PURPOSE: BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib. METHODS: Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived. RESULTS: Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months). CONCLUSION: This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.

Concomitant intake of proton pump inhibitors (PPIs) may create drug-drug interactions, potentially impacting efficacy of anticancer agents. In the phase III PALLAS trial, the addition of palbociclib capsules to standard adjuvant endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer did not improve invasive disease-free survival (iDFS). We explored whether concomitant use of PPIs affected survival outcomes in patients treated with palbociclib in PALLAS. This is an exploratory analysis of PALLAS including patients who received at least one dose of palbociclib capsules. We aimed to determine the association of concomitant PPI use with iDFS, distant relapse-free survival and overall survival. Uni- and multivariable Cox models with time-dependent PPI were used. The association between PPI use and neutropenia was also investigated. Of 2840 patients treated with palbociclib + endocrine therapy, 525 (18.5%) had concomitant PPI and palbociclib intake. PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors, higher body mass index, and worse Eastern Cooperative Oncology Group status (all P < 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (iDFS, distant relapse-free survival, overall survival). All-grade neutropenia rates were numerically lower in patients who initiated a PPI before study start compared with patients never initiating PPIs (adjusted odds ratio 0.81, 95% confidence interval 0.60-1.09). Our exploratory analysis did not demonstrate worse survival outcomes in patients receiving concomitant palbociclib and PPIs in PALLAS. Nonetheless, careful consideration of possible drug-drug interactions is important, especially when studying novel agents in the early breast cancer setting.

Summary: Clinical trials are subject to an ever-evolving landscape of treatment options, regulatory requirements, socioeconomic conditions, and paradigms of scientific research. In this opinion paper, we illustrate current methods and topics with a focus on clinical trial designs, conduct and modes of collaboration. The example of successful clinical breast cancer research in Austria demonstrates the opportunities, but also the challenges for academic research. We also investigate potential pitfalls, and suggest new ideas and strategies on how to increase practicability along with transparency and fairness, but ultimately also scientific and clinical relevance of clinical trials in oncology.

Advances in endocrine therapies for hormone receptor (HR)-positive/HER2-negative advanced breast cancer (ABC) continue to transform care and significantly improve patient outcomes. However, the integration of molecular and clinical risk stratification into guiding individualized treatment selection remains a key challenge. We therefore evaluated whether the integration of baseline circulating tumor DNA (ctDNA)-derived tumor metrics enhances risk stratification among patients receiving early lines of treatment of HR-positive ABC in a real-world multicenter cohort of patients in Austria. Patients with HR-positive/HER2-negative ABC treated at multiple Austrian centers were included. CtDNA was analyzed using a 77-gene panel (AVENIO ctDNA Expanded Kit). Tumor fraction (TFx) was estimated via two complementary approaches: untargeted aneuploidy assessment using mFAST-SeqS, and the highest variant allele frequency (hVAF) from the AVENIO assay. Somatic variants and single, binary, and three-level composite TFx metrics were assessed for their association with progression-free and overall survival (PFS, OS). We analyzed 225 ctDNA samples from 184 patients [128 before first-line (1L) and 76 before second-line (2L) treatment], including 40 paired samples. Overall TFx was low (median z-score 2.49; range -0.5-208.3), with higher levels in 2L, although the difference did not reach statistical significance (P = 0.058). In contrast, the hVAF was significantly higher in the 2L cohort (P = 0.007). Somatic variant burden was significantly increased in 2L (P < 0.001), with notably more frequent ESR1 mutations (26.7% versus 7.1% in 1L). Median PFS was 29.2 months in 1L and 6.0 months in 2L, while median OS was 57.3 months and 16.1 months, respectively. TP53 and ESR1 mutations, and all ctDNA-based metrics were significantly associated with PFS and OS, with a three-level composite ctDNA variable showing the highest prognostic discrimination. Our findings demonstrate that integrating baseline ctDNA-derived TFx metrics with established clinical variables significantly improves risk stratification in HR-positive/HER2-negative ABC.

The PALLAS phase III, randomized trial investigated whether the addition of 2 years of palbociclib to adjuvant endocrine therapy (ET) improved invasive disease-free survival (iDFS) over adjuvant ET alone. This study reports the patient-reported outcomes (PROs) by treatment arm. A total of 4688 of 5796 PALLAS patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, stage II-III breast cancer completed PRO measures. Patients were randomly assigned (1 : 1) to either 2 years of palbociclib (125 mg/day, 3 weeks on 1 week off) plus ongoing provider or patient-choice adjuvant ET (palbociclib + ET) versus ongoing ET alone. Eight PRO endpoints were measured serially (i.e. day 1 of each monthly cycle for the first 3 months, then every 3 months for 2 years, and once at 3 years). These endpoints were the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality-of-life (QoL) score, the Brief Fatigue Inventory (BFI) score, the modified Brief Pain Inventory (mBFI) severity and pain interference scores, the EORTC Core Quality of Life Questionaire-Breast 23 (QLQ-BR23) alopecia score, and the Breast Cancer Prevention Trial (BCPT) hot flash symptoms, vaginal problems, and musculoskeletal pain scores. Treatment with palbociclib stopped after the second interim analysis (May 2020) due to futility, and patients transitioned to follow-up. After adjustment for baseline covariates, on average, no significant differences between arms were observed on any of the eight endpoints over the study period. However, there were differences by treatment regimen in the worsening of symptoms over time, and by race and ethnicity. These findings have important implications for the management of symptoms in HR-positive/HER2-negative breast cancer survivors receiving endocrine and/or other therapies long term. No clinically significant differences in patient-reported QoL or symptom severity were found by treatment arm. However, the results of the PRO analyses may inform patient-centered communication and adherence efforts regarding treatment toxicity in subgroups of survivors.