductions versus standard care, and each of diet alone, exercise alone and combination strategies demonstrated greater reductions in waist circumference than standard care. CONCLUSION: Diet and exercise alone or in combination are effective lifestyle interventions to improve anthropometric measures in cancer patients and survivors. All reputable diets appear to be similarly effective to achieve weight loss.

Genome profiles of pathologist-defined cell clusters by multiregional LCM and G&T-seq in one triple-negative breast cancer patient.

Pathological examination is the gold standard for cancer diagnosis, and breast tumor cells are often found in clusters. We report a case study on one triple-negative breast cancer (TNBC) patient, analyzing tumor development, metastasis, and prognosis with simultaneous DNA and RNA sequencing of pathologist-defined cell clusters from multiregional frozen sections. The cell clusters are isolated by laser capture microdissection (LCM) from primary tumor tissue, lymphatic vessels, and axillary lymph nodes. Data are reported for a total of 97 cell clusters. A combination of tumor cell-cluster clonality and phylogeny reveals 3 evolutionarily distinct pathways for this patient, each associated with a unique mRNA signature, and each correlated with disparate survival outcomes. Hub gene analysis indicates that extensive downregulation of ribosomal protein mRNA is a potential marker of poor prognosis in breast cancer.

A randomised trial of 4- versus 12-weekly administration of bone-targeted agents in patients with bone metastases from breast or castration-resistant prostate cancer.

BACKGROUND: Optimal dosing of bone-targeted agents (BTAs), in patients with bone metastases remains an important clinical question. This trial compared 4-weekly versus 12-weekly therapy. PATIENTS AND METHODS: Patients with bone metastases from breast or castration-resistant prostate cancer (CRPC), who were going to start or already on BTAs, were randomised 1:1 to 4-weekly or 12-weekly BTA treatment for one year. Primary end point was change in health-related quality of life (HRQoL)-physical function European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30). Secondary end points included pain (EORTC-QLQ-BM22), global health status (EORTC-QLQ-C30), symptomatic skeletal events (SSEs) rates and time to SSEs. Primary analysis was per protocol and a non-inferiority margin of 5 points was used. RESULTS: Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). Using repeated-measures analysis, across all time points, patients in the 4-weekly arm had a mean HRQL-physical subdomain score which was 1.2 (95% confidence interval: -1.6 to 4.0) higher than the 12-weekly arm. The study met the definition of non-inferiority for our primary outcome. Secondary outcomes showed no significant difference in scores for pain, global health status, SSE rates and SSE-free survival between arms. Subgroup analyses for cancer type, prior BTA use or BTA type showed no significant difference between arms. CONCLUSION: These results in addition to those previously reported for de-escalating zoledronate and systematic reviews in both breast and prostate cancers, would support that de-escalation of commonly used BTAs is a reasonable treatment option.

Positive progress: current and evolving role of immune checkpoint inhibitors in metastatic triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with historically poor overall outcomes, due primarily to a lack of effective targeted agents. Chemotherapy has been the primary treatment approach, although immune checkpoint inhibitors (ICIs) are currently being investigated to improve patient outcomes. This review examines the clinical implications of current evidence on the use of ICIs for the treatment of metastatic TNBC. METHODS: Our systematic search identified two phase III and five phase I/II trials reporting on the efficacy of ICIs used as monotherapy or combined with chemotherapy for the treatment of metastatic TNBC. RESULTS: The phase III IMpassion 130 trial showed a significant improvement in median progression-free survival in the intent-to-treat (net 1.7 months, p = 0.002) and PD-L1-positive populations (net 2.5 months, p < 0.001) for the addition of first-line atezolizumab versus placebo to nab-paclitaxel in metastatic TNBC. Although median overall survival was not significantly improved in patients receiving atezolizumab overall [net 2.3 months, hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.72-1.02, p = 0.078], numerical improvements in the PD-L1-positive population were compelling (net 7.0 months, HR 0.71; 95% CI 0.54-0.93). Toxicity profiles were as expected, and no new safety signals were observed. Pembrolizumab monotherapy did not significantly improve overall survival in similar patients that had received prior treatment in KEYNOTE-119. CONCLUSIONS: Atezolizumab plus nab-paclitaxel represents a potential new first-line standard of care for patients with metastatic PD-L1-positive TNBC. Other ICIs used as monotherapy, or combined with chemotherapy for advanced TNBC, as well as their use for earlier stage disease, are areas of ongoing investigation.

Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

Rapid atrophy of cardiac left ventricular mass in patients with non-small cell carcinoma of the lung.

BACKGROUND: Cancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac function, symptoms, and clinical outcomes. METHODS: Treatment naïve metastatic non-small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin-based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function [LV ejection fraction, global longitudinal strain (GLS), diastolic function], computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival. RESULTS: During 112 ± 6 days, the median change in LVM was -8.9% [95% confidence interval (95% CI) -10.8 to -4.8, P < 0.001]. Quartiles of LVM loss were -20.1%, -12.9%, -4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle [odds ratio (OR) = 4.5, 95% CI: 1.4-14.8, P=0.01] and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7-36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9-22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C-reactive protein (P=0.008), high sensitivity troponin T (hs-TnT) (P=0.03), and galectin-3 (P=0.02) increased over time, while N-terminal pro B-type natriuretic peptide and hs-cTnI did not change over time. C-reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2-46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4-153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9-22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4-35.8, P<0.001), and deterioration of performance status (OR = 4.8, 95% CI: 1.3-18.3,P=0.02). Patients with concurrent loss of LVM, skeletal muscle, and fat were more likely to deteriorate in all three symptom domains and to have reduced survival (P=0.05). CONCLUSIONS: Intense LVM atrophy is associated with non-small cell lung cancer-induced cachexia. Loss of LVM was associated with emerging alterations of GLS, indicating subtle changes in left ventricular function. Longer term studies are needed to assess the full scope of cardiac atrophy and its impact. LVM atrophy arises in conjunction with losses of fat and skeletal muscle and is temporally associated with meaningful declines in performance status, worsening of fatigue, and dyspnoea, as well as poorer tumour response and decreased survival. The specific contribution of LVM atrophy to these outcomes requires further study.