Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review.

BACKGROUND: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. MATERIALS AND METHODS: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. RESULTS: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. CONCLUSION: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice.

Efficacy of front-line treatment for hormone receptor-positive HER2-negative metastatic breast cancer with germline BRCA1/2 mutation.

BACKGROUND: Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation. METHODS: The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1). RESULTS: A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03-1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03-2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17-2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88-1.41], p = 0.350; PFS1: 1.09 [0.90-1.31], p = 0.379). CONCLUSION: In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.

Information needs on nutrition in link to cancer prevention among cancer patients, high-risk individuals and general population - A national cross-sectional study.

BACKGROUND & AIMS: Nutrition is one of the fundamentals of cancer prevention. Knowing what are the patients' needs and beliefs in terms of "nutrition and cancer" information helps tailor future nutritional interventions. The aim of this study was to evaluate specific information needs about "nutrition in relation to cancer prevention", including primary and tertiary prevention, among cancer patients, cancer-free individuals, and genetic high cancer risk individuals. METHODS: This online survey was shared within two large National cancer social networks and proposed to all attendees and carers of a comprehensive cancer center. RESULTS: 2887 individuals answered the survey (of whom 33% were cancer patients, 13% high-risk individuals and 55% participants of the general population). More than 80% of participants were women, had at least a high school degree. Median body mass index was 23.2 kg/m2. Eleven percent (n = 321) were following a diet, mostly low carbohydrate and weight-loss diets. Around 70% of all categories felt they lacked information on nutrition and cancer interplays. Only 12% of cancer patients (n = 108) considered they had received enough information on nutrition during their care pathway. A majority of participants agreed that food can modify cancer risk (93%, n = 2526) and 66% (n = 1781) considered that nutrition should be personalized according to the risk of cancer. Only twenty-nine percent (n = 792) believed that eating 5 fruits and vegetables a day was enough to avoid cancer, but 64% (n = 1720) thought that dietary supplements could help obtain a better health. All proposed nutrition topics were considered important by the participants. CONCLUSIONS: Although cancer patients and cancer-free respondents, whether at high risk of cancer or not, share a common broad interest on the interplay between nutrition and cancer and seek after more information on this topic, some false beliefs are observed. Healthcare providers could successfully propose more evidence-based information to these populations.

Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program.

SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA-mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8-52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95% CI = 1.1-2.1), >5 lines of prior treatments (HR = 1.4, 95% CI = 1.0-2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3-13.6). N = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Final results of the global and Asia cohorts of KAMILLA, a phase IIIB safety trial of trastuzumab emtansine in patients with HER2-positive advanced breast cancer.

BACKGROUND: KAMILLA is a single-arm safety study of trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC; NCT01702571). We report the final analysis of cohort 2 (Asia) within the context of published cohort 1 (Global) findings. METHODS: Patients had HER2-positive, locally advanced, or metastatic BC progressing after chemotherapy and anti-HER2 therapy or ≤6 months after adjuvant therapy. The primary objective was to further evaluate T-DM1 (3.6 mg/kg, administered intravenously every 3 weeks) safety/tolerability, including the following adverse events of primary interest (AEPIs): grade ≥3 AEPIs (hepatic events, allergic reactions, thrombocytopenia, hemorrhage events), all grade ≥3 treatment-related AEs, and all-grade pneumonitis. RESULTS: KAMILLA enrolled 2185 patients (cohort 1, n = 2003; cohort 2, n = 182) as of 31 July 2019. Of these, 2002 and 181 per cohort were treated and included in the safety population. Approximately 70% of patients had two or more previous treatment lines in the metastatic setting. Median T-DM1 exposure was 5.6 and 5.0 months per cohort; median follow-up was 20.6 and 15.1 months. The overall AEPI rate was higher in cohort 2 (93/181; 51.4%) versus cohort 1 (462/2002; 23.1%), mostly driven by a higher grade ≥3 thrombocytopenia rate in cohort 2. In cohort 2, grade ≥3 thrombocytopenia was not associated with grade ≥3 hemorrhagic events and most (128/138) fully resolved. Grade ≥3 treatment-related AEPI rates were 18.4% (cohort 1) and 48.6% (cohort 2), the latter mainly due to thrombocytopenia. Any-grade pneumonitis rates were 1.0% and 2.2%. No new safety signals were identified. Median (95% confidence interval) progression-free survival was 6.8 months (5.8-7.6 months) and 5.7 months (5.5-7.0 months) in cohorts 1 and 2, respectively; median overall survival was 27.2 months (25.5-28.7 months) and 29.5 months (21.1 months to non-estimable). In both cohorts, median progression-free survival and overall survival decreased with increasing prior therapy lines. CONCLUSIONS: Cohort 2 results aligned with previous findings in Asian patients, supporting the manageable safety profile and use of T-DM1 in advanced BC.

Risk-adapted modulation through de-intensification of cancer treatments: an ESMO classification.

BACKGROUND: The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments. METHODS: An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients' representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs. RESULTS: The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations. CONCLUSIONS: ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials.

Breast Cancer Patients' Experience and Wishes Regarding Communication on Sexual Health: The BEROSE Study.

BEROSE is a single-center observational study, which aimed to determine the proportion of women with breast cancer who received information on sexual health from health professionals throughout their whole care pathway. A total of 318 women with all stages of breast cancer (30% metastatic) and at different time interval from diagnosis (up to 7 years) participated to the survey. Sixty-five percent of women reported that they had not received any information about sexual health over the whole care. Increased awareness among the healthcare professionals and particularly the oncology community is needed to discuss sexual health in women with breast cancer.

[Surgery or not on an atypical breast lesion? Taking anxiety into account in shared decision support from a prospective cohort of 300 patients]. / Opérer ou non une lésion atypique du sein ? Prise en compte de l'anxiété dans l'aide à la décision partagée à partir d'une cohorte prospective de 300 patientes.

INTRODUCTION: Organized and individual breast screening have been accompanied by an increase in the detection of "atypical breast lesions (ABL)". Recently, the NOMAT multicenter study proposed a predictive model of the risk of developing breast cancer after detection of an ABL in order to avoid surgical removal of "low-risk" lesions. It also aimed to provide information on psychological experience, in particularly anxiety, to assist in the shared medical decision process. METHODS: Three hundred women undergoing surgery for ABL were included between 2015 and 2018 at 18 French centers. Women completed questionnaires before and after surgery assessing their level of anxiety (STAI-State, STAI-Trait), their level of tolerance to uncertainty, their perceived risk of developing a breast cancer, and their satisfaction with the management care. RESULTS: One hundred nighty nine patients completed the STAI-Status before and after surgery. Overall, a decrease in anxiety level (35.4 vs 42.7, P<0.001) was observed. Anxious temperament and greater intolerance to uncertainty were significantly associated swith decreased anxiety (33%), whereas younger age was associated with increased anxiety (8%). CONCLUSION: Surgery for ABL seems to be associated with only a few cases with an increase in anxiety and seems to increase the perception of the risk of developing breast cancer. Taking into account the psychological dimension remains in all cases essential in the process of shared therapeutic decision.

Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort.

BACKGROUND: Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. PATIENTS AND METHODS: We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2-; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). RESULTS: The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2- MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2- and TNBC cohorts, respectively, whatever YOD. CONCLUSION: OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed.

Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial☆.

BACKGROUND: Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. PATIENTS AND METHODS: KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease lasting ≥6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety. RESULTS: Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% [95% confidence interval (CI) 14.6-29.6] and 42.9% (95% CI 34.1-52.0), respectively. A reduction in the sum of the major diameters of BM ≥30% occurred in 42.9% (95% CI 34.1-52.0), including 49.3% (95% CI 36.9-61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3-5.6) months and 18.9 (95% CI 17.1-21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with [208 (52.3%)] versus without [701 (43.7%)] baseline BM. CONCLUSION: This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01702571.

Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: a prospective patient-reported outcomes analysis.

BACKGROUND: In early breast cancer (BC), there has been a trend to escalate endocrine therapy (ET) and to de-escalate chemotherapy (CT). However, the impact of ET versus CT on the quality of life (QoL) of early BC patients is unknown. Here, we characterize the independent contribution of ET and CT on patient-reported outcomes (PROs) at 2 years after diagnosis. PATIENTS AND METHODS: We prospectively collected PROs in 4262 eligible patients using the European Organization for Research and Treatment of Cancer QLQ-C30/BR23 questionnaires inside CANTO trial (NCT01993498). The primary outcome was the C30 summary score (C30-SumSc) at 2 years after diagnosis. RESULTS: From eligible patients, 37.2% were premenopausal and 62.8% postmenopausal; 81.9% received ET and 52.8% CT. In the overall cohort, QoL worsened by 2 years after diagnosis in multiple functions and symptoms; exceptions included emotional function and future perspective, which improved over time. ET (Pint = 0.004), but not CT (Pint = 0.924), had a persistent negative impact on the C30-SumSc. In addition, ET negatively impacted role and social function, pain, insomnia, systemic therapy side-effects, breast symptoms and further limited emotional function and future perspective recovery. Although CT had no impact on the C30-SumSc at 2-years it was associated with deteriorated physical and cognitive function, dyspnea, financial difficulties, body image and breast symptoms. We found a differential effect of treatment by menopausal status; in premenopausal patients, CT, despite only a non-significant trend for deteriorated C30-SumSc (Pint = 0.100), was more frequently associated with QoL domains deterioration than ET, whereas in postmenopausal patients, ET was more frequently associated with QoL deterioration, namely using the C30-SumSc (Pint = 0.004). CONCLUSION(S): QoL deterioration persisted at 2 years after diagnosis with different trajectories by treatment received. ET, but not CT, had a major detrimental impact on C30-SumSc, especially in postmenopausal women. These findings highlight the need to properly select patients for adjuvant ET escalation.

T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. PATIENTS AND METHODS: We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding 'healthy tissue' and 24 mLN-related parameters were analyzed. RESULTS: HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. CONCLUSION: TCB should be developed in BC to circumvent low MHC/peptide complexes.

Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.

BACKGROUND: In the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population. PATIENTS AND METHODS: OlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC. Patients were randomized to olaparib tablets (300 mg bid) or predeclared TPC (capecitabine, vinorelbine, or eribulin). OS and safety were secondary end points. RESULTS: A total of 205 patients were randomized to olaparib and 97 to TPC. At 64% data maturity, median OS was 19.3 months with olaparib versus 17.1 months with TPC (HR 0.90, 95% CI 0.66-1.23; P = 0.513); median follow-up was 25.3 and 26.3 months, respectively. HR for OS with olaparib versus TPC in prespecified subgroups were: prior chemotherapy for mBC [no (first-line setting): 0.51, 95% CI 0.29-0.90; yes (second/third-line): 1.13, 0.79-1.64]; receptor status (triple negative: 0.93, 0.62-1.43; hormone receptor positive: 0.86, 0.55-1.36); prior platinum (yes: 0.83, 0.49-1.45; no: 0.91, 0.64-1.33). Adverse events during olaparib treatment were generally low grade and manageable by supportive treatment or dose modification. There was a low rate of treatment discontinuation (4.9%), and the risk of developing anemia did not increase with extended olaparib exposure. CONCLUSIONS: While there was no statistically significant improvement in OS with olaparib compared to TPC, there was the possibility of meaningful OS benefit among patients who had not received chemotherapy for metastatic disease. Olaparib was generally well-tolerated, with no evidence of cumulative toxicity during extended exposure. Please see the article online for additional video content.