Véronique Brouste

Predictors of Early Death Risk in Older Patients Treated With First-Line Chemotherapy for Cancer

PURPOSE Objective factors for making choices about the treatment of elderly patients with cancer are lacking. This investigation aimed to help physicians select appropriate treatments through the identification of factors that predict early death (< 6 months) after initiation of chemotherapy treatment. PATIENTS AND METHODS Previously untreated patients greater than 70 years of age who were scheduled for first-line chemotherapy for various types of cancer were included. Baseline abbreviated comprehensive geriatric assessment (aCGA), including the Mini-Mental State Exam, Timed Get Up and Go (GUG), Activities of Daily Living (ADL), Instrumental Activities in Daily Living (IADL), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS15), and comorbidities index (Cumulative Index Rating Scale-Geriatric), was carried out. Prognostic factors of early death were sought from aCGA results and traditional oncology measures. RESULTS A total of 348 patients were included across 12 centers in Southwest France (median age, 77.45 years; ratio of men to women, 1.47; advanced disease, 65%). Abnormal aCGA scores were observed for 18.1% of patients on the ADL, 73.0% of patients on the IADL, 24.1% of patients on the GUG, 19.0% of patients on the MMS, 44.0% of patients on the GDS15, and 64.9% of patients on the MNA. Advanced disease (odds ratio [OR], 3.9; 95% CI, [1.58 to 9.73]), a low MNA score (OR 2.77; 95% CI, [1.24 to 6.18]), male sex (OR, 2.40; 95% CI, [1.2 to 4.82]), and long GUG (OR, 2.55; 95% CI, [1.32 to 4.94] were associated with higher risk of early death. CONCLUSION In patients greater than 70 years of age with cancer, advanced disease, a low MNA score, and poor mobility predicted early death. We recommend that the MNA and GUG, performed by a trained nurse, be maintained as part of routine pretreatment workup in these patients to identify at-risk patients and to inform the decision-making process for chemotherapy.

High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome

Background PTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype–phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations. Methods 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype–phenotype analyses were performed. Results Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05). Conclusions This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype–phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.

Variables with time-varying effects and the Cox model: Some statistical concepts illustrated with a prognostic factor study in breast cancer

BackgroundThe Cox model relies on the proportional hazards (PH) assumption, implying that the factors investigated have a constant impact on the hazard - or risk - over time. We emphasize the importance of this assumption and the misleading conclusions that can be inferred if it is violated; this is particularly essential in the presence of long follow-ups.MethodsWe illustrate our discussion by analyzing prognostic factors of metastases in 979 women treated for breast cancer with surgery. Age, tumour size and grade, lymph node involvement, peritumoral vascular invasion (PVI), status of hormone receptors (HRec), Her2, and Mib1 were considered.ResultsMedian follow-up was 14 years; 264 women developed metastases. The conventional Cox model suggested that all factors but HRec, Her2, and Mib1 status were strong prognostic factors of metastases. Additional tests indicated that the PH assumption was not satisfied for some variables of the model. Tumour grade had a significant time-varying effect, but although its effect diminished over time, it remained strong. Interestingly, while the conventional Cox model did not show any significant effect of the HRec status, tests provided strong evidence that this variable had a non-constant effect over time. Negative HRec status increased the risk of metastases early but became protective thereafter. This reversal of effect may explain non-significant hazard ratios provided by previous conventional Cox analyses in studies with long follow-ups.ConclusionsInvestigating time-varying effects should be an integral part of Cox survival analyses. Detecting and accounting for time-varying effects provide insights on some specific time patterns, and on valuable biological information that could be missed otherwise.

High frequency of β -catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management

Background:Fibromatosis comprises distinct clinical entities, including sporadic extra-abdominal fibromatosis, which have a high tendency for recurrence, even after adequate resection. There are no known molecular biomarkers of local recurrence. We searched for β-catenin mutations in a European multicentre series of fibromatosis tumours to relate β-catenin mutational status to disease outcome.Methods:Direct sequencing of exon 3 β-catenin gene was performed for 155 frozen fibromatosis tissues from all topographies. Correlation of outcome with mutation rate and type was performed on the extra-abdominal fibromatosis group (101 patients).Results:Mutations of β-catenin were detected in 83% of all cases. Among 101 extra-abdominal fibromatosis, similar mutation rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%), and deletion (2%). None of the clinico-pathological parameters were found to be significantly associated with β-catenin mutational status. With a median follow-up of 62 months, 51 patients relapsed. Five-year recurrence-free survival was significantly worse in β-catenin-mutated tumours regardless of a specific genotype, compared with wild-type tumours (49 vs 75%, respectively, P=0.02).Conclusion:A high frequency (87%) of β-catenin mutation hallmarks extra-abdominal fibromatosis from a large multicentric retrospective study. Moreover, wild-type β-catenin seems to be an interesting prognostic marker that might be useful in the therapeutic management of extra-abdominal fibromatosis.

Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors.

Desmoid tumors are fibroblastic/myofibroblastic proliferations. Previous studies reported that CTNNB1 mutations were detected in 84% and that mutations of the APC gene were found in several cases of sporadic desmoid tumors lacking CTNNB1 mutations. Forty tumors were analyzed by comparative genomic hybridization (CGH). Karyotype and fluorescence in situ hybridization revealed a nonrandom occurrence of trisomy 8 associated with an increased risk of recurrence. We report the first molecular characterization including a large series of patients. We performed array CGH on frozen samples of 194 tumors, and we screened for APC mutations in patients without CNNTB1 mutation. A high frequency of genomically normal tumors was observed. Four relevant and recurrent alterations (loss of 6q, loss of 5q, gain of 20q, and gain of Chromosome 8) were found in 40 out of 46 tumors with chromosomal changes. Gain of Chromosomes 8 and 20 was not associated with an increased risk of recurrence. Cases with loss of 5q had a minimal common region in 5q22.5 including the APC locus. Alterations of APC, including loss of the entire locus, and CTNNB1 mutation could explain the tumorigenesis in 89% of sporadic desmoids tumors and desmoids tumors occurring in the context of Gardners syndrome. A better understanding of the pathogenetic pathways in the initiation and progression of desmoid tumors requires studies of 8q and 20q gains, as well as of 6q and 5q losses, and study of the Wnt/β‐catenin pathway.

Determination of ERCC2 Lys751Gln and GSTP1 Ile105Val gene polymorphisms in colorectal cancer patients: relationships with treatment outcome

INTRODUCTION Glutathione S-transferase P1 (GSTP1) and excision-repair cross-complementing repair deficiency group 2 protein (ERCC2 or XPD) may modulate the activity of platinum derivatives. The SNPs, Ile105Val for GSTP1 and Lys751Gln for ERCC2, may affect the efficiency of oxaliplatin in patients treated with an oxaliplatin-based regimen for metastatic colorectal carcinoma. PATIENTS & METHODS A total of 107 patients treated with first-line chemotherapy, 59 with an oxaliplatin-based regimen and 48 with an irinotecan-based regimen, were included retrospectively. GSTP1 and ERCC2 genotypes were identified on DNA samples extracted from paraffin blocks containing either normal tissue (nodes) or tumor tissue. We analyzed treatment response, event-free and overall survival. RESULTS GSTP1 genotype distribution was Ile/Ile 58%, Ile/Val 35% and Val/Val 7%. ERCC2 genotype distribution was Lys/Lys 49%, Lys/Gln 44%, Gln/Gln 7%. Event-free and overall survivals were not significantly different as a function of the GSTP1 genotype, whatever the treatment received. Event-free survival was significantly different as a function of the ERCC2 genotype only in patients receiving oxaliplatin: patients having at least one variant allele had a shorter median event-free survival (6 months) than those having no variant allele (11.6 months, p = 0.008). This difference was maintained for median overall survival (15.6 vs 25.3 months, p = 0.016). Using univariate analysis, ERCC2 genotype, hemoglobinemia and carbohydrate antigen 19.9 plasma levels were significantly related to overall and event-free survival in patients receiving oxaliplatin. CONCLUSION The ERCC2 genotype appears as an important predictive factor of the survival of patients treated with oxaliplatin in first-line therapy for metastatic colorectal cancer.

Distinction between isolated tumor cells and micrometastases in breast cancer: is it reliable and useful?

In routine practice, the distinction between isolated tumor cells (ITC) and micrometastases (MIC) in patients with breast cancer is sometimes difficult to discern. The authors assessed differences in classifying patients according to the American Joint Commission on Cancer (AJCC) and the International Union Against Cancer (UICC) definitions and method of sizing.

Prediction of HER2 gene status in Her2 2+ invasive breast cancer: a study of 108 cases comparing ASCO/CAP and FDA recommendations

Most Her2 testing guidelines recommend that all cases scoring Her2 2+ by immunohistochemistry should be analyzed by fluorescent in situ hybridization (FISH) to determine HER2 status to confirm eligibility for Trastuzumab therapy in breast cancer. The aim of our study was to determine HER2 gene and chromosome 17 (CEN17) status in a series of 108 Her2 2+ consecutive cases and study the correlation between pathological characteristics of the tumors and HER2 amplification. Invasive breast cancers were tested by FISH using the Dako HER2 FISH pharmDx® kit. The Her2 immunohistochemistry protocol was performed using the polyclonal AO485 antibody (Dako®) diluted to 1:1500. HER2 and CEN17 status were correlated to tumor SBR grade, mitotic count, estrogen receptor, progesterone receptor status and percentage of Her2 immunohistochemistry-positive cells. Following Food and Drug Administration guidelines, ie, HER2/CEN17 ratio ≥2 and an HER2 copy number >4, amplified cases were observed in 36 (33%) and 49 (45%) cases, respectively, and following American Society of Clinical Oncology/College of American Pathologists guidelines, ie, HER2/CEN17 ratio >2.2 and an HER2 copy number >6, amplified cases represented 30 and 24% of the study population, respectively. Chromosome 17 polysomy (CEN17 >2.25) was observed in 39 (36%) tumors. Significant positive correlations were found between FISH HER2 amplified cases and Her2 immunostaining >60% (P=1.1.10−5), SBR grade 3 (P=0.0001), nuclear atypia (P=0.03) and mitotic count (P=0.008). By multivariate analysis, Her2 immunostaining >60% (P<10−3) and SBR grade 3 (P<10−3) were independent factors predicting HER2 amplification status irrespective to cutoff guidelines. All SBR grade 3 cases with more than 60% Her2+ cells had an HER2/CEN17 ratio ≥2, only one had a ratio ≤2.2. In our series of consecutive Her2 2+ cases, one-third demonstrated HER2 amplification, and one-third had chromosome 17 polysomy. Pathological factors, in particular SBR grade 3 and more than 60% Her2+ cells, were significantly correlated with HER2 amplification.

Radiofrequency Ablation as a Substitute for Surgery in Elderly Patients with Nonresected Breast Cancer: Pilot Study with Long-term Outcomes

PURPOSE To determine the efficacy and tolerance of ultrasonography (US)-guided percutaneous radiofrequency (RF) ablation with endocrine therapy in elderly patients with breast cancer who decline or are not candidates for surgery. MATERIALS AND METHODS Internal ethics committee approval was obtained, and patients gave informed written consent. Women older than 70 years with breast carcinoma, who had undergone neoadjuvant endocrine therapy within the past 6 months, underwent US-guided RF ablation while under local anesthesia and sedation. Only tumors measuring 3 cm or smaller and situated at least 1 cm from the skin, nipple, and chest wall were selected. Multitine electrodes were used. Endocrine therapy was continued for a total of 5 years, and breast irradiation was not performed. Clinical follow-up included US, mammography, and dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging every 2 months for 6 months and then every 6 months until 5 years. Primary end points were RF ablation efficacy at 1 year on the basis of DCE MR imaging follow-up and procedural tolerance. The secondary end point was delayed local efficacy at the end of endocrine therapy (5 years) on the basis of DCE MR imaging follow-up. RESULTS Twenty-one women were treated from December 2004 to April 2010 (median age, 79 years; age range, 70-88 years). Efficacy was demonstrated at 1 year, with only one patient presenting with a local relapse. No general complications were noted. Skin burn occurred in four patients, with spontaneous healing after a maximum of 2 months. Ten patients were followed up for 5 years, with three additional patients presenting with cancer recurrence outside the ablation zone at 30, 48, and 60 months-including two with lobular carcinoma. Four patients died during the full follow-up, two of breast cancer-related causes and two of unrelated causes. CONCLUSION RF ablation in elderly patients with nonresected breast cancer is well tolerated and efficient at 1-year follow-up. The technique is not recommended for lobular carcinoma.

Combined Ablation and Resection (CARe) as an Effective Parenchymal Sparing Treatment for Extensive Colorectal Liver Metastases

Background Combined intra-operative ablation and resection (CARe) is proposed to treat extensive colorectal liver metastases (CLM). This multicenter study was conducted to evaluate overall survival (OS), local recurrence-free survival (LRFS), hepatic recurrence-free survival (HRFS) and progression-free survival (PFS), to identify factors associated with survival, and to report complications. Materials and Methods Four centers combined retropectively their clinical experiences regarding CLM treated by CARe. CLM characteristics, pre- and post-operative chemotherapy regimens, surgical procedures, complications and survivals were analyzed. Results Of the 288 patients who received CARe, 210 (73%) had synchronous and 255 (88%) had bilateral CLM. Twenty-two patients (8%) had extrahepatic disease. Median follow-up was 3.17 years (95%CI 2.83–4.08). Median OS was 3.33 years (95%CI 3.08–4.17) and 5-year OS was 37% (95%CI 29–45). One- and 5-year LRFS from ablated lesions were 87.9% (95%CI 83.3–91.2) and 78.0% (95%CI 71–83), respectively. Median HRFS and PFS were 14 months (95%CI 11–18) and 9 months (95%CI 8–11), respectively. One hundred patients experienced complications: 29 grade I, 68 grade II–III–IV, and three deaths. In the multivariate models adjusted for center, the occurrence of complications was confirmed as a major independent factor associated with 3-year OS (HR 1.80; P = 0.008). Five-year OS was 25.6% (95%CI 14.9–37.6) for patients with complications and 45% (95%CI 33.3–53.4) for patients without. Conclusions Recent strategies facing advanced CLM include non-anatomic resections, portal-induced hypertrophy of the future remnant liver and aggressive medical preoperative treatments. CARe has the qualities of an approach that allows effective tumor clearance while maintaining good tolerance for the patient.