BACKGROUND:The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS:Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS:EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS:The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

BACKGROUND:Older patients with ovarian cancer represent a heterogeneous population. The French National Group of Investigators for the Study of Ovarian and Breast Cancer developed the geriatric vulnerability score (GVS) to identify geriatric parameters predictive of poor outcomes. A prospective validation of the GVS was needed. METHODS:The EWOC-1 study (NCT02001272) was an international, open-label, phase 2, three-arm trial designed according to a two-step process. Patients aged 70 years or older with newly diagnosed stage III or IV ovarian cancer were identified and the GVS determined. Those with a GVS of 3 or greater were randomly assigned to the EWOC-1 trial, stratified by country and surgical outcome, to receive three different carboplatin with or without paclitaxel regimens; those not included in the EWOC-1 trial were followed up in the EWOC-1 registry. External validation of the GVS was a secondary endpoint of the trial. Three validation cohorts were identified: the total population (validation cohort 1 [V1], n=447), the registry-only population (validation cohort 2 [V2], n=327), and the carboplatin-paclitaxel-treated population (validation cohort 3 [V3], n=320). FINDINGS:From Dec 11, 2013, to Nov 16, 2018, 447 patients were included in 48 academic centres in six countries; 120 in the EWOC-1 trial and 327 in the EWOC-1 registry. Median follow-up was 19·7 (95% CI 8·5-29·7) months for the total cohort; missing values were low (<2%). According to the maximum likelihood analysis, the hazard ratio (HR) of death in V1 was 1·8 (95% CI 1·1-3·1, p=0·029) for those with a GVS of 1; 2·4 (1·4-4·0, p=0·0009) with a GVS of 2; 4·1 (2·5-7·0, p<0·0001) for a GVS of 3; 5·5 (3·3-9·3, p<0·0001) for a GVS of 4; and 9·1 (4·7-17·5, p<0·0001) for a GVS of 5 compared with a score of 0. Whatever the validation cohort, GVS of 3 or more significantly segregated two groups with different overall survival: V1 (median 13·2 [95% CI: 10·8-18·7] vs 40·8 [32·0-45·6] months; HR 2·8 [95% CI 2·2-3·7]; p<0·0001); V2 (11·9 [95% CI 8·8-18·1] vs 40·8 [32·0-45·6] months, HR 3·5 [2·5-4·9]; p<0·0001); and V3 (18·1 [95% CI 15·8-31·8] vs 43·0 [40·6-49·7] months, HR 2·6 [1·9 to 3·7]; p<0·0001). INTERPRETATION:The GVS has high prognostic performance for overall survival in patients with advanced ovarian cancer, independently of geographic and historic effect (V1), as well as treatment patterns (V3), validated in an international population. Even though the GVS is time consuming it will allow the stratification of populations for clinical research and might permit the orientation of the geriatric intervention to specific domains. FUNDING:French National Cancer Institute. TRANSLATION:For the French translation of the abstract see Supplementary Materials section.

Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). While ESR1 mutations (ESR1mut) are a characterized mechanism of resistance to AI as single agent, it remains unknown how these mutations, when detected prior to treatment initiation, may affect the efficacy of Pal+AI. In a subsidiary analysis of the first line PADA-1 trial, we report the ESR1mut detection rate at baseline and, in patients with ESR1mut detected at baseline, how ESR1 circulating tumor DNA levels changed after the first cycle of AI-Pal therapy. Methods: PADA-1 (NCT03079011) is a randomized phase III trial testing the clinical utility of real time ESR1mut detection (baseline, at 1 month and then every 2 months) in the blood of patients treated with AI-Pal (first step). Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations during first line AI-Pal therapy) are randomized in a second step between keeping AI-Pal or switching to Fulvestrant-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for >12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. #90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Results: From 04/2017 to 05/2018, 803 MBC patients have been included in 80 centers. Among these patients, ESR1mut were detected at baseline, prior to any systemic therapy, in 17 patients (2.1%, 95%CI=[1.3;3.3%]). ESR1mut levels ranged from 6 to 3959 copies/ml of plasma (median: 30 copies/ml); allelic frequency ranged from 0.3% to 47% (median=3.5%). ESR1mut were not associated with any of the tumor pathological characteristics (including PR status, primary TNM stage, number and type of metastatic sites); a non-significant association was observed with primary tumor grade (1.7% vs 4.1% in grade I-II vs III, Fisher: p=0.15). Among patients who received a prior adjuvant endocrine therapy, ESR1mut detection rate was lower in patients treated with tamoxifen (0.9% with any tamoxifen exposure vs 5.7% with no tamoxifen exposure; Yates Chi2: p=0.01) and observed only in patients treated with AI (4.9% with any AI exposure vs 0% with no AI exposure, Yates Chi2: p=0.009). Among the 17 patients with ESR1mut detected at baseline, only 4 patients had residual detectable ESR1mut detected after 1 month of AI-Pal therapy (3 of these 4 had decreased levels of ESR1 mutation). Conclusion:ESR1mut is a rare event in untreated AI-sensitive, ER+ HER2- MBC patients. Such detection is primarily associated with prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Pal therapy, suggesting that this combination may retain early antitumor efficacy. Funding: Pfizer Citation Format: Bidard F-C, Pistilli B, Dalenc F, De la Motte Rouge T, Sabatier R, Frenel J-S, Ladoire S, Dubot C, Ferrero J-M, Levy C, Lortholary A, Stefani L, Mouret-Reynier M-A, Hardy A-C, Jacquin J-P, Grenier J, Chakiba C, Teixeira L, Soulie P, Everhard S, Lemonnier J, Jeannot E, Bieche I, Berger F, Pierga J-Y, Bachelot T, Delaloge S. Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-06.

BACKGROUND Maintenance strategies beyond response or tumor stabilization with first-line chemotherapy in metastatic breast cancer (MBC) have not been extensively studied. Endocrine therapy combined with continued bevacizumab may be a helpful option for estrogen receptor (ER)-positive MBC. PATIENTS AND METHODS In this prospective, open-label, phase III study, patients with histologically confirmed ER-positive, HER2-negative MBC and non-progressive disease after 16-24 weeks of taxane plus bevacizumab (T + BEV) were randomized to continuation of T + BEV or maintenance bevacizumab plus exemestane (E + BEV). The primary end point was progression-free survival (PFS) from randomization. To have 80% power to detect an improvement in the 6-month PFS rate (PFS6m) from 50% to 65%, 186 assessable patients were needed for a total of 141 PFS events. An interim analysis was planned after 40% of the required events. RESULTS The interim analysis with 98 patients showed that the probability of reaching a statistically significant improvement in PFS by the end of the study was only 7%. This led the Independent Data and Monitoring Committee to recommend termination of patient enrollment. After a median of 21-month follow-up of all randomized patients (117 in total), PFS6m from randomization was 67.2% [95% confidence interval (CI) 53.6-77.7] with T + BEV and 55.2% (95% CI 41.5-66.9) with E + BEV [hazard ratio (HR): 1.0, 95% CI 0.7-1.5, P = 0.998]. Median PFS from BEV initiation was 12.5 and 12.3 months in the T + BEV and E + BEV arms, respectively. In the T + BEV arm, taxane was prematurely stopped for the majority of patients (94.9%), mainly due to toxicity (49.2%). Updated data after 35 months' median follow-up showed death rates of 44% and 55% in T + BEV and E + BEV arms, respectively. CONCLUSION In this trial, maintenance therapy with E + BEV in ER-positive, HER2-negative MBC patients with no evidence of progression after first-line T + BEV did not achieve longer PFS compared with continuation of T + BEV. CLINICALTRIALSGOV NCT01303679.

BACKGROUND:Two previous GINECO elderly specific studies in advanced ovarian cancer (AOC) patients highlighted the prognostic value of geriatric covariates for overall survival (OS). PATIENTS AND METHODS:This open-label prospective trial was designed to identify the impact of geriatric covariates on OS in AOC patients ≥70 years treated with first-line carboplatin. RESULTS:Geriatric covariates of the 111 patients included median age 79 years (≥80 years: 41%); performance status (PS) ≥2: 47%; ≥3 major comorbidities: 24%; ≥4 comedications: 68%; activities of daily living (ADL) score <6: 55%; instrumental activities of daily living (IADL) score <25: 69%; Hospital Anxiety and Depression Scale (HADS) >14: 37%. The median OS was 17.4 months. Overall, 74% of patients completed the six planned chemotherapy cycles. Grade 3-4 haematological toxic effects were frequent (50%) but manageable. Grade 3-4 non-haematological toxicities included fatigue (15%), anorexia (12%), infections (9%) and thrombosis (2%). A survival score = exp(0.327*GVS) was developed, where the geriatric vulnerability score (GVS) is the sum of the following (each assigned a value of one): albuminaemia <35 g/l; ADL score <6; IADL score <25; lymphopaenia <1 G/l; and HADS >14. With a cut-off ≥3, GVS discriminated two groups with significantly different OS, treatment completion, severe adverse events and unplanned hospital admissions rates. CONCLUSIONS:The GVS is a valuable tool for identifying vulnerable patients when treating an elderly AOC population.

BACKGROUND:To determine the feasibility of two chemotherapy regimens in elderly patients with advanced ovarian carcinoma (AOC).PATIENTS AND METHODS:Eighty-three patients >or=70 years were previously enrolled in a trial evaluating carboplatin and cyclophosphamide (CC). On the basis of identical eligibility criteria, 75 further patients were enrolled in a trial evaluating carboplatin and paclitaxel (Taxol) (CP). The primary end point of these studies was the feasibility of six courses of chemotherapy. Comprehensive geriatric assessment (CGA) parameters were assessed in terms of prognostic factors.RESULTS:More patients in the CC group presented with performance status of two or more, depression symptoms, use of co-medications, hypoalbuminemia, abnormal Mini-Mental Status score, or sub-optimal surgery. Both regimens appeared feasible: 75.6% in the CC group and 68.1% in the CP group completed six courses. CC and CP groups had similar overall survival (OS). Independent prognostic factors of poorer OS were the following: increasing age (P = 0.013), depression symptoms at baseline (P < 0.001), International Federation of Gynecology and Obstetrics stage IV (P = 0.001), and use of paclitaxel (P = 0.025).CONCLUSION:As this is a non-randomised retrospective review of two consecutive studies, no firm conclusion can be drawn. It seems, however, that in elderly patients with AOC the use of paclitaxel results in more toxicity. CGA parameters and particularly emotional disorders might help to determine a priori the risk/benefit ratio of chemotherapy in this patient population.