Importance:Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective:To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review:This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings:Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug's approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance:Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens' related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.
BACKGROUND:In patients with hormone receptor (HR)-positive early breast cancer (BC), the POSITIVE trial demonstrated that temporary interruption of adjuvant endocrine therapy (ET) for pregnancy is feasible and safe in early follow-up (median 41 months). In this article, we report updated results from a preplanned analysis with 2.5 years of additional follow-up. PATIENTS AND METHODS:POSITIVE, a single-arm prospective trial evaluating temporary interruption of adjuvant ET (after 18-30 months and for up to 2 years) to attempt pregnancy in young patients with BC, enrolled 518 eligible women (≤42 years of age, stage I-III BC, desiring pregnancy) from December 2014 to December 2019. Using the bootstrap-matching method, 5-year breast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) event rates were compared with those of the SOFT/TEXT trials as external controls. RESULTS:At a median follow-up of 71 months in the POSITIVE cohort and 80 months in the SOFT/TEXT cohort, the 5-year cumulative incidence of BCFI events was 12.3% in POSITIVE and 13.2% in SOFT/TEXT [-0.9% difference, 95% confidence interval (CI) -4.2% to 2.6%]. The 5-year cumulative incidence of DRFI events was 6.2% and 8.3%, respectively (-2.1% difference, 95% CI -4.5% to 0.4%). Among 497 women followed for nondisease outcomes, 377 (76%) had ≥1 documented pregnancy on trial, and 343 of 497 (69%) had ≥1 live birth, totaling 440 offspring. In an unadjusted analysis comparing the 180 women (36%) who had pre-enrollment embryo/oocyte cryopreservation with those who did not, the 5-year cumulative incidence of BCFI events was 14.0% (95% CI 9.6% to 20.2%) and 11.5% (95% CI 8.4% to 15.7%), respectively. CONCLUSION:Longer-term follow-up of the POSITIVE trial demonstrates that temporary interruption of ET for pregnancy, including use of fertility preservation, does not increase the risk of BC events. Continued follow-up is warranted given the known risk of late recurrence in this population.
To explore the immune microenvironment of RAS‐mutated (RASmt) microsatellite stable (MSS) colon cancer (CC), we retrospectively performed whole exome sequencing, RNA sequencing, and robust digital pathology analyses and studied immune markers in a cohort of 161 patients treated with standard‐of‐care therapies with early stage disease (both fresh frozen and formalin‐fixed paraffin‐embedded [FFPE] samples) or 121 patients with metastatic setting (primary tumor FFPE samples). Only a small proportion of cases exhibited a highly infiltrated immune microenvironment, with a strong association between Immunoscore® (IS)‐high (13% of the samples) and Tumor Lymphocytes Infiltrating Score (TuLIS)‐high scores (25% of the samples). Immunoscore Immune‐Checkpoint (ISIC)‐high tumors (52% of the samples) shared a similar microenvironment composition to IS‐high and TuLIS‐like high tumors and displayed higher mutational burdens than ISIC‐low tumors. In conclusion, a substantial proportion of MSS RASmt CCs exhibit high ISIC scores, meriting evaluation in prospective trials of immunotherapy‐based combination regimens.
Bevacizumab was approved for first-line treatment of metastatic colorectal cancer (mCRC) in 2004. However, adding bevacizumab to treatment consistently fails to be cost-effective owing to modest response rates. Recently, the European Commission (EC) funded ANGIOPREDICT consortium ( www.angiopredict.com ) identified a link between bevacizumab treatment response and intermediate-to-high chromosomal instability (CIN) in mCRC. Thus, the objective of the current study was to compare the cost-effectiveness of adding bevacizumab with first-line chemotherapy in the bevacizumab responsive CIN subtype across three European countries (Germany, Ireland and Spain) with varying costs of care and reimbursement policies. We developed an open-source health economic model to estimate cost-effectiveness. The ANGIOPREDICT cohort informed progression risks and cause-specific mortality. Health utilities and adverse events probabilities were obtained from the literature. Costs were derived from surveys of collaborating consortium hospitals in Germany, Ireland, and Spain that participated in the recently completed EC funded COLOSSUS translational study (ANGIOPREDICT successor initiative) and the literature. Sensitivity analyses included individual and simultaneous variation of input parameters from a priori defined distributions. Bevacizumab was not cost effective even at willingness–to-pay (WTP) thresholds that are appreciably higher than those considered realistic. The highest incremental cost-effectiveness ratio (ICER) was in Germany at €241,188 per quality-adjusted life year (QALY), while the lowest was in Ireland at €180,477 per QALY. All deterministic and probabilistic sensitivity analyses demonstrated that these results were robust. Even for patients with mCRC manifesting improved outcomes, adding bevacizumab to first-line chemotherapy is invariably not cost-effective in any of the countries examined. Variability in pricing, healthcare costs and WTP thresholds across countries did not commute this result.
BACKGROUND AND OBJECTIVE:ENZAMET randomised 1125 participants with metastatic hormone-sensitive prostate cancer to receive enzalutamide or a standard nonsteroidal antiandrogen (NSAA) combined with testosterone suppression with or without docetaxel. Enzalutamide demonstrated superior progression-free and overall survival (OS). Radiographic progression without prior/concurrent prostate-specific antigen progression (discordant progression; DP) portends poor outcomes. Our aim was to determine the frequency of DP in ENZAMET and the impact of enzalutamide on disease-state transitions. METHODS:A multistate Cox proportional-hazards regression model was used to partition participants into four states: (1) event-free; (2) discordant progression (DP); (3) other types of progression (other progression; OP); and (4) death. KEY FINDINGS AND LIMITATIONS:Enzalutamide prolonged OS in the entire cohort of 1125 participants (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58-0.84; p < 0.0001). Radiographic progression occurred in 388/1125 (34%) participants, and DP in 114/1125 (10%), with similar proportions in the enzalutamide arm (55/114, 48%) and NSAA arm (59/114, 52%). Participant characteristics in the DP group were similar between the treatment arms. Enzalutamide delayed DP (HR 0.66, 95% CI 0.46-0.96; p = 0.03) and OP (HR 0.37, 95% CI 0.31-0.44; p < 0.001). The 5-yr OS rate was lower in the DP group (24%) than in the OP group (42%). Among participants whose cancer had not progressed (495/1125), 51/495 (10%) died of non-prostate cancer causes (median follow-up 68 mo). This exploratory analysis is limited by its post hoc nature. CONCLUSIONS AND CLINICAL IMPLICATIONS:DP occurred in 10% of participants and accounted for 30% of progression events observed in ENZAMET. DP was associated with worse OS regardless of treatment. Enzalutamide delayed DP and reduced the risk of DP and OP. Regularly scheduled imaging may be preferable to for-cause imaging in metastatic hormone-sensitive prostate cancer.
