Prevention of aromatase inhibitor-induced bone loss with anti-resorptive therapy in post-menopausal women with early-stage breast cancer.

We assessed if antiresorptive treatment can prevent aromatase inhibitor-induced bone loss in patients with early breast cancer. We observed that patients who did not receive antiresorptive treatment had a 20.8-fold increase in risk of bone loss after 24 months of aromatase inhibitors therapy. PURPOSE: This study aimed to describe changes in femoral and lumbar bone mineral density (BMD) after 24 months of aromatase inhibitors (AIs) and antiresorptive treatment in postmenopausal women with estrogen receptor-positive breast cancer. METHODS: Prospective, longitudinal study in a real-life setting with a 2-year follow-up. Patients underwent a complete baseline bone assessment including clinical assessment, biological evaluation, BMD measurement, and spine X-ray. Antiresorptive treatment was prescribed to patients with a T-score < - 2 or a T-score < - 1.5 SD with additional osteoporosis risk factors. A follow-up bone assessment was carried out after 24 months. RESULTS: Among 328 patients referred to our center, 168 patients (67.7 ± 10.6 years) were included in our study, and 144 were eligible for antiresorptive treatment. After 24 months, patients receiving antiresorptive treatment experienced a significant increase of + 6.28% in femoral-BMD (F-BMD) and + 7.79% in lumbar-BMD (L-BMD). This increase was not significantly different between osteoporotic and osteopenic patients. Conversely, patients not receiving antiresorptive treatment presented significant F-BMD and L-BMD loss regardless of the baseline BMD. In the multivariate logistic model, the lack of antiresorptive treatment was the only predictive factor for major femoral bone loss with a 20.83 odds ratio (CI95%:4.2-100, p < 0.001). CONCLUSION: This real-life study confirmed that antiresorptive treatment significantly increases femoral and lumbar BMD regardless of the baseline BMD in postmenopausal patients receiving AIs for early breast cancer. Patients who did not receive antiresorptive treatment had a 20.8-fold increased risk of major bone loss. Nevertheless, the best threshold to adopt for starting antiresorptive agents remains undetermined.

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial.

BACKGROUND: The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. METHODS: This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. FINDINGS: Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). INTERPRETATION: Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. FUNDING: GERCOR and F Hoffmann-La Roche.

Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial.

BACKGROUND: Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers. METHODS: In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m(2)) and oxaliplatin (100 mg/m(2)) with or without cetuximab (500 mg/m(2)), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149. FINDINGS: Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52-74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43-65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1-7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7-6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1-13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6-16·0) in the chemotherapy alone group. The most common grade 3-4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group. INTERPRETATION: The addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option. FUNDING: Institut National du Cancer, Merck Serono.

Contributing to research via biobanks: what it means to cancer patients.

CONTEXT AND OBJECTIVE: Biobanks have become strategic resources for biomedical and genetic research. The aim of the present empirical qualitative study was to investigate how patients with cancer perceive and experience the process of donation to biobanks, focussing on the subjective meanings associated with their decisions when they are asked in a routine context to agree to their own biological specimens being used for research projects. DESIGN: A qualitative study, using semi-structured interviews to explore in depth the reasons why patients with cancer agree to participating in biobanking. Participants Nineteen patients (aged 28-82 years) being treated for colorectal cancer or leukaemia at a French cancer centre participated in this study. RESULTS: Contributing to biobanks was experienced here as a rewarding and empowering individual experience because of the psychological issues involved, such as feelings of hope associated with research, because it makes the relationship with researchers and clinicians less asymmetrical, revalorization of otherwise 'wasted' tissue, and also as an act of solidarity and reciprocity, which makes patients part of a community. DISCUSSION AND CONCLUSION: Patients seem to regard contributing to biobanks as an act of benevolence, which they are motivated to perform because of societal welfare considerations as well as the hope of subjective benefits. Knowledge about the patients' perspective and of the psychological rewards associated with tumour donation should be taken into account by physicians and caregivers discussing this topic with their patients.

Neoadjuvant chemotherapy for breast cancer: Pathologic response rates but not tumor size, has an independent prognostic impact on survival.

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 (<2 cm), even in absence of clinically suspicious lymph nodes. Residual lymph node disease after NAC is the most powerful adverse prognostic factor.

The Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Elderly Breast Cancer Patients: What Do We Know?

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.

Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial.

The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3-81) in cohort 1, 37.5% (95% CI 26.4-49.7) in cohort 2 and 29.7% (95% CI 15.9-47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8-64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7-65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960 .).

Genome profiling of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is one of the most aggressive human cancers. It displays many different chromosomal abnormalities and mutations. By using 244 K high-resolution array-comparative genomic hybridization (aCGH) we studied the genome alterations of 39 fine-needle aspirations from pancreatic adenocarcinoma and eight human adenocarcinoma pancreatic cell lines. Using both visual inspection and GISTIC analysis, recurrent losses were observed on 1p, 3p, 4p, 6, 8p, 9, 10, 11q, 15q, 17, 18, 19p, 20p, 21, and 22 and comprised several known or suspected tumor suppressor genes such as ARHGEF10, ARID1A, CDKN2A/B, FHIT, PTEN, RB1, RUNX1-3, SMAD4, STK11/LKB1, TP53, and TUSC3. Heterozygous deletion of the 1p35-p36 chromosomal region was identified in one-third of the tumors and three of the cell lines. This region, commonly deleted in human cancers, contains several tumor suppressor genes including ARID1A and RUNX3. We identified frequent genetic gains on chromosome arms 1q, 3q, 5p, 6p, 7q, 8q, 12q, 15q, 18q, 19q, and 20q. Amplifications were observed in 16 tumors. AKT2, CCND3, CDK4, FOXA2, GATA6, MDM2, MYC, and SMURF1 genes were gained or amplified. The most obvious amplification was located at 18q11.2 and targeted the GATA6 gene, which plays a predominant role in the initial specification of the pancreas and in pancreatic cell type differentiation. In conclusion, we have identified novel biomarkers and potential therapeutic targets in pancreatic adenocarcinoma.

Pathological complete response rate and disease-free survival after neoadjuvant chemotherapy in patients with HER2-low and HER2-0 breast cancers.

BACKGROUND: Half of HER2-negative breast cancers (BC) show HER2-low expression. The strong efficacy of recent anti-HER2 antibody-drug conjugates (ADC) in HER2-low tumours has risen the interest of HER2-low as a proper BC subtype. Chemosensitivity and prognosis of this subtype are not clear when compared to HER2-0 tumours. We investigated the pathological complete response (pCR) and disease-free survival (DFS) rates in BC patients receiving neoadjuvant chemotherapy for HER2-low or HER2-0 tumours. METHODS: Data were collected from the Institut Paoli-Calmettes database. HER2-low tumours were defined by HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-0 by IHC score of 0. Clinicopathological characteristics, pCR (defined as [ypT0/ypTis] and [pN0sn or ypN0]) and DFS rates were compared between the two cohorts. RESULTS: From Jan/2005 to Jun/2021, 1111 patients receiving neoadjuvant chemotherapy were evaluable. The incidence of HER2-low was 41%, including 63% of hormone receptor (HR)-positive and 37% of HR-negative tumours (p < 0.001). In the whole population, the pCR rate was lower in HER2-low (23%) versus HER2-0 (30%) tumours (p = 0.013), but this association was lost in multivariate analysis. In HR-positive patients, HER2-low negatively impacted pCR rates when compared to HER2-0 (10% vs. 16%, p = 0.046), but not in HR-negatives (46% vs. 42%), and this result was maintained in multivariate analysis. No correlation existed between DFS and HER2-status. CONCLUSION: HER2-low is associated with HR positivity. HER2 status did not impact pCR in HR-negative patients, whereas HER2-low was associated with lower pCR rate in HR-positive patients.

Neoadjuvant Chemotherapy for Breast Cancer: Evolution of Clinical Practice in a French Cancer Center Over 16 Years and Pathologic Response Rates According to Tumor Subtypes and Clinical Tumor Size: Retrospective Cohort Study.

We examined characteristics trends in early breast cancer patients receiving neoadjuvant chemotherapy (NAC) over a 16-year period. Our primary objective was to analyze variations in tumor stage and subtype over time. Secondary objectives included analyses of type of surgery and pathological response, from January 2005 to May 2021, 1623 patients receiving NAC were identified. Three periods were determined: 2005-2009 (P1), 2010-2014 (P2), 2015-2021 (P3). Correlations between periods and patient features with cT stage, pathological breast and axillary node response, pathological complete response (pCR), and type of surgery were assessed in univariate and multivariate analyses. We observed a significant increase in cT0-1 and N0 stages with periods (from 6.8% at P1 to 21.2% at P3, and from 43.2% at P1 to 55.9% at P3, respectively) and in the proportion of HER2+ and triple negative (TN) subtypes. In a multivariate analysis, a decrease of cT2-3-4 tumors during P3 was observed for HER2+ (OR:0.174; p=0.004) and TN tumors (OR:0.287; p=0.042). In-breast pCR and pCR were observed in 40.8% and 34.4% of all patients, respectively, with strong association with tumor subtypes, but not with tumor size in multivariate analysis (37.0% pCR for cT0-1 tumors, 36.4% for cT2 tumors, 29.1% for cT3 tumors (cT0-1 versus cT≥2; p=0.222)). pCR was negatively associated with cN1 stage (OR:1.499; p<0.001 for cN1 patients compared to cN0). We observed an increase in the proportion of small cT0-1 and N0 stages treated with NAC, especially in HER2+ and TN subtypes. No significant impact of tumor size on pCR rates was found.

Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial.

BACKGROUND: Triplet chemotherapy has demonstrated manageable toxicities and a favorable response rate. The addition of cetuximab to chemotherapy can increase treatment efficacy. We evaluated the efficacy and safety of cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), the ERBIRINOX regimen, as first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a phase II study, treatment consisted of weekly cetuximab plus biweekly. Treatment was continued for a maximum of 12 cycles and tumor response was evaluated every four cycles. The primary efficacy criterion was the complete response (CR) rate. RESULTS: From April 2006 to April 2008, 42 patients were enrolled. The median age was 60 years (range, 32-76 years). The median duration of treatment was 5.2 months (range, 0.7-8.5 months), and a median of nine cycles was given per patient (range, 1-12 cycles). Five patients (11.9%) showed a CR, with a median duration of 23.1 months (95% confidence interval [CI], 10.8-39.7 months). The objective response rate was 80.9% (95% CI, 65.9%-91.4%). The median overall and progression-free survival times were 24.7 months (95% CI, 22.6 months to not reached) and 9.5 months (95% CI, 7.6-10.4 months), respectively. The most frequent grade 3-4 adverse events were diarrhea (52%), neutropenia (38%), and asthenia (32%). CONCLUSION: The ERBIRINOX regimen appears to be effective and feasible in first-line treatment of mCRC patients. These promising results led us to initiate a multicenter, randomized, phase II trial ([Research Partnership for Digestive Oncology] PRODIGE 14) in patients with potentially resectable mCRC.

Pancreatic head resectable adenocarcinoma: preoperative chemoradiation improves local control but does not affect survival.

BACKGROUND: This study assesses the impact of preoperative chemoradiation on recurrence, surgical morbidity, histopathological data and survival in resectable adenocarcinoma of the pancreatic head. METHODS: We carried out a retrospective study with an intention-to-treat analysis. From 1997 to 2006, 173 patients with resectable pancreas head carcinoma were treated in two reference centres in France using different treatment strategies. RESULTS: Sixty-seven of 85 (79%) patients in the surgery-first (SF) group and 38 of 88 (43%) patients in the chemoradiation (CR) group underwent surgical resection (P < 0.001). Overall morbidity was 40% (15/38) in the CR group and 43% (29/67) in the SF group (P= 0.837). In the CR group, median tumour size was smaller (1.5 cm vs. 3.0 cm; P < 0.001) and fewer patients were node-positive (29% vs. 64%; P= 0.001) than in the SF group. There was less perineural (43% vs. 93%; P < 0.001), lymphatic and vascular (21% vs. 92%; P < 0.001) invasion in the CR group than in the SF group. In both groups, 89% of patients had recurrence (31/35 in the CR group and 57/64 in the SF group; P= 1.000), predominantly involving metastasis and carcinomatosis in the CR group (30/31 vs. 35/57; P < 0.001) and locoregional recurrence in the SF group (24/57 vs. 3/31; P= 0.002). Median survival for all patients and for resected patients in the CR and SF groups was, respectively, 15 months vs. 17 months, and 21 months vs. 18 months (P= non-significant). CONCLUSIONS: Preoperative chemoradiation allows for good local control of the disease but does not increase survival, mainly for reasons of metastatic spread. Other options should be developed to improve both local and distant control of the disease.

Eribulin Efficacy on Brain Metastases in Heavily Pretreated Patients with Metastatic Breast Cancer.

The onset of brain metastases (BM) is a major turning point during advanced breast cancer (ABC) evolution, with only few treatment options when local therapies have failed. The therapeutic effect of eribulin, a wildly used drug in the treatment of ABC, remains unclear in this setting. PATIENTS AND METHODS: We performed a retrospective observational study to assess eribulin efficacy in patients with ABC who displayed BM at time of eribulin initiation. We collected data from the medical files of all ABC patients who received eribulin at our institution from 2012 until 2020. Our main endpoint was the central nervous system (CNS) progression-free survival. (CNS-PFS). Other evaluation criteria were extra-cranial progression free survival (PFS) and overall survival (OS). RESULTS: Twenty patients with BM monitoring data available were selected out of the 549 who received eribulin during the inclusion period. Fifteen patients (75%) had BM progressive as the best response, three patients (15%) had disease stabilization for more than 6 months and only one patient had a partial response according to RECIST 1.1 criteria. Median CNS-PFS was 3.39 months (95CI (3.02-3.76)). Cox univariate analysis identified molecular subtype as the only prognostic parameter in our cohort, with patients with hormone-receptor positive tumors less likely to experience CNS progression than those with triple-negative MBC (HR = 0.23 (95CI = 0.07-0.80), p = 0.021). Median extra-cranial PFS was 2.67 months (95CI (2.33-3.01)). Median OS was 7.68 months (95CI (0-17.41)). CONCLUSION: Eribulin seems to have only a limited impact on BM evolution. Hormone receptors expression may identify a subset of patients with better BM control.

Bevacizumab-related surgical site complication despite primary tumor resection in colorectal cancer patients.

BACKGROUND: Combining conventional systemic chemotherapy with the angiogenesis inhibitor bevacizumab is now recommended as a first treatment for metastatic colorectal neoplasms. The risk for short-term postoperative complications related to bevacizumab has been assessed. Late postoperative complications related to bevacizumab have also been suggested by preliminary reports. METHODS: We reviewed a cohort of 142 patients with previous surgery for primary colonic or rectal tumor and without evidence of local recurrence, receiving bevacizumab for metastatic disease. RESULTS: Four patients experienced a late surgical site complication related to bevacizumab. Common features were rectal location, low anastomosis, and preoperative irradiation. Combining these three factors, the risk of a bevacizumab-related complication was 4 in 27 (14.8%); if previous history of postoperative leakage was reported, the risk was raised to 2 in 4. No complications occurred in colonic location or the non-irradiated patients. The mechanism of these complications could be ischemic lesion in post-irradiated tissues involving anastomoses. CONCLUSION: We conclude that angiogenesis inhibitors should be carefully considered for patients having low colorectal anastomosis and previous irradiation.

Neoadjuvant 5 fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single institution experience.

OBJECTIVES: It is the aim of this study to assess the outcome of patients who received neoadjuvant 5-fluorouracil-cisplatin chemoradiation (CRT) for stage I/III pancreatic adenocarcinoma. METHODS: Eligible patients (n = 101) received radiation therapy (45 Gy) associated with continuous infusion of 5-fluorouracil accompanied by a cisplatin bolus. RESULTS: Of the 102 patients enrolled in the study, 26 patients had progression of cancer during treatment and were deemed unresectable; 1 patient died during CRT of septic shock. Sixty-two of 75 remaining patients underwent pancreaticoduodenectomy. The overall median survival of all 102 patients in the study was 17 months, with a 5-year survival of 10%. For patients who underwent resection, the median survival was 23 months. Correspondingly, the median survival was 11 months for the 40 unresected patients (p = 0.002). The 5-year survivals for resected and unresected patients were 18 and 0% (p = 0.01), respectively. A complete pathological response to neoadjuvant CRT was noted for 8 patients (13%). Margin and lymph node positivity was present in 5 (8%) and 15 (24%) patients, respectively. There was documented local recurrence in 8 (13%) and distant recurrence in 36 (58%) patients, with the liver being the most common site. CONCLUSION: Neoadjuvant 5-fluorouracil-based CRT had a limited impact on survival but appeared to be associated with improved local control.

[Metastatic colorectal cancers and targeted therapy against EGFR]. / Cancers colorectaux métastatiques et thérapies ciblées anti-EGFR.

Colorectal cancer (CRC) (CRC) is one of the leading causes of mortality and accounts for approximately 200 000 deaths per year in Europe and the USA. Chemotherapy and radiotherapy have established roles in the treatment of colorectal cancer and can contribute to cure rate, prolongation of survival, reduction of local rates of recurrence and enhanced quality of life in patients with advanced disease. However, over the past few years there have been major advances in our understanding of the molecular basis of this tumour and its progression from adenoma to carcinoma that hold potential for translation into novel strategies for the treatment of CRC. Furthermore, newer agents directed against different intracellular targets have also been shown to be efficacious in CRC treatment. Such improvements should continue to lead to increased cure rates in early disease and better overall survival in advanced cases.

A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment.

BACKGROUND: Cetuximab, a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), is currently used in metastatic colorectal cancer (mCRC), but predictive factors for therapeutic response are lacking. Mutational status of KRAS and EGFR, and EGFR copy number are potential determinants of cetuximab activity. METHODS: We analyzed tumor tissues from 32 EGFR-positive mCRC patients receiving cetuximab/irinotecan combination and evaluable for treatment response. EGFR copy number was quantified by fluorescence in situ hybridization (FISH). KRAS exon 1 and EGFR exons coding for extracellular regions were sequenced. RESULTS: Nine patients experienced an objective response (partial response) and 23 were considered as nonresponders (12 with stable disease and 11 with progressive disease). There was no EGFR amplification found, but high polysomy was noted in 2 patients, both of which were cetuximab responders. No EGFR mutations were found but a variant of exon 13 (R521K) was observed in 12 patients, 11 of which achieved objective response or stable disease. Progression-free and overall survivals were significantly better in patients with this EGFR exon 13 variant. KRAS mutations were found in 14 cases. While there was a trend for an increased KRAS mutation frequency in nonresponder patients (12 mutations out of 23, 52%) as compared to responder patients (2 out of 9, 22%), authentic tumor response or long-term disease stabilization was found in KRAS mutated patients. CONCLUSION: This preliminary study suggests that: an increase in EGFR copy number may be associated with cetuximab response but is a rare event in CRC, KRAS mutations are associated with low response rate but do not preclude any cetuximab-based combination efficacy and EGFR exon 13 variant (R521K) may predict for cetuximab benefit.

Lung cancer in elderly patients: a retrospective analysis of practice in a single institution.

UNLABELLED: Incidence of non-small cell lung cancer is increasing especially among elderly with about 40% arising in patients over 70 years old. Most of these elderly patients are under treated. Seventy-one patients with lung cancer over 70 years old were treated in Institut Paoli-Calmettes from January 2000 until December 2003 (male/female: 57/14). Median age was 75.5 years (70-92). OMS 0-1-2-3=4.2-60.6-25.4-4.2%, respectively. Comorbidities were represented by arterial hypertension, coronaropathy, cardiac failure, thrombo-embolism, respiratory failure, diabetes, vascular cerebral dysfunction, and renal failure. 29.6% of patients were without comorbidity, and 14.1% had at least three comorbidities. The averages of the Charlson comorbidity score and the Age-Charlson comorbidity score were 3.4 and 6.6, respectively. Histological characteristics: epidermoïd/adenocarcinoma/undifferentiated/small cells: 39.4%/26.8%/15.5%/9.9%. Most of them were advanced lung cancer: St IIIB=14 (19.7%) and St IV=37 (52.1%). Forty-six patients received chemotherapy (64.8%) with 40 patients (86.9%) with platin (carboplatin or cisplatin). The median number of treatment cycles was 4.1 (range 1-7). Two patients achieved complete response and 15 had partial response. The response rate was 39.6%. The 1-year survival rate was 48.5% and the estimated median survival time was 11 months (95%; 7-18 months) for all patients. The 1-year survival rate was 75% and 21.6% and the estimated median survival time was 25.9 months (95%; 12.6, ND) and 5.7 months (95%; 4.2-9.6) for stage IIIB and IV, respectively. Toxicities were judged acceptable with 19 hospitalizations after chemotherapy, for 16 patients who represent 34.8% of patients who received chemotherapy. CONCLUSIONS: Chemotherapy is feasible in elderly patients with lung cancer. Patients should be evaluated for chemotherapy based on their performance status and comorbidities especially with geriatric assessment rather than age alone. The chemotherapy with platinum seems to be tolerable and effective.

Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer.

PURPOSE: Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks). PATIENTS AND METHODS: Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m(2) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. RESULTS: Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. CONCLUSION: The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.

[Genetic factors and colorectal cancers development: therapeutic impact]. / Identification des facteurs génétiques associés à l'évolution des cancers coliques: impact sur la prise en charge thérapeutique.

Colorectal tumorigenesis is associated with the progressive increase of epithelium dysplasia and wall invasion. These criteria are evaluated through histological staging, that enables a reliable estimation of patient prognosis, and is the best tool for therapeutic decision. Adjuvant chemotherapy is systematically proposed in case of lymph nodes and/or distant metastases (stages III and IV respectively). Its benefit in stage II tumors however remains unclear. Independently of the nature of the treatment, one third of all stage II-III tumors will metastasize. One important element to improve our tools for therapeutic decision is the identification of prognostic parameters, independent of the histological and morphological classifications. In a preliminary study, we allelotyped a series of 401 colon tumors and have shown that 5q and 8p allelic status were significantly predictive of the patients evolution. As a first approach, analysis of 47 tumors using microarray expression measures has allowed to validate the strong correlation between RNA levels and genomic status (i.e. mutation and allelic status) of known genes (APC, SMAD4, TP53, MLH1). We are now planning to characterize a series of 185 stage II-III colon tumors at both genomic and transcriptomic levels, in combination with the clinicopathological findings. Disease-free patients were followed at least 3 years after surgical resection. A tight collaboration of 5 departments of digestive oncology allowed to collect all clinical and biological resources for this project. Depending on our findings, correlations will be made between gene expression levels and somatic mutations of the coreesponding genes. Real time RT-PCR and immunohistochemical analyses will be performed on selected genes. Finally, biological mechanisms will be investigated to look for new therapeutic targets.