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Background Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).Patients and methods Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab.Results In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.Conclusions Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.Trial registration number NCT03668119.

Abstract The efficacy of pembrolizumab monotherapy versus chemotherapy increased with increasing programmed death ligand 1 (PD‐L1) expression, as quantified by combined positive score (CPS; PD‐L1 expression on both tumour cells and immune cells) in patients with previously treated metastatic triple‐negative breast cancer (mTNBC) in the phase 3 KEYNOTE‐119 study. This exploratory analysis was conducted to determine whether the expression of PD‐L1 on tumour cells contributes to the predictive value of PD‐L1 CPS in mTNBC. PD‐L1 expression in tumour samples was assessed using PD‐L1 IHC 22C3 pharmDx and quantified using both CPS and tumour proportion score (TPS; PD‐L1 expression on tumour cells alone). Calculated immune cell density (CID) was defined as CPS minus TPS. The ability of each scoring method (CPS, TPS, and CID) to predict clinical outcomes with pembrolizumab was evaluated. With pembrolizumab, the area under the receiver operating characteristic curve was 0.69 (95% CI = 0.58–0.80) for CPS, 0.55 (95% CI = 0.46–0.64) for TPS, and 0.67 (95% CI = 0.56–0.77) for CID. After correction for cutoff prevalence, CPS performed as well as, if not better than, CID with respect to predicting objective response rate, progression‐free survival, and overall survival. Data from this exploratory analysis suggest that, although PD‐L1 expression on immune cells alone is predictive of response to programmed death 1 blockade in mTNBC, adding tumour PD‐L1 expression assessment (i.e. CPS, which combines immune cell and tumour cell PD‐L1 expression) may improve prediction. PD‐L1 CPS thus remains an effective and broadly applicable uniform scoring system for enriching response to programmed death 1 blockade with pembrolizumab in mTNBC as well as other tumour types.

Abstract Aim We investigated the pathologic complete response rates (pCR) and survival outcomes of early breast cancer patients who underwent neoadjuvant chemotherapy (NAC) over 14 years at a French comprehensive cancer center and reported pCR and survival outcomes by tumor subtypes and size. Methods From January 2005 to December 2018, 1150 patients receiving NAC were identified. Correlations between cT stage, breast tumor response, axillary lymph node response, pCR, surgery, and outcomes were assessed. pCR was defined as (ypT0/ypTis) and (ypN0/pN0sn). Results A pCR was reached in 31.7% (365/1150) of patients and was strongly associated with tumor subtypes, but not with tumor size (pretreatment cT category). Luminal‐B Her2‐negative and triple‐negative (TN) subtypes, cN1 status, older age, and no‐pCR had an independent negative prognostic value. Overall survival (OS), relapse‐free survival (RFS), and metastasis‐free survival (MFS) were not significantly different for cT0‐1 compared to cT2 stages. In Cox‐model adjusted on in‐breast pCR and pN status, ypN1 had a strong negative impact (OS, RFS, and MFS: HR = 3.153, 4.677, and 6.133, respectively), higher than no in‐breast pCR (HR = 2.369, 2.252, and 2.323). A negative impact of no pCR on OS was observed for cN0 patients and TN tumors (HR = 4.972) or HER2‐positive tumors (HR = 11.706), as well as in Luminal‐B Her2‐negative tumors on MFS (HR = 2.223) and for Luminal‐A on RFS (HR = 4.465) and MFS (HR = 4.185). Conclusion Achievement of pCR, but not tumor size (pretreatment cT category), has an independent prognostic impact on survival. These results suggest potential NAC benefits in patients with small tumors (

Background: Breast cancer (BC) incidence increases with age, particularly in HR-positive/HER2-negative subtypes. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6is) alongside endocrine therapy (ET) have emerged as promising treatments for HR-positive/HER2-negative advanced and early BC. However, their efficacy, safety, and impact on quality of life (QoL) in older and frail patients remain underexplored. Methods: This position paper assesses the existing literature from 2015 to 2024, focusing on CDK4/6is use in patients aged 65 years and older with HR-positive/HER2-negative BC. Results: Our analysis methodically addresses critical questions regarding the utilization of CDK4/6is in the elderly BC patient population, organizing findings from the metastatic and adjuvant settings. In the metastatic setting, CDK4/6is significantly improve progression-free survival (PFS), paralleling benefits observed in younger patients, and suggest potential overall survival (OS) benefits, warranting further investigation. Despite an increased incidence of grade ≥ 3 adverse events (AEs), such as neutropenia and asthenia, CDK4/6is present a markedly lower toxicity profile compared to traditional chemotherapy, with manageable side effects. QoL analysis indicates that integrating CDK4/6is into treatment regimens does not significantly impact elderly BC patients’ daily life and symptom management. Special attention is given to frail subgroups, and personalized approaches are recommended to balance efficacy and adverse effects, such as starting with ET alone and introducing CDK4/6is upon progression in patients with a low disease burden. Transitioning to the adjuvant setting, early results, particularly with abemaciclib, indicate positive effects on disease-free survival (DFS), emphasizing the need for continued analysis to validate these findings and assess long-term implications. However, data on older patients are insufficient to conclude whether they truly benefit from this treatment. Conclusion: Overall, CDK4/6is present a favorable benefit-risk profile in older BC patients, at least in advanced BC; however, further research is warranted to optimize treatment strategies and improve outcomes in this population

Background: There is a scarcity of data exploring early breast cancer (eBC) in very young patients. We assessed shared and intrinsic prognostic factors in a large cohort of patients aged ≤35, compared to a control group aged 36 to 50. Methods: Patients ≤50 were retrospectively identified from a multicentric cohort of 23,134 eBC patients who underwent primary surgery between 1990 and 2014. Multivariate Cox analyses for DFS and OS were built. To assess the independent impact of age, 1 to 3 case-control analysis was performed by matching ≤35 and 36–50 years patients. Results: Of 6481 patients, 556 were aged ≤35, and 5925 from 36 to 50. Age ≤35 was associated with larger tumors, higher grade, ER-negativity, macroscopic lymph node involvement (pN + macro), lymphovascular invasion (LVI), mastectomy, and chemotherapy (CT) use. In multivariate analysis, age ≤35 was associated with worse DFS [HR 1.56, 95% CI 1.32–1.84; p

BackgroundElderly breast cancer (BC) patients have been underrepresented in clinical trials whereas ~60% of deaths from BC occur in women aged 70 years and older. Only limited data are available on the prognostic impact of age according to treatment, especially in the triple-negative (TN) and Her2-positive because of the lower frequency of these subtypes in elderly patients. We report herein the results of a multicenter retrospective study analyzing the prognostic impact of age according to treatment delivered in TN and Her2-positive BC patients of 70 years or older, including comparison by age groups.MethodsThe medical records of 31,473 patients treated from January 1991 to December 2018 were retrieved from 13 French cancer centers for retrospective analysis. Our study population included all ≥70 patients with TN or Her2-positive BC treated by upfront surgery. Three age categories were determined: 70-74, 75-80, and > 80 years.ResultsOf 528 patients included, 243 patients were 70-74 years old (46%), 172 were 75-80 years (32.6%) and 113 were >80 years (21.4%). Half the population (51.9%, 274 patients) were TN, 30.1% (159) Her2-positive/hormone receptors (HR)-positive, and, 18% (95) Her2-positive/endocrine receptors (ER)-negative BC. Advanced tumor stage was associated with older age but no other prognostic factors (tumor subtype, tumor grade, LVI). Adjuvant chemotherapy delivery was inversely proportional to age. With 49 months median follow-up, all patient outcomes (overall survival (OS), disease-free survival (DFS), breast cancer-specific survival (BCSS), and recurrence-free survival (RFS)) significantly decreased as age increased. In multivariate analysis, age >80, pT2-3 sizes, axillary macrometastases, lymphovascular involvement, and HR-negativity tumor negatively affected DFS and OS. Comparison between age >80 and 80 (HR=1.771, p=0.031).ConclusionTN and Her2-positive subtypes occur at similar frequency in elderly patients. Older age is associated with more advanced tumor stage presentation. Chemotherapy use decreases with older age without worse other pejorative prognostic factors. Age >80, but not ≤80, independently affected DFS and OS.

Background. An incidental axillary dose of adjuvant radiotherapy using tangential beams is usually given after breast-conserving surgery for breast cancer. The goal of this sub-study was to evaluate this incidental dose in the setting of post-mastectomy radiotherapy (PMRT) according to two different radiotherapy techniques. Methods. Patients participating in a randomized SERC trial who received PMRT in a single center were included. We collected the incidental axillary dose delivered to the Berg level 1 using different dosimetric parameters and compared two techniques using Student’s t-test: three-dimensional conformal radiotherapy (3D-CRT) and volumetric arc therapy (VMAT). Results. We analyzed radiotherapy plans from 52 patients who received PMRT from 2012 to 2021. The mean dose delivered to the Berg level 1 was 37.2 Gy. It was significantly higher with VMAT than with 3D-CRT—43.6 Gy (SD = 3.1 Gy) versus 34.8 Gy (SD = 8.6 Gy) p < 0.001. Eighty-four percent of the Berg level 1 was covered by 40 Gy isodose in the VMAT group versus 55.5% in the 3D-CRT group p < 0.001. Conclusions. On the Berg level 1, PMRT gives a dose at least equivalent to the one given by post-breast-conserving surgery radiotherapy, making it possible to limit completion axillary lymph node dissections in select pN1a patients treated with a mastectomy. Modern radiotherapy techniques like VMAT tend to increase this incidental dose.

Background Dysthyroidism (DT) is a common toxicity of immune checkpoint inhibitors (ICIs) and prior work suggests that dysthyroidism (DT) might be associated with ICI efficacy.Patients and methods ConSoRe, a new generation data mining solution, was used in this retrospective study, to extract data from electronic patient records of adult cancer patients treated with ICI at Institut Paoli-Calmettes (Marseille, France). Every DT was verified and only ICI-induced DT was retained. Survival analyses were performed by Kaplan-Meier method (log-rank test) and Cox model. To account for immortal time bias, a conditional landmark analysis was performed (2 months and 6 months), together with a time-varying Cox model.Results Data extraction identified 1385 patients treated with ICI between 2011 and 2021. DT was associated with improved overall survival (OS) (HR 0.46, (95% CI 0.33 to 0.65), p

(1) Background: The independent negative prognostic value of isolated tumor cells or micro-metastases in axillary lymph nodes has been established in triple-negative breast cancers (BC). However, the prognostic significance of pN0(i+) or pN1mi in HER2-positive BCs treated by primary surgery remains unexplored. Therefore, our objective was to investigate the impact of pN0(i+) or pN1mi in HER2-positive BC patients undergoing up-front surgery on their outcomes. (2) Methods: We retrospectively analyzed 23,650 patients treated in 13 French cancer centers from 1991 to 2013. pN status was categorized as pN0, pN0(i+), pN1mi, and pNmacro. The effect of pN0(i+) or pN1mi on outcomes was investigated both in the entire cohort of patients and in pT1a-b tumors. (3) Results: Of 1771 HER2-positive BC patients included, pN status distributed as follows: 1047 pN0 (59.1%), 60 pN0(i+) (3.4%), 118 pN1mi (6.7%), and 546 pN1 macro-metastases (30.8%). pN status was significantly associated with sentinel lymph node biopsy, axillary lymph node dissection, age, ER status, tumor grade, and size, lymphovascular invasion, adjuvant systemic therapy (ACt), and radiation therapy. With 61 months median follow-up (mean 63.2; CI 95% 61.5–64.9), only pN1 with macro-metastases was independently associated with a negative impact on overall, disease-free, recurrence-free, and metastasis-free survivals in multivariate analysis. In the pT1a-b subgroup including 474 patients, RFS was significantly decreased in multivariate analysis for pT1b BC without ACt (HR 2.365, 1.04–5.36, p = 0.039) and for pN0(i+)/pN1mi patients (HR 2.518, 1.03–6.14, p = 0.042). (4) Conclusions: Survival outcomes were not adversely affected by pN0(i+) and pN1mi in patients with HER2-positive BC. However, in the case of pT1a-b HER2-positive BC, a negative impact on RFS was observed specifically for patients with pN0(i+) and pN1mi diseases, particularly among those with pT1b tumors without ACt. Our findings highlight the importance of considering the pN0(i+) and pN1mi status in the decision-making process when discussing trastuzumab-based ACt for these patients.

Abstract Doxorubicin is a common treatment for breast cancer. However, not all patients respond to this drug, which sometimes causes life‐threatening side effects. Accurately anticipating doxorubicin‐resistant patients would therefore permit to spare them this risk while considering alternative treatments without delay. Stratifying patients based on molecular markers in their pretreatment tumors is a promising approach to advance toward this ambitious goal, but single‐gene gene markers such as HER2 expression have not shown to be sufficiently predictive. The recent availability of matched doxorubicin‐response and diverse molecular profiles across breast cancer patients permits now analysis at a much larger scale. 16 machine learning algorithms and 8 molecular profiles are systematically evaluated on the same cohort of patients. Only 2 of the 128 resulting models are substantially predictive, showing that they can be easily missed by a standard‐scale analysis. The best model is classification and regression tree (CART) nonlinearly combining 4 selected miRNA isoforms to predict doxorubicin response (median Matthew correlation coefficient (MCC) and area under the curve (AUC) of 0.56 and 0.80, respectively). By contrast, HER2 expression is significantly less predictive (median MCC and AUC of 0.14 and 0.57, respectively). As the predictive accuracy of this CART model increases with larger training sets, its update with future data should result in even better accuracy.

IntroductionThe poor prognosis of ovarian carcinoma (OvC) is due to the advanced stage at diagnosis, a high risk of relapse after first-line therapies, and the lack of efficient treatments in the recurrence setting. Circulating tumor DNA (ctDNA) analysis is a promising tool to assess treatment-resistant OvC and may avoid iterative tissue biopsies. We aimed to evaluate the genomic profile of recurrent heavily pre-treated OvC.MethodsWe performed tumor panel-based sequencing as well as low-coverage whole-genome sequencing (LC-WGS) of tumor and plasma collected in patients with ovarian cancer included in the PERMED-01 trial. Whole-exome sequencing (WES) data of plasma samples were also analyzed and compared to mutation and copy number alteration (CNA) tumor profiles. The prognostic value [progression-free survival (PFS)] of these alterations was assessed in an exploratory analysis.ResultsTumor and plasma genomic analyses were done for 24 patients with heavily pretreated OvC [67% high-grade serous carcinoma (HGSC)]. Tumor mutation burden was low (median 2.04 mutations/Mb) and the most frequent mutated gene was TP53 (94% of HGSC). Tumor CNAs were frequent with a median of 50% of genome altered fraction. Plasma LC-WGS and WES detected ctDNA in 21/24 cases (88%) with a median tumor fraction of 12.7%. We observed a low correlation between plasma and tumor CNA profiles. However, this correlation was significant in cases with the highest circulating tumor fraction. Plasma genome altered fraction and plasma mutation burden (p = 0.011 and p = 0.041, respectively, log-rank tests) were associated with PFS.ConclusionsCombination of LC-WGS and WES can detect ctDNA in most pre-treated OvCs. Some ctDNA characteristics, such as genome altered fraction and plasma mutation burden, showed prognostic value. ctDNA assessment with LC-WGS may be a promising and non-expansive tool to evaluate disease evolution in this disease with high genomic instability.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02342158, identifier NCT02342158.

Background: MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes. Methods: The MOST-plus trial used a randomized discontinuation design. After 12 weeks of sorafenib (400 mg, po BID), patients with progressive disease discontinued study, patients with objective response were proposed to continue sorafenib, whereas patients with stable disease (SD) were randomly assigned (1:1) to the maintenance or interruption of treatment. The primary endpoint was RECIST version 1.1 progression-free rate at 16 weeks after randomization (PFR-16w). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Statistical analyses used a sequential Bayesian approach with interim efficacy analyses. The enrolment could be stopped in the case of a 95% probability for the estimated PFR-16w to be higher in the maintenance than in the interruption arm (NCT02029001). Results: 151 patients were included, of whom 35 had SD at 12 weeks of Sorafenib. For the 35 patients with SD on sorafenib, the PFR-16w was 65% [95% credibility interval 43.4–83.7] in the continuation arm and 25% [7.8–48.1] in the interruption arm. Median PFS and OS were improved in the maintenance versus the interruption arm (mPFS: 5.6 [95%CI 1.97–6.77] months versus 2.0 [95%CI 1.61–3.91] months (p = 0.0231) and mOS: 14.3 [95%CI 8.9–23.8] versus 8.0 months [95%CI 3.5–15.2] (p = 0.0857)). Conclusion: Sorafenib showed activity in progressive patients with solid tumors harboring somatic genomic alterations in sorafenib-targeted genes. Continuing sorafenib when SD is achieved improves PFR compared to interruption.

Abstract Background The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. Methods Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 “candidate cancer” genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a “matched therapy” and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). Results Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68–75%). Only 94/550 patients (17%, 95%CI 14–21) received an “AGA-matched therapy” on progression. The most frequent AGAs leading to “matched therapy” included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such “matched therapy” improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of “matched therapy” was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with “matched therapy,” and 6-month overall survival (OS) was 62% (95%CI 52–73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. Conclusions Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a “matched therapy” in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. Trial registration ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .

Abstract Background Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). Methods Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). Results MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). Conclusions Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). Trial registration ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.

The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most altered pathways in human cancers, and it plays a central role in cellular growth, survival, metabolism, and cellular mobility, making it a particularly interesting therapeutic target. Recently, pan-inhibitors and then selective p110α subunit inhibitors of PI3K were developed. Breast cancer is the most frequent cancer in women and, despite therapeutic progress in recent years, advanced breast cancers remain incurable and early breast cancers are at risk of relapse. Breast cancer is divided in three molecular subtypes, each with its own molecular biology. However, PI3K mutations are found in all breast cancer subtypes in three main “hotspots”. In this review, we report the results of the most recent and main ongoing studies evaluating pan-PI3K inhibitors and selective PI3K inhibitors in each breast cancer subtype. In addition, we discuss the future of their development, the various potential mechanisms of resistance to these inhibitors and the ways to circumvent them.

Background: As a result of progress in diagnosis and treatment, there is a growing prevalence of metastatic breast cancer (MBC) with isolated CNS metastases. This study describes the largest-to-date real-life cohort of this clinical setting and compares it to other clinical presentations. Methods: We retrospectively analysed the French Epidemiological Strategy and Medical Economics (ESME) MBC database including patients who initiated treatment for MBC between 2008 and 2016. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Descriptive statistics and multivariate Cox model were used. Results: Of 22,266 patients, 647 (2.9%) and 929 (4.2%) patients had isolated first-site CNS metastases or combined with extra-CNS metastases, with longer OS for the group with isolated CNS metastases (16.9 versus 13.9 months, adjusted HR = 1.69 (95% CI: 1.50–1.91), p

Background: Breast cancer (BC) in young women merits a specific approach given the associated fertility, genetic and psychosocial issues. De novo metastatic breast cancer (MBC) in young women is an even more serious condition, with limited data available. Methods: We evaluated management of women aged ⩽40 years with de novo MBC in a real-life national multicentre cohort of 22,463 patients treated between 2008 and 2016 (NCT0327531). Our primary objective was to compare overall survival (OS) in young women versus women aged 41–69 years. The secondary objectives were to compare first-line progression-free survival (PFS1) and to describe treatment patterns. Results: Of the 4524 women included, 598 (13%) were ⩽40 years. Median age at MBC diagnosis was 36 years (range = 20–40). Compared with women aged 41–69 years, young women had more grade III tumours (49% versus 35.7%, p

Background: Young age is a poor prognostic factor in early stage breast cancer (BC) but its value is less established in metastatic BC (MBC). We evaluated the impact of age at MBC diagnosis on overall survival (OS) across three age groups ( 60 years(y)). Methods: ESME MBC database is a national cohort, collecting retrospective data from 18 participating French cancer centers between January 01, 2008 and December 31, 2014. Results: Among 14 403 women included, 1077 (7.5%), 6436 (44.7%) and 6890 (47.8%) pts were 60 y respectively. Pts 60y) and triple negative subtypes (27.4 vs 14.6% in >60y), and more frequent visceral involvement (36.3 vs 29.8% in >60y). At a median follow-up of 48 months, median OS differed across age groups: 38.8, 38.4 and 35.6 months for pts 60y, respectively (p 60y, respectively (p

Inflammatory breast cancer (IBC) is the most pro‐metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non‐IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next‐generation sequencing (tNGS) and array‐comparative genomic hybridization (aCGH) to 57 IBC and 50 non‐IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non‐IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor‐positive (HR+)/HER2−, HER2+, and triple‐negative] were 68%, 15%, and 17% in non‐IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non‐IBC. We identified 96 genes with an alteration frequency (p

During the COVID-19 pandemic, it was rapidly established that cancer patients have an increased risk of developing severe forms of the 2019 coronavirus disease (COVID-19) due to a backlog of cancer diagnostics and immunosuppressive treatments. Cancer centers had to quickly adapt to continue cancer therapies despite the high infection risks and major disruptions in the French healthcare system. We described and analyzed the impact of the pandemic in our institution: management adjustments, COVID-19 infection rates in patients and staff, and impacts on clinical activities and finances during the first wave of the pandemic from March to September 2020. We also compared the results to the clinical activity data from preceding periods. A crisis unit was rapidly created that met 27 times over 66 days, generating numerous changes in hospital protocol. While our area was devastated by the pandemic, the infection rate of our staff and patients remained low (less than 1.5% of all employees). However, the lockdown period was accompanied with a reduction of most clinical activities, leading to decreases of 43%, 36%, 36%, 1%, and 10% in surgery, endoscopy, radiotherapy, and in- and out-patient chemotherapy sessions, respectively, with substantial financial loss. Our report highlights the need for the rapid creation, implementation, and adaptation of new protocols during a pandemic’s evolution to prevent disease transmission. Lessons from this situation should provide motivation to better prepare for/limit the dismantling of cancer therapies that can dramatically impact patient care and have deleterious consequences on an institution’s financial situation.

Background Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting.Methods The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria.Results From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III–IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3–4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR.Conclusions Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach.Trial registration number ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.

PURPOSE: The prevalence of breast cancer is increasing in low- to middle-income countries such as Senegal. Our prospective study assessed the quality of life (QoL) of patients with breast cancer undergoing chemotherapy in Senegal. PATIENTS AND METHODS: Our study included women with breast cancer undergoing chemotherapy as initial treatment at the Center Aristide Le Dantec University Hospital in Dakar. Clinical, sociodemographic, and QoL data were collected and analyzed at three different times: baseline, 3 months, and 6 months after the start of systemic therapy. Health-related QoL was assessed using a Functional Assessment of Cancer Therapies-Breast (FACT-B) questionnaire after translation into the Wolof language. Linear mixed-effects models were performed to assess the changes in QoL scores. RESULTS: Between July 2017 and February 2018, 120 patients were included in the study. Their median age was 45 years. Most patients (n = 105; 92%) had locally advanced disease (T3 to T4 stage) and lymph node involvement (n = 103; 88%), and half had metastatic disease. The FACT-B total scores significantly improved over time (β = 1.58; 95% CI, 0.50 to 2.67; P < .01). Nausea and vomiting were significantly associated with a decrease in FACT-B total scores (β = −16.89, 95% CI, −29.58 to −4.24, P = .012; and β = −13.44, 95% CI, −25.15 to −1.72, P = .028, respectively). CONCLUSION: Our study confirmed the feasibility of standardized QoL assessment in Senegalese patients with breast cancer. Our results indicated a potential improvement of QoL over the course of chemotherapy. Optimizing nausea and vomiting prevention may improve QoL.

Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio ≥ 1.3 versus 5% in the “non-matched therapy group” (n = 25). The objective response and disease control rates were higher in the “matched therapy group” (33% and 58%, respectively) than in the “non-matched therapy group” (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to “matched therapy” in 19%, and provided clinical benefit in 8%.

Background. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. Methods. From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. Results. The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in M1 macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (HAVCR2/TIM3, CD27, CD70, CTLA4, ICOS, IDO1, LAG3, PDCD1, TNFRSF9, PVRIG, CD274/PDL1, and TIGIT) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs versus non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. Conclusion. Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials.

Inflammatory breast cancer (IBC) is a highly aggressive entity with a poor outcome and relative resistance to treatment. Despite progresses achieved during the last decades, the survival remains significantly lower than non-IBC. Recent clinical trials assessing PD-1/PD-L1 inhibitors showed promising results in non-IBC. Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment of different cancers. Several recent studies suggested a potential interest of targeting the immune system in IBC by revealing a more frequent PD-L1 expression and an enriched immune microenvironment when compared with non-IBC. Here, we describe the rationale and design of PELICAN-IPC 2015-016/Oncodistinct-003 trial, an open-label, randomized, non-comparative, phase II study assessing efficacy, and safety of pembrolizumab in combination with anthracycline-containing neoadjuvant chemotherapy in HER2-negative IBC. The trial is ongoing. The primary endpoint is the pCR rate (ypT0/Tis, ypN0) in overall population and the co-primary endpoint is safety profile during a run-in phase. Key secondary objectives include tolerability, invasive disease-free, event-free and overall survivals, as well as collection of tumor and blood samples for translational research.Clinical Trial Registrationhttps://clinicaltrials.gov/ (NCT03515798).

To address the problem of resistance to paclitaxel treatment, we have investigated to which extent is possible to predict Breast Cancer (BC) patient response to this drug. We carried out a large-scale tumor-based prediction analysis using data from the US National Cancer Institute’s Genomic Data Commons. These data sets comprise the responses of BC patients to paclitaxel along with six molecular profiles of their tumors. We assessed 10 Machine Learning (ML) algorithms on each of these profiles and evaluated the resulting 60 classifiers on the same BC patients. DNA methylation and miRNA profiles were the most informative overall. In combination with these two profiles, ML algorithms selecting the smallest subset of molecular features generated the most predictive classifiers: a complexity-optimized XGBoost classifier based on CpG island methylation extracted a subset of molecular factors relevant to predict paclitaxel response (AUC = 0.74). A CpG site methylation-based Decision Tree (DT) combining only 2 of the 22,941 considered CpG sites (AUC = 0.89) and a miRNA expression-based DT employing just 4 of the 337 analyzed mature miRNAs (AUC = 0.72) reveal the molecular types associated to paclitaxel-sensitive and resistant BC tumors. A literature review shows that features selected by these three classifiers have been individually linked to the cytotoxic-drug sensitivities and prognosis of BC patients. Our work leads to several molecular signatures, unearthed from methylome and miRNome, able to anticipate to some extent which BC tumors respond or not to paclitaxel. These results may provide insights to optimize paclitaxel-therapies in clinical practice.

The phase II AVASTEM trial explored the impact of chemotherapy-bevacizumab combination on breast cancer stem cells in the neoadjuvant setting. We aimed to identify biological features associated with preoperative chemotherapy efficacy and prognosis by analyses of circulating tumor cells (CTCs) and bevacizumab pharmacokinetics (PK). The main objective was to assess the prognostic (relapse-free survival and overall survival) and predictive (pathological complete response, pCR) values of CTCs (CellSearch technology) and bevacizumab PK (ELISA). Seventy-five patients were included. Out of them 50 received bevacizumab-chemotherapy and 25 received chemotherapy alone. CTC results were available for 60 patients and PK data for 29 patients in the experimental arm. The absence of CTC at inclusion was correlated to better outcome. Five-years overall survival (OS) was 91% for CTC-negative patients vs. 54% for CTC-positive cases (HR = 6.21; 95%CI (1.75–22.06), p = 0.001, log-rank test). Similar results were observed for RFS with 5 y-RFS of 78% vs. 44% (HR = 3.51; 95%CI (1.17–10.52), p = 0.017, log-rank test). However, CTC status at baseline was not predictive of pCR (p = 0.74). CTC status after one cycle was not a significant prognostic factor (HR = 1.56; 95%CI (0.19–12.67); p = 0.68 for OS and HR = 2.76; 95%CI (0.60–12.61); p = 0.17 for RFS, log-rank test). Bevacizumab serum levels could not predict pCR and survival. PK values were not associated with treatment-related toxicities. In conclusion, CTCs detection at baseline is a prognostic marker for breast cancer receiving a neoadjuvant chemotherapy-bevacizumab combination independently of tumor response.

Little is known about cancer survivors’ sexual health (SH)—particularly, from well after diagnosis and in cancers unrelated to sexuality. This study aimed to assess SH deterioration five years after diagnosis. We analyzed data from the French national VIe après le CANcer (VICAN) survey. Six items from the Relationship and Sexuality Scale were used to assess SH. Respondents were grouped according to an ascending hierarchical classification in four clusters: strong, moderate, and weak deterioration or stable (WD, SD, MD, or St). Out of 2195 eligible participants, 57.3% reported substantial SH deterioration as either SD (30.8%) or MD (26.5%), while WD and St accounted for 31.2% and 11.5% of respondents, respectively. Substantial deterioration was reported in all cancer sites (from 27.7% in melanoma to 83.1% in prostate). Treatment type, cancer sequelae, and pain, as well as psychological consequences (depression and anxiety, especially for younger patients) were associated with substantial SH deterioration. The same factors were identified after restricting the analysis to survivors of cancers unrelated to sexuality. Five years after diagnosis, the majority of cancer survivors reported SH deterioration. Interventions should be developed to improve SH regardless of cancer site. Particular attention should be paid to depression and anxiety, especially in younger survivors.

Over the last few decades, improved knowledge of oncogenic activation mechanisms of HER2 protein has led to the development of HER2 targeted therapies that are currently commonly used in HER2-positive advanced breast cancer, such as trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine. The management of this breast cancer subgroup has thus been revolutionized and its prognosis has changed dramatically. Nevertheless, HER2-positive advanced breast cancer remains an incurable disease and resistance to conventional anti-HER2 drugs is almost unavoidable. Nowadays, biochemical and pharmaceutical advances are meeting the challenge of developing increasingly sophisticated therapies directed against HER2, including novel anti HER2 antibodies with increased affinity. New antibody-drug conjugates (ADC) with more advanced pharmacological properties, and dual targeting of epitopes via bispecific monoclonal antibodies are also emerging. In addition, more potent and more specific HER2 tyrosine kinase inhibitors have shown interesting outcomes and are under development. Finally, researchers’ interest in tumor microenvironment, particularly tumor-infiltrating lymphocytes, and the major role that signaling pathways, such as the PI3K/AKT/mTOR pathway, play in the development of resistance to anti-HER2 therapies have spurred the development of clinical trials evaluating innovative combinations of anti-HER2 with PD-1/PDL-1, CDK4/6 and PI3K inhibitors. However, several questions remain unresolved, like the optimal management of HER2-positive/HR-positive advanced breast cancer and the identification of predictive biomarkers to better define populations that can benefit most from these new therapies and approaches.

Exquisitely exploiting defects in homologous recombination process, poly(ADP-ribose) polymerase (PARP) inhibitors have recently emerged as a promising class of therapeutics in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with germline breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) mutations (gBRCA1/2m). In this setting, PARP inhibitors, either as single agent or in combination with platinum-based chemotherapy, significantly increased progression-free survival, as compared to conventional chemotherapy. Accordingly, further therapeutic advances are expected at an earlier stage of the disease. In the neoadjuvant setting, veliparib failed to increase the pathological complete response rate when added to a carboplatin-based regimen, in unselected triple-negative breast cancer patients. Similarly, when administered before anthracycline-cyclophosphamide, the neoadjuvant olaparib-paclitaxel combination was not superior to carboplatin–paclitaxel, in patients with HER2-negative breast cancer and BRCA1/2 mutation, or homologous recombination defect. Yet, neoadjuvant talazoparib, administered as a single-agent in patients with HER2-negative breast cancer and germline BRCA1/2 mutation, achieved an impressive pathological complete response rate of nearly 50%. In the adjuvant setting, the results from the OlympiA phase III study, evaluating adjuvant olaparib in HER2-negative early breast cancer and germline BRCA1/2 mutations, are eagerly awaited. Ongoing trials should clarify whether PARP inhibitors might improve outcome when administered in the adjuvant or neoadjuvant setting in early breast cancer patients with BRCA1/2 mutation or homologous recombination defect.

BackgroundMajor advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing.Methods and findingsWhole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival.ConclusionsThis work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.

Triple negative breast cancer (TNBC) represent 15% of breast cancers. Histoclinical features and marketed prognostic gene expression signatures (GES) failed to identify good- and poor-prognosis patients. Tyrosine kinases (TK) represent potential prognostic and/or therapeutic targets for TNBC. We sought to define a prognostic TK GES in a large series of TNBC. mRNA expression and histoclinical data of 6379 early BCs were collected from 16 datasets. We searched for a TK-based GES associated with disease-free survival (DFS) and tested its robustness in an independent validation set. A total of 1226 samples were TNBC. In the learning set of samples (N = 825), we identified a 13-TK GES associated with DFS. This GES was associated with cell proliferation and immune response. In multivariate analysis, it outperformed the previously published GESs and classical prognostic factors in the validation set (N = 401), in which the patients classified as “low-risk” had a 73% 5-year DFS versus 53% for “high-risk” patients (p = 1.85 × 10−3). The generation of 100,000 random 13-gene signatures by a resampling scheme showed the non-random nature of our classifier, which was also prognostic for overall survival in multivariate analysis. We identified a robust and non-random 13-TK GES that separated TNBC into subgroups of different prognosis. Clinical and functional validations are warranted.

Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.

Preclinical works have suggested cytotoxic chemotherapies may increase the number of cancer stem cells (CSC) whereas angiogenesis inhibition may decrease CSC proliferation. We developed a proof of concept clinical trial to explore bevacizumab activity on breast CSC. Breast cancer patients requiring preoperative chemotherapy were included in this open-label, randomized, prospective, multicenter phase II trial. All received FEC-docetaxel combination, and patients randomized in the experimental arm received concomitant bevacizumab. The primary endpoint was to describe ALDH1 (Aldehyde dehydrogenase 1) positive tumor cells rate before treatment and after the fourth cycle. Secondary objectives included safety, pathological complete response (pCR) rate, disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). Seventy-five patients were included. ALDH1+ cells rate increase was below the predefined 5% threshold in both arms for the 32 patients with two time points available. Grade 3 or 4 adverse events rates were similar in both arms. A non-significant increase in pCR was observed in the bevacizumab arm (42.6% vs. 18.2%, p = 0.06), but survival was not improved (OS: p = 0.89; DFS: p = 0.45; and RFS: p = 0.68). The increase of ALDH1+ tumor cells rate after bevacizumab-based chemotherapy was less than 5%. However, as similar results were observed with chemotherapy alone, bevacizumab impact on breast CSC cells cannot be confirmed.

In oncology, the treatment of patients outside of hospitals has become imperative due to an increasing number of patients who are older and live longer, along with issues such as medical desertification, oncologist hyperspecialization, and difficulties in financing mounting health expenditures. Treatments have become less “invasive„, with greater precision and efficiency. Patients can therefore receive most of their care outside of hospitals. The development of e-health can address these new imperatives. In this letter, we describe the different e-health tools and their potential clinical impacts in oncology, as already reported at every level of care, including education, prevention, diagnosis, treatment, and monitoring. A few randomized studies have yet demonstrated the clinical benefit. We also comment on issues and limits of “cancer outside the hospital walls„ from the point of view of patients, health care professionals, health facilities, and public authorities. Care providers in hospitals and communities will have to adapt to these changes within well-coordinated networks in order to better meet patient expectations regarding increasing education and personalizing management. Ultimately, controlled studies should aim to definitively demonstrate areas of interest, benefits, and incentives, for not only patients, but also caregivers (formal and informal) and health care providers, health care facilities, and the nation.

Breast cancers (BC) associated with germline mutations of BRCA1/2 represent 3⁻5% of cases. BRCA1/2-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize clinical trials of chemotherapy and PARP inhibitors (PARPi), alone or in combination, at the early or late stage of BRCA1/2-associated BC. We will also present the mechanisms of resistance to PARPi as well as the new therapeutic strategies of association with PARPi. Finally, we will discuss under which conditions the use of DNA damaging agents can be extended to the BRCA1/2-wild type population, the BRCAness concept.

Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.

BACKGROUND:Breast cancer stem cells (BCSCs) have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL), BrCA-MZ-01. METHODS:ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+) and mature cancer (ALDH-) cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE). Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS. RESULTS:2-D DIGE identified poly(ADP-ribose) polymerase 1 (PARP1) as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor. CONCLUSION:An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors.