Metabolomic prediction of breast cancer treatment induced neurological and metabolic toxicities.

BACKGROUND: Long-term treatment-related toxicities, such as neurological and metabolic toxicities, are major issues in breast cancer. We investigated the interest of metabolomic profiling to predict toxicities. METHODS: Untargeted high-resolution metabolomic profiles of 992 patients with ER+/HER2- breast cancer from the prospective CANTO cohort were acquired (n=1935 metabolites). A residual-based modeling strategy with a discovery and validation cohort was used to benchmark machine learning algorithms, taking into account confounding variables. RESULTS: Adaptive LASSO has a good predictive performance, has limited optimism bias, and allows the selection of metabolites of interest for future translational research. The addition of low-frequency metabolites and non-annotated metabolites increases the predictive power. Metabolomics adds extra performance to clinical variables to predict various neurological and metabolic toxicity profiles. CONCLUSIONS: Untargeted high-resolution metabolomics allows better toxicity prediction by considering environmental exposure, metabolites linked to microbiota, and low-frequency metabolites.

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8+PD-1+ T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2+ endothelial cells, could overcome immune resistance of ovarian cancers.

Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial.

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.

Prognostic stratification ability of the CPS+EG scoring system in HER2-low and HER2-zero early breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: The CPS+EG scoring system was initially described in unselected early breast cancer (eBC) patients treated with neoadjuvant chemotherapy (NAC), leading to refined prognostic stratification, and thus helping to select patients for additional post-NAC treatments. It remains unknown whether the performance is the same in new biological breast cancer entities such as the HER2-low subtype. PATIENTS AND METHODS: Outcomes (disease-free (DFS) and overall survival OS)) of 608 patients with HER2-non amplified eBC and treated with NAC were retrospectively analyzed according to CPS-EG score. We compared the prognostic stratification abilities of the CPS+EG in HER2-low and HER2-0 eBC, analyzing ER+ and ER- tumors separately. RESULTS: In ER+ eBC, the CPS+EG scoring system seems to retain a prognostic value, both in HER2-low and HER2-0 tumors, by distinguishing populations with significantly different outcomes (good: score 0-1, poor: score 2-3, and very poor: score 4-5). Using C-indices for DFS and OS, CPS+EG provided the highest prognostic information in ER+ eBC, especially in HER2-0 tumors. In contrast, in ER- eBC, the CPS+EG does not appear to be able to distinguish different outcome groups, either in HER2-low or HER2-0 tumors. In ER- eBC, C-indices for DFS and OS were highest for pathological stage, reflecting the predominant prognostic importance of residual disease in this subtype. CONCLUSIONS: HER2-low status does not influence the prognostic performance of the CPS+EG score. Our results confirm the usefulness of the CPS+EG score in stratifying the prognosis of ER+ eBC after NAC, for both HER2-0 and HER2-low tumors. For ER- eBC, HER2-low status does not influence the performance of the CPS+EG score, which was lower than that of the pathological stage alone.

Neoadjuvant anthracycline-based (5-FEC) or anthracycline-free (docetaxel/carboplatin) chemotherapy plus trastuzumab and pertuzmab in HER2 + BC patients according to their TOP2A: a multicentre, open-label, non-randomized phase II trial.

PURPOSE: Previous studies have reported the benefit of dual HER2-targeting combined to neoadjuvant chemotherapy in HER2-amplified breast cancer (HER2 + BC). Moreover, besides the cardiac toxicity following their association to Trastuzumab, anthracyclines chemotherapy may not profit all patients. The NeoTOP study was designed to evaluate the complementary action of Trastuzumab and Pertuzumab, and the relevance of an anthracycline-based regimen according to TOP2A amplification status. METHODS: Open-label, multicentre, phase II study. Eligible patients were aged ≥ 18 with untreated, operable, histologically confirmed HER2 + BC. After centralized review of TOP2A status, TOP2A-amplified (TOP2A+) patients received FEC100 for 3 cycles then 3 cycles of Trastuzumab (8 mg/kg then 6 mg/kg), Pertuzumab (840 mg/kg then 420 mg/kg), and Docetaxel (75mg/m2 then 100mg/m2). TOP2A-not amplified (TOP2A-) patients received 6 cycles of Docetaxel (75mg/m2) and Carboplatin (target AUC 6 mg/ml/min) plus Trastuzumab and Pertuzumab. Primary endpoint was pathological Complete Response (pCR) using Chevallier's classification. Secondary endpoints included pCR (Sataloff), Progression-Free Survival (PFS), Overall Survival (OS), and toxicity. RESULTS: Out of 74 patients, 41 and 33 were allocated to the TOP2A + and TOP2A- groups respectively. pCR rates (Chevallier) were 74.4% (95%CI: 58.9-85.4) vs. 71.9% (95%CI: 54.6-84.4) in the TOP2A + vs. TOP2A- groups. pCR rates (Sataloff), 5-year PFS and OS were 70.6% (95%CI: 53.8-83.2) vs. 61.5% (95%CI: 42.5-77.6), 82.4% (95%CI: 62.2-93.6) vs. 100% (95%CI: 74.1-100), and 90% (95%CI: 69.8-98.3) vs. 100% (95%CI: 74.1-100). Toxicity profile was consistent with previous reports. CONCLUSION: Our results showed high pCR rates with Trastuzumab and Pertuzumab associated to chemotherapy. They were similar in TOP2A + and TOP2A- groups and the current role of neoadjuvant anthracycline-based chemotherapy remains questioned. TRIAL REGISTRATION NUMBER: NCT02339532 (registered on 14/12/14).

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Low RNA disruption during neoadjuvant chemotherapy predicts pathologic complete response absence in patients with breast cancer.

In previously reported retrospective studies, high tumor RNA disruption during neoadjuvant chemotherapy predicted for post-treatment pathologic complete response (pCR) and improved disease-free survival at definitive surgery for primary early breast cancer. The BREVITY (Breast Cancer Response Evaluation for Individualized Therapy) prospective clinical trial (NCT03524430) seeks to validate these prior findings. Here we report training set (Phase I) findings, including determination of RNA disruption index (RDI) cut points for outcome prediction in the subsequent validation set (Phase II; 454 patients). In 80 patients of the training set, maximum tumor RDI values for biopsies obtained during neoadjuvant chemotherapy were significantly higher in pCR responders than in patients without pCR post-treatment (P = .008). Moreover, maximum tumor RDI values ≤3.7 during treatment predicted for a lack of pCR at surgery (negative predictive value = 93.3%). These findings support the prospect that on-treatment tumor RNA disruption assessments may effectively predict post-surgery outcome, possibly permitting treatment optimization.