Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial

Antecedents: L'assaig Opti-HER HEART tenia com a objectiu optimitzar l'activitat i minimitzar el risc cardíac combinant trastuzumab, pertuzumab i paclitaxel amb doxorubicina liposomal no pegilada en el tractament del càncer de mama precoç HER2-positiu. Mètodes: Els pacients amb càncer de mama HER2 positiu en fase II-IIIB van rebre trastuzumab neoadjuvant, pertuzumab, paclitaxel i una doxorubicina liposomal no pegilada cada tres setmanes durant sis cicles. El principal criteri final va ser la seguretat cardíaca durant la teràpia neoadjuvant. Es van avaluar els esdeveniments cardíacs tipus A (insuficiència cardíaca congestiva simptomàtica) i B (reducció asimptomàtica de la fracció d'ejecció del ventricle esquerre). Els criteris finals secundaris van incloure l'avaluació de la taxa de resposta patològica completa (pCR) i la taxa de resposta global, entre d'altres. Com a anàlisi exploratòria ad-hoc , es va mesurar l'expressió de 55 gens relacionats amb el càncer de mama, inclosos els gens PAM50 , en 58 mostres de tumors basals i 60 mostres quirúrgiques. Resultats: Es van reclutar vuitanta-tres pacients. La incidència d'esdeveniments cardíacs durant el tractament neoadjuvant va ser del 2,4%. No es va observar cap esdeveniment cardíac de tipus A. La taxa global de pCR va ser del 56,6% (interval de confiança (IC) del 95%: 45,3-67,5%). El subtipus enriquit amb HER2, que representava el 52,0% de totes les mostres basals, es va associar amb una taxa de pCR més alta en comparació amb els tumors no enriquits amb HER2 (83,3% vs. 46,3%; odds ratio 5,76; 95% CI 1,71-19,42). L'associació de subtipus amb pCR va ser independent de les variables clínicopatològiques conegudes, inclòs l'estat del receptor hormonal. En comparació amb les mostres basals, els exemplars quirúrgics van mostrar una significativa regulació descendent dels nivells relacionats amb la proliferació ( MKI67 i CCNB1 ) i ERBB2 , i una regulació ascendent significativa dels relacionats amb la llum (ESR1 i PGR ) i gens immunes ( CD8A ). Conclusions: La combinació de doble bloqueig HER2 amb trastuzumab i pertuzumab amb paclitaxel i doxorubicina liposomal no pegilada s'associa amb una baixa taxa d'esdeveniments cardíacs. El subtipus enriquit amb HER2 s'associa a una alta taxa de pCR

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicenter, retrospective analysis

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies

Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial

Abstract Background The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2-positive early breast cancer. Methods Patients with stage II–IIIB HER2-positive breast cancer received neoadjuvant trastuzumab, pertuzumab, paclitaxel, and a non-pegylated liposomal doxorubicin every three weeks for six cycles. The primary endpoint was cardiac safety during neoadjuvant therapy. Type A (symptomatic congestive heart failure) and B (asymptomatic reduction of left ventricular ejection fraction) cardiac events were evaluated. Secondary endpoints included the evaluation of the pathological complete response (pCR) rate and overall response rate, among others. As an ad-hoc exploratory analysis, the expression of 55 breast cancer-related genes, including the PAM50 genes, was measured in 58 baseline tumor samples and 60 surgical specimens. Results Eighty-three patients were recruited. The incidence of cardiac events during neoadjuvant treatment was 2.4%. No type A cardiac event was observed. The overall pCR rate was 56.6% (95% confidence interval (CI) 45.3–67.5%). The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pCR rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% CI 1.71–19.42). The association of subtype with pCR was independent of known clinicopathological variables, including hormone receptor status. Compared to baseline samples, surgical specimens showed a significant downregulation of proliferation-related genes (MKI67 and CCNB1) and ERBB2 levels, and a significant upregulation of luminal-related (ESR1 and PGR) and immune (CD8A) genes. Conclusions The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events. The HER2-enriched subtype is associated with a high rate of pCR. Trial registration clinicaltrials.gov, NCT01669239, Registered 20 August 2012

Predictors of surgical outcomes of minimally invasive right colectomy: the MERCY study

PURPOSE: The optimal approach for minimally invasive (MIS) right colectomy remains under debate. This study aimed to describe surgical trends in the treatment of nonmetastatic right colon cancer and to identify predictors of short-term surgical outcomes. METHODS: A retrospective multicenter cohort study of Minimally-invasivE surgery for oncologic Right ColectomY (MERCY) was conducted on patients who underwent laparoscopic or robotic right colectomy between 2014 and 2020. Classification tree approach was used to describe the extracorporeal (EA) or intracorporeal (IA) anastomosis choice. Mixed-model regressions were used to identify patient- and surgery-related factors predictive of postoperative outcomes. A questionnaire was used to evaluate the surgeons' perspectives. RESULTS: The MERCY database comprised 1870 patients; 87.2% underwent laparoscopy, and 68.1% received an EA. A clear surgical trend was noted, with an increasing rate of IA and robotic procedures after 2017. EA represented 41% of anastomoses in centers equipped with a robotic surgical system. Mixed-model regressions (on 1088 patients) showed that age, sex, BMI, comorbidity, robotics, IA, and conversion to open surgery were predictors of surgical outcomes. In particular, IA was a predictor of a shorter time to regular diet and fewer surgical site infections. Based on the questionnaire, IA was the preferred over EA by 72% of surgeons. CONCLUSION: MIS continues to evolve, with an increasing number of IA being performed in the recent years and when using a robotic surgical system. Understanding the role of predictors of surgical outcomes may help surgeons personalize decision-making among the different MIS options to manage right colon cancer

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicenter, retrospective analysis

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicenter, retrospective analysis

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies