The effects of adding palbociclib to endocrine therapy to treat advanced breast cancer: a plain language summary of a study using the PALOMA-2 and PALOMA-3 trial results.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article that reported results of a study using data from two phase 3 clinical trials called "PALOMA-2" and "PALOMA-3." Both PALOMA-2 and PALOMA-3 trials included women with HR+/HER2- advanced breast cancer. HR+/HER2- breast cancer means the breast cancer cells of these women have receptors for female sex hormones and little or no HER2 receptors. Both PALOMA trials tested the effect of adding a medication called palbociclib (brand name, Ibrance®) to a hormone therapy. Hormone therapy, also known as endocrine therapy, is a treatment that blocks or removes hormones that cause cancer cells to grow and divide. In both trials, women took endocrine therapy with either palbociclib or a placebo. WHAT WAS THE AIM OF THIS STUDY?: The researchers aimed to see if the results from the PALOMA trials were similar for subgroups of women in the 2 trials. The subgroups in the study included women who shared certain features about their cancer or treatment history, for example, women whose cancer had spread to the liver. For each subgroup, the study compared the results from the 2 treatment groups: (1) women who took palbociclib plus endocrine therapy, and (2) women who took placebo plus endocrine therapy. WHAT WERE THE RESULTS & WHAT DO THEY MEAN?: The same effect was found in all subgroups. Compared with those who took placebo, women who took palbociclib lived longer without their cancer getting worse (growing or spreading). Also, among women who had chemotherapy after stopping the trial treatment, those who took palbociclib started chemotherapy later than those who took placebo. Because palbociclib slows cancer growth and leads to tumor shrinkage, this may have played a part in starting chemotherapy later. These results show that palbociclib plus endocrine therapy is better at slowing the progression of advanced HR+/HER2- breast cancer than endocrine therapy alone. This can be said for women with different advanced HR+/HER2- breast cancer features and treatment history. Overall, the results support women taking palbociclib with an endocrine therapy if they have advanced HR+/HER2- breast cancer.

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.

Reply to Trudeau, M.; Fraser, B. The CADTH pCODR Expert Review Committee Process Explained. Comment on "Rayson et al. Access to Neoadjuvant Pertuzumab for HER2 Positive Breast Cancer in Canada: A Dilemma Increasingly Difficult to Explain. Curr. Oncol. 2022, 29, 9891-9895".

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Phase angle is associated with muscle health and cardiorespiratory fitness in older breast cancer survivors.

BACKGROUND & AIM: Phase angle (PhA) obtained from bioelectrical impedance analysis (BIA) is an indicator of cellular integrity and relates to several chronic conditions. The purpose of this secondary analysis was to evaluate the association of PhA with health-related physical fitness, namely, cardiorespiratory fitness, skeletal muscle volume, and myosteatosis (i.e. muscle health) in older breast cancer survivors. METHODS: Twenty-two women ≥60 years with a body mass index (BMI) ≥25 kg/m2 and who completed chemotherapy for early-stage breast cancer were included. BIA, cardiopulmonary exercise tests and magnetic resonance imaging scans were completed before and after eight weeks of time-restricted eating. RESULTS: At baseline, PhA was associated with cardiorespiratory fitness (R2 = 0.54, p < 0.01) and skeletal muscle volume (R2 = 0.83, p < 0.01) and myosteatosis (R2 = 0.25, p = 0.02). Results were similar at follow-up. CONCLUSION: Findings from this pilot study suggest that higher values of PhA are associated with better health-related physical fitness among older breast cancer survivors.

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.

Time-Restricted Eating in Breast Cancer Survivors: Effects on Body Composition and Nutritional Status.

In this secondary analysis of an 8-wk single-arm feasibility study of weekday time-restricted eating (TRE), we explored the effects of TRE on body composition. Women (n = 22; ≥60 yr) who had completed chemotherapy for early-stage breast cancer and had a body mass index ≥25 kg/m2 were enrolled. Bioelectrical impedance analysis was performed before and after 8 wk of TRE, and nutritional status was evaluated by bioelectrical impedance vector analysis (BIVA). Body weight (p = 0.01) and total fat mass (p = 0.04) decreased with TRE. Phase angle was low (defined as ≤5.6°) in 86% of participants at baseline and did not change. Four participants who initially presented with obesity (>95% ellipse, BIVA) had favorable body composition modifications after TRE. Our study highlighted a less favorable body composition profile, poorer cell integrity and overhydration in these patients. BIVA was a useful method to assess body composition and hydration. A short TRE intervention was associated with decreased estimated fat mass and a favorable change in nutritional status in those with obesity.

Implementation of weekday time-restricted eating to improve metabolic health in breast cancer survivors with overweight/obesity.

OBJECTIVE: This study aimed to evaluate the implementation of telephone-based delivery of weekday-only time-restricted eating (TRE), its preliminary efficacy for metabolic outcomes, and concurrent lifestyle changes. METHODS: Twenty-two breast cancer survivors aged 60+ years with overweight/obesity completed an 8-week feasibility study of 12 to 8 p.m. weekday-only ad libitum TRE. The intervention was delivered by one registered dietitian call, twice-daily automated text messages asking about eating start and stop times, and three support phone calls. Magnetic resonance imaging, venipuncture, and 3 days of diet records and accelerometry were performed at baseline and after intervention. RESULTS: Participants had a mean age of 66 (SD 5) years with BMI of 31.8 (4.8) kg/m2 . Intervention implementation was successful, including excellent adherence (98%), participant acceptability, and a low symptom profile and cost ($63/participant). There were no significant changes in individual components of metabolic syndrome, lipid profile, or hemoglobin A1c , despite clinically relevant changes occurring within individual participants. Magnetic resonance imaging-derived hepatic steatosis and thigh myosteatosis did not change. Dietary intake changes included reduced energy (-22%) and protein (-0.2 g/kg). Physical activity and sleep did not change. CONCLUSIONS: Eight weeks of telephone-delivered weekday TRE is a feasible, acceptable, low-symptom, and low-cost intervention. Future studies may consider a longer intervention length for more consistent metabolic improvements and counseling to enhance protein intake.

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.

Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3.

BACKGROUND: Previous analyses from the PALOMA-2 and PALOMA-3 studies showed that palbociclib (PAL) plus endocrine therapy (ET) prolongs time to first subsequent chemotherapy (TTC) versus placebo (PBO) plus ET in the overall population of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+/HER2-) advanced breast cancer (ABC). Here, we evaluated TTC in relevant patient subgroups. METHODS: These post hoc analyses evaluated TTC by subgroup using data from 2 randomized, phase 3 studies of women with HR+/HER2- ABC. In PALOMA-2, postmenopausal patients previously untreated for ABC were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus letrozole (LET; 2.5 mg/day; n = 444) or PBO plus LET (n = 222). In PALOMA-3, premenopausal or postmenopausal patients whose disease had progressed after prior ET were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus fulvestrant (FUL; 500 mg; n = 347) or PBO plus FUL (n = 174). RESULTS: First subsequent chemotherapy was received by 35.5% and 56.2% in PALOMA-2 and PALOMA-3 after progression on palbociclib plus ET or placebo plus ET. Across all subgroups analyzed, the median progression-free survival (PFS) was longer in the PAL plus ET arm than the PBO plus ET arm. TTC was longer with PAL plus ET versus PBO plus ET across the same patient subgroups in both studies. CONCLUSIONS: Across all subgroups, PAL plus ET versus PBO plus ET had longer median PFS and resulted in prolonged TTC in both the PALOMA-2 and PALOMA-3 studies. Pfizer Inc (NCT01740427, NCT01942135).

Access to Neoadjuvant Pertuzumab for HER2 Positive Breast Cancer in Canada: A Dilemma Increasingly Difficult to Explain.

The addition of pertuzumab to neoadjuvant trastuzumab and chemotherapy for women with early-stage, high-risk, HER2+ breast cancer has been observed to lead to higher pathologic complete response rates (pCR), and improved event-free survival compared to trastuzumab and chemotherapy alone. Based on available data, neoadjuvant pertuzumab is recommended by ESMO, ASCO, and NICE as well as by a Canadian Consensus Guideline Group. We discuss the implications for Canadian patients with HER2+ early breast cancer due to a second and final negative funding decision by the Canadian Agency for Drugs and Technologies in Health (CADTH) related to neoadjuvant pertuzumab. This decision will have adverse impacts for up to 1 in 6 women receiving neoadjuvant therapy for high-risk HER2+ breast cancer, due to suboptimal pCR rates and higher risks of invasive breast cancer recurrent events, resulting in the need for more toxic adjuvant therapy.

Virtual or In-Person: A Mixed Methods Survey to Determine Exercise Programming Preferences during COVID-19.

A survey was conducted to identify barriers and facilitators to engaging in virtual and in-person cancer-specific exercise during COVID-19. A theory-informed, multi-method, cross-sectional survey was electronically distributed to 192 individuals with cancer investigating preferences towards exercise programming during COVID-19. Respondents had previously participated in an exercise program and comprised two groups: those who had experience with virtual exercise programming ('Virtual') and those who had only taken part in in-person exercise ('In-Person'). Quantitative data were summarized descriptively. Qualitative data were thematically categorized using framework analysis and findings were mapped to an implementation model. The survey completion response rate was 66% (N = 127). All respondents identified barriers to attending in-person exercise programming during COVID-19 with concerns over the increased risk of viral exposure. Virtual respondents (n = 39) reported: (1) feeling confident in engaging in virtual exercise; and (2) enhanced motivation, accessibility and effectiveness as facilitators to virtual exercise. In-Person respondents (n = 88) identified: (1) technology as a barrier to virtual exercise; and (2) low motivation, accessibility and exercise effectiveness as barriers towards virtual exercise. Sixty-six percent (n = 58) of In-Person respondents reported that technology support would increase their willingness to exercise virtually. With appropriately targeted support, perceived barriers to accessing virtual exercise-including motivation, accessibility and effectiveness-may become facilitators. The availability of technology support may increase the engagement of individuals with cancer towards virtual exercise programming.

Feasibility of Implementing Cancer-Specific Community-Based Exercise Programming: A Multi-Centre Randomized Trial.

BACKGROUND: There is growing recognition of the importance of reporting preliminary work on the feasibility of a trial. The present study aimed to assess the feasibility of (1) a proposed fitness testing battery, and (2) processes related to the implementation of cancer-specific exercise programming in a community setting. METHODS/DESIGN: A randomized controlled implementation feasibility trial was performed in advance of a large-scale implementation study. Eligible participants within 18 months of a cancer diagnosis were randomized to immediate or delayed community-based exercise at YMCA locations in Calgary and Edmonton, Canada for an 8-week period. The primary outcome for the trial was the feasibility of the physical fitness testing battery, defined as a 70% or greater completion rate across the 24-week study period. The Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework was used to evaluate processes related to implementation of the exercise program across the two sites. RESULTS: Eighty participants were recruited, 73 (91%) completed the 8-week trial, and 68 (85%) completed the 16- and 24-week follow-ups. Sixty participants (75%) completed the full physical fitness test battery at each time point, and 59 (74%) completed the patient-reported outcome measures. Statistically significant between-group differences were found in favor of the exercise group for functional aerobic capacity, upper and lower extremity strength, and symptoms. Differences were found between the sites, however, in completion rates and processes related to program implementation. DISCUSSION: Findings suggest the need for minor adaptations to the physical fitness battery and outcome measures to better fit the community context. While findings support feasibility, context-specific challenges related to implementation processes were identified.

Heal-me PiONEer (personalized online nutrition and exercise): An RCT assessing 2 levels of app-based programming in individuals with chronic disease.

Background App-based strategies are a promising solution to deliver nutrition and exercise interventions during social distancing. With limited RCT data in individuals with chronic disease, further information is required both to determine impact, and to guide delivery. The Heal-Me app is an evidence-based, theoretically informed nutrition and exercise solution that can be tailored for use across a range of individuals with chronic disease. As compared to controls receiving educational material, the aim of this study is to assess the acceptability, effectiveness, and cost of Heal-Me app programming delivered alongside two levels of dietitian and exercise-specialist support. Methods Heal-Me PiONEer is a 12-week, 3-arm RCT with randomization to one of three study groups (n=72 per group, 216 total). Group 1 (control: educational material), Group 2 (Heal-Me app + virtual group dietitian/exercise-specialist sessions), Group 3 (Heal-Me app + virtual group and 1-to-1 dietitian/exercise-specialist sessions). Inclusion criteria: adults with cancer, chronic lung disease or status post-transplantation from liver or lung transplant; previous completion of an exercise rehabilitation program; access to an internet-connected device. Study outcomes measured at study weeks 0 and 12 include: Primary - Lower Extremity Functional Scale; Secondary - virtual physical function tests, loneliness, resilience, anxiety, well-being and health-related quality of life; Exploratory outcomes - protein intake, behavioral beliefs around exercise and nutrition, adherence, adverse events, acceptability, and cost-utility. Conclusions The Heal-Me PiONEer RCT holds promise to provide a comprehensive understanding of the delivery and impact of app-based nutrition and exercise programming in a diverse group of participants with chronic disease.

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.

Documenting patients' and providers' preferences when proposing a randomized controlled trial: a qualitative exploration.

BACKGROUND: With advances in cancer diagnosis and treatment, women with early-stage breast cancer (ESBC) are living longer, increasing the number of patients receiving post-treatment follow-up care. Best-practice survivorship models recommend transitioning ESBC patients from oncology-provider (OP) care to community-based care. While developing materials for a future randomized controlled trial (RCT) to test the feasibility of a nurse-led Telephone Survivorship Clinic (TSC) for a smooth transition of ESBC survivors to follow-up care, we explored patients' and OPs' reactions to several of our proposed methods. METHODS: We used a qualitative study design with thematic analysis and a two-pronged approach. We interviewed OPs, seeking feedback on ways to recruit their ESBC patients for the trial, and ESBC patients, seeking input on a questionnaire package assessing outcomes and processes in the trial. RESULTS: OPs identified facilitators and barriers and offered suggestions for study design and recruitment process improvement. Facilitators included the novelty and utility of the study and simplicity of methods; barriers included lack of coordination between treating and discharging clinicians, time constraints, language barriers, motivation, and using a paper-based referral letter. OPs suggested using a combination of electronic and paper referral letters and supporting clinicians to help with recruitment. Patient advisors reported satisfaction with the content and length of the assessment package. However, they questioned the relevance of some questions (childhood trauma) while adding questions about trust in physicians and proximity to primary-care providers. CONCLUSIONS: OPs and patient advisors rated our methods for the proposed trial highly for their simplicity and relevance then suggested changes. These findings document processes that could be effective for cancer-patient recruitment in survivorship clinical trials.

A Canadian national guideline on the neoadjuvant treatment of invasive breast cancer, including patient assessment, systemic therapy, and local management principles.

PURPOSE: The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles. METHODS: An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data. RESULTS: Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus. CONCLUSIONS: Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management.

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.

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. RESULTS: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. CONCLUSIONS: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

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.