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Introduction The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2−) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety.Methods PADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients.Ethics and dissemination The study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals.Trial registration numbers EudraCT: 2016-004360-18; NCT03079011.

Background: The standard of care for the treatment of locally advanced rectal cancer (LARC) results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free survival (DFS) and metastasis-free survival (MFS) with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival (OS) is reported here., Patients and Methods: The study design, participants, and primary endpoint DFS have been reported for this multicenter, randomized, open-label, phase III trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on magnetic resonance imaging, and staged cT3/T4. Key secondary endpoints included OS, MFS, and local and metastatic recurrence rate., Results: With a median follow-up of 82.2 months, the 7-year DFS was 67.6% [95% confidence interval (CI) 60.7% to 73.9%] and 62.5% (95% CI 55.6% to 68.6%) [restricted mean survival time (RMST) difference 5.73 months, 95% CI 0.05-11.41 months, P = 0.048] in the neoadjuvant chemotherapy and the standard-of-care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0% to 84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8% to 77.8%) in the standard-of-care group (RMST difference 6.1 months, 95% CI 0.93-11.37 months, P = 0.021). The 7-year OS was 81.9% (95% CI 75.8% to 86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7% to 81.2%) in the standard-of-care group (RMST difference 4.37 months, 95% CI 0.35-8.38 months, P = 0.033). The safety profile remained unchanged since the previous analysis., Conclusions: Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in LARC patients, and should be considered as one of the best options of care for these patients., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis., Methods: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma., Results: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4 + and CD8 + T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy., Conclusions: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors., (© 2024. The Author(s).)

This study aimed to evaluate the prognostic value of 18 F-FDG PET/CT qualitative assessment in terms of recurrence-free survival (RFS), colostomy-free survival (CFS), and overall survival (OS) after radiation therapy (RT) of squamous cell carcinoma of the anus (SCCA). Secondary objectives were to evaluate the prognostic value of baseline and posttherapeutic quantitative 18 F-FDG PET/CT parameters in terms of RFS, CFS, and OS. Methods: We included all consecutive patients from the French multicentric cohort FFCD-ANABASE who had undergone 18 F-FDG PET/CT at baseline and 4-6 mo after RT or chemoradiotherapy for a localized SCCA. Qualitative assessments separated patients with complete metabolic response (CMR) and non-CMR. Quantitative parameters were measured on baseline and posttreatment 18 F-FDG PET/CT. RFS, CFS, and OS were analyzed using the Kaplan-Meier method. Associations among qualitative assessments, quantitative parameters, and RFS, CFS, and OS were analyzed using univariate and multivariate Cox regression. Results: Among 1,015 patients treated between January 2015 and April 2020, 388 patients (300 women and 88 men) from 36 centers had undergone 18 F-FDG PET/CT at diagnosis and after treatment. The median age was 65 y (range, 32-90 y); 147 patients (37.9%) had an early-stage tumor and 241 patients (62.1%) had a locally advanced-stage tumor; 59 patients (15.2%) received RT, and 329 (84.8%) received chemoradiotherapy. The median follow-up was 35.5 mo (95% CI, 32.8-36.6 mo). Patients with CMR had better 3-y RFS, CFS, and OS, at 84.2% (95% CI, 77.8%-88.9%), 84.7% (95% CI, 77.2%-89.3%), and 88.6% (95% CI, 82.5%-92.7%), respectively, than did non-CMR patients, at 42.1% (95% CI, 33.4%-50.6%), 47.9% (95% CI, 38.1%-56.8%), and 63.5 (95% CI, 53.2%-72.1%), respectively ( P < 0.0001). Quantitative parameters were available for 154 patients from 3 centers. The following parameters were statistically significantly associated with 3-y RFS: baseline SUV max (primitive tumor [T]) (hazard ratio [HR], 1.05 [95% CI, 1.01-1.1; P = 0.018]), SUV peak (T) (HR, 1.09 [95% CI, 1.02-1.15; P = 0.007]), MTV 41% (T) (HR, 1.02 [95% CI, 1-1.03; P = 0.023]), MTV 41% (lymph node [N]) (HR, 1.06 [95% CI, 1.03-1.1; P < 0.001]), MTV 41% (T + N) (HR, 1.02 [95% CI, 1-1.03; P = 0.005]), and posttreatment SUV max (HR, 1.21 [95% CI, 1.09-1.34; P < 0.001]). Conclusion: Treatment response assessed by 18 F-FDG PET/CT after RT for SCCA has a significant prognostic value. 18 F-FDG PET/CT could be useful for adapting follow-up, especially for patients with locally advanced-stage tumors. Quantitative parameters could permit identification of patients with a worse prognosis but should be evaluated in further trials., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Early-stage anal squamous cell carcinomas (ASCC) are usually treated with chemoradiotherapy (CRT), with good outcomes. Radiotherapy (RT) alone might be sufficient while reducing toxicity., Methods: Patients included in the French prospective FFCD-ANABASE and treated for T1-2N0 ASCC between 2015/01 and 2020/04 were divided into CRT and RT groups. Clinical outcomes and toxicity were reported. Propensity score matching was conducted for 105 pairs of patients., Results: 440 patients were analyzed: 261 (59.3 %) in the CRT group and 179 (40.7 %) in the RT group. The median follow-up was 35.7 months. Patients receiving CRT were younger, had better Performance Status (PS) and larger tumors. No statistical difference was observed for 3-year Disease-free survival (85.3 % vs 83 %, p = 0.28), Overall survival (89.6 % vs 94.8 %, p = 0.69) and Colostomy-free survival (84.5 % vs 87.2 %, p = 0.84) between CRT and RT groups, respectively. Propensity score-matched analysis confirmed these findings. Treatment interruptions were significantly more frequent in the CRT group (36.3 % vs 21.9 %, p = 0.0013), resulting in an Overall Treatment Time (OTT) extended by 7 days. Grade 3 CTCAE v4.0 toxicities were more prevalent in the CRT group (46 % vs 19 %, p < 0.001)., Conclusion: Adding chemotherapy to radiotherapy did not significantly improve outcomes for T1-2N0 ASCC in our study, but increased toxicity and OTT., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited., Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma., Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy., Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023., Main Outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators., Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%)., Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.

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/m 2 then 100mg/m 2 ). TOP2A-not amplified (TOP2A-) patients received 6 cycles of Docetaxel (75mg/m 2 ) 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)., (© 2024. The Author(s).)

Purpose: While perioperative chemotherapy provides a survival benefit over surgery alone in gastric and gastroesophageal junction (G/GEJ) adenocarcinomas, the results need to be improved. This study aimed to evaluate the efficacy and safety of perioperative cetuximab combined with 5-fluorouracil and cisplatin., Patients and Methods: Patients received six cycles of cetuximab, cisplatin, and simplified LV5FU2 before and after surgery. The primary objective was a combined evaluation of the tumor objective response (TOR), assessed by computed tomography, and the absence of major toxicities resulting in discontinuation of neoadjuvant chemotherapy (NCT) (45% and 90%, respectively)., Results: From 2011 to 2013, 65 patients were enrolled. From 64 patients evaluable for the primary endpoint, 19 (29.7%) had a morphological TOR and 61 (95.3%) did not stop NCT prematurely due to major toxicity. Sixty patients (92.3%) underwent resection. Sixteen patients (/56 available, 28.5%) had histological responses (Mandard tumor regression grade ≤3). After a median follow-up of 44.5 months, median disease-free and overall survival were 24.4 [95% CI: 16.4-39.4] and 40.3 months [95% CI: 27.5-NA], respectively., Conclusion: Adding cetuximab to the NCT regimen in operable G/GEJ adenocarcinomas is safe, but did not show enough efficacy in the present study to meet the primary endpoint (NCT01360086).

Aim: The oral anti-angiogenic therapy nintedanib prolongs progression-free survival (PFS) when combined with chemotherapy after primary surgery for advanced epithelial ovarian cancer. The randomized phase II CHIVA trial evaluated the impact of combining nintedanib with neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer., Methods: Patients with newly diagnosed unresectable FIGO stage IIIC-IV epithelial ovarian cancer received 3-4 cycles of carboplatin plus paclitaxel every 3 weeks as NACT before interval debulking surgery (IDS), followed by 2-3 post-operative cycles. Patients were randomized 2:1 to receive either nintedanib 200 mg twice daily or placebo on days 2-21 every 3 weeks during NACT (omitting peri-operative cycles), and then as maintenance therapy for up to 2 years. The primary endpoint was PFS., Results: Between January 2013 and May 2015, 188 patients were randomized (124 to nintedanib, 64 to placebo). PFS was significantly inferior with nintedanib (median 14.4 versus 16.8 months with placebo; hazard ratio 1.50, p = 0.02). Overall survival (OS) was also inferior (median 37.7 versus 44.1 months, respectively; hazard ratio 1.54, p = 0.054). Nintedanib was associated with increased toxicity (grade 3/4 adverse events: 92% versus 69%, predominantly hematologic and gastrointestinal), lower response rate by RECIST (35% versus 56% before IDS), and lower IDS feasibility (58% versus 77%) versus placebo., Conclusions: Adding nintedanib to chemotherapy and in maintenance as part of NACT for advanced epithelial ovarian cancer cannot be recommended as it increases toxicity and compromises chemotherapy efficacy (IDS, PFS, OS)., Clinicaltrials: govregistration: NCT01583322., Competing Interests: Declaration of Competing Interest Gwénaël Ferron: Advisory boards (Clovis, AstraZeneca, GSK, MSD, Roche, RanD Biotech, Olympus), lectures/symposia (AstraZeneca, Clovis, GSK, MSD, PharmaMar). Nicolas Delanoy: Advisory boards/honoraria (GSK, AstraZeneca, MSD, Clovis Oncology). Florence Joly: Advisory boards (Clovis, AstraZeneca, GSK, MSD, Seagen), lectures/symposia (AstraZeneca, Clovis, GSK, MSD); non-gynecology: Ipsen, Janssen, Sanofi, Bayer, Astellas, Pfizer, Amgen. Alain Lortholary: Advisory board fees (AstraZeneca, MSD Tesaro), speaker honoraria (Clovis Oncology, Roche), congress participation (Novartis, Pfizer, MSD, Lilly, Roche), member of CS3 sein UNICANCER. Benoît You: Consulting (MSD, AstraZeneca, GSK–Tesaro, Bayer, Roche/Genentech, ECS Progastrin, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, Seagen, Myriad). Nadine Dohollou: Consulting/expert (Daiichi, Lilly, Roche, Seagen), conferences/training (Daiichi, Lilly, Roche, Seagen), research grants/clinical trials (AstraZeneca, BMS, Boehringer Ingelheim, Genomic Health, Lilly, MSD, Novartis, Pfizer, Roche). Anne Floquet: Advisory boards (MSD, AstraZeneca, GSK, Clovis Oncology), congress participation (AstraZeneca, GSK, MSD, PharmaMar, Roche). Michel Fabbro: AstraZeneca, GSK, Clovis. Jérôme Alexandre: AstraZeneca, GSK, Clovis, MSD, Eisai, Novartis. Isabelle Ray-Coquard: Advisory/consultancy (Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Mersana, Deciphera, Novocure, Eisai, Sutro Pharma, Merck Sharp & Dohme, Pfizer/Merck Serono, PharmaMar, Roche), research grant/funding (Roche, BMS, MSD, GSK), travel/accommodation/expenses (AstraZeneca, Roche, GSK, Clovis)., (Copyright © 2023. Published by Elsevier Inc.)

Background: Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences., Methods: We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , and fluorouracil 2400 mg/m 2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m 2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m 2 and leucovorin 400 mg/m 2 , followed by intravenous 400 mg/m 2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m 2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m 2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete., Findings: Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction)., Interpretation: Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice., Funding: Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer., Competing Interests: Declaration of interests P-LE reports grants and non-financial support from Bristol Myers Squibb; and non-financial support from Amgen, Ipsen, Novartis, Roche, Sanofi, and Servier, outside the submitted work. OB reports personal fees from Amgen, Bayer, Bristol Myers Squibb, Grunenthal, Merck, Pierre Fabre, Roche, and Servier, outside the submitted work, and has been invited to congresses by Roche and Servier. VB reports grants from Merck Serono; personal fees from Merck Serono, Bayer, Bristol Myers Squibb, Sanofi, Eisai, Ipsen, Merck Sharpe and Dohme, and Prestizia; and non-financial support from Merck Serono, Bayer, Sanofi, and Roche, outside the submitted work. CL reports personal fees from Amgen, Celgene, Halozyme, Merck Sharpe and Dohme, and Roche, outside the submitted work. CdlF reports personal fees from Eisai, Amgen, Bayer, Pierre Fabre Oncologie, Roche, and Servier; and non-financial support from Amgen, Bayer, Pierre Fabre Oncologie, Roche, Servier, and Bristol Myers Squibb, outside the submitted work. CB reports grants from Roche; and personal fees from Servier, Pierre Fabre, and Merck Sharpe and Dohme, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical-surgical treatment., Experimental Design: The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin-paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests., Results: The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03-0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11-0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery., Conclusions: The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance. See related commentary by May and Oza, p. 4432 ., (©2020 American Association for Cancer Research.)

Background: Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice., Patients and Methods: Patients with ROC after at least one platinum-based regimen received 1.1 mg/m 2 trabectedin plus 30 mg/m 2 PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)]., Results: Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups., Conclusion: Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Data are lacking with regard to curative resection of metastasis from small bowel adenocarcinoma (SBA). This study evaluated outcomes and prognostic factors in patients with curatively resected metastatic SBA., Methods: A series of 34 patients undergoing resection of metastatic SBA from January 2009 to November 2014 at French centers were included into this cohort study. The primary endpoint was overall survival (OS). Secondary endpoints were recurrence-free survival (RFS) and prognostic factors. Univariate analyses were performed to determine prognostic risk factors., Results: The sites of SBA metastases were peritoneal (29.4%), liver (26.5%), lymph nodes (11.8%), lung (2.9%), multiple (14.7%), and other (14.7%). Thirty (88.2%) patients received adjuvant or perioperative chemotherapy, mainly was oxaliplatin-based (76.5%). The median OS was 28.6 months and RFS was 18.7 months. Fourteen (41.2%) patients survived for more than 36 months. In univariate analysis, poor differentiation (P = 0.006), invaded margins (P = 0.003), and lymphatic invasion in the primary tumor (P = 0.039) were associated with decreased OS., Conclusion: Overall survival of patients after resection of metastatic SBA remains poor, but long-term survivors are observed. Resection of metastatic SBA should be consider if patients are expected to be operated on with curative intent and have moderately or well-differentiated tumors., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Senescence is a tumor-suppressive mechanism induced by telomere shortening, oncogenes, or chemotherapy treatment. Although it is clear that this suppressive pathway leads to a permanent arrest in primary cells, this might not be the case in cancer cells that have inactivated their suppressive pathways. We have recently shown that subpopulations of cells can escape chemotherapy-mediated senescence and emerge as more transformed cells that induce tumor formation, resist anoikis, and are more invasive. In this study, we characterized this emergence and showed that senescent cells favor tumor growth and metastasis, in vitro and in vivo. Senescence escape was regulated by secreted proteins produced during emergence. Among these, we identified thrombospondin-1 (TSP1), a protein produced by senescent cells that prevented senescence escape. Using SWATH quantitative proteomic analysis, we found that TSP1 can be detected in the serum of patients suffering from triple-negative breast cancer and that its low expression was associated with treatment failure. The results also indicate that senescence escape is explained by the emergence of CD47 low cells that express a reduced level of CD47, the TSP1 receptor. The results show that CD47 expression is regulated by p21waf1. The cell cycle inhibitor was sufficient to maintain senescence since its downregulation in senescent cells increased cell emergence. This leads to the upregulation of Myc, which then binds to the CD47 promoter to repress its expression, allowing the generation of CD47 low cells that escape the suppressive arrest. Altogether, these results uncovered a new function for TSP1 and CD47 in the control of chemotherapy-mediated senescence.

This study aimed to determine whether the expression of various tumor biomarkers of the mTOR pathway predicts tumor response to everolimus in metastatic recurrent endometrial cancer. Tumor blocks from 44 patients of a phase II clinical trial receiving everolimus until progression or toxicity were collected and evaluated at 3 and 6 months for response. Thirty-six blocks were available for analysis of ER, PR, HER2, LKB1, PI3K, PTEN, pAKT, 4E-BP1, p4E-BP1, and S6RP expression by immunohistochemistry, PTEN deletion by FISH, and mutational status of K-RAS, PIK3CA, PTEN, and AKT1 genes. Twelve of 34 evaluable patients had partial response or stable disease (PR, SD) and 22 had progressive disease (PD). Immunohistochemistry showed that no protein expression could predict response to everolimus. Neither could loss of PTEN expression or PTEN deletion or PTEN mutation predict patient outcome. Thirty-one samples were assessable for K-RAS mutations (ten for PR+SD and 21 for PD). There are only four patients with K-RAS mutations and none of them responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were longer in patients without K-RAS mutations (PFS 3.12 ± 1.7 months versus 1.05 ± 0.4 months, p < 0.001; OS 9.28 ± 2.0 months versus 2.30 ± 1.4 months, p = 0.034). In conclusion, the level of expression of proteins of the PI3K/mTOR pathway tested in this study cannot predict response to everolimus. However, endometrial cancer patients with K-RAS mutations do not seem to derive benefit from everolimus treatment.