This document is a summary of the French Intergroup guidelines regarding the management of gastric cancer published in October 2016, available on the website of the French Society of Gastroenterology ...(SNFGE) (www.tncd.org), updated in October 2017.
This collaborative work was realized under the auspices of several French medical societies involved in management of gastric cancer. Recommendations are graded in three categories (A–C), according to the amount of evidence found in the literature until July 2017.
There are several known risk factors for gastric cancer, including Helicobacter pylori and genetic predispositions, both requiring a specific screening for patients and their relatives. The diagnosis and staging evaluation are essentially based on gastroscopy plus biopsies and computed tomography scan. The endoscopic ultrasonography can be used for superficial tumors in case of discussion for endoscopic resection (T1N0). For local disease (N+ and/or T > T1), the strategic therapy is based on surgery associated with perioperative chemotherapy. In the absence of preoperative treatment (for any raison), the postoperative chemoradiotherapy (or chemotherapy) should be discussed for patients with stage II or III tumor. For metastatic disease, the treatment is based on “palliative” chemotherapy consisting in a doublet or triplet regimens depending of age, performance status and HER2 tumor status. For patients with limited metastatic disease, surgical resection could be discussed in multidisciplinary meeting in case of stable disease after chemotherapy.
These guidelines in gastric cancer are done to help decision for daily clinical practice. These recommendations are permanently being reviewed. Each individual case must be discussed within a multidisciplinary team.
Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients ...enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.
According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses.
Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1;
= 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5;
< 0.001) and a reduction of 1-year overall survival rate (OR = 7.0;
= 0.02).
This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.
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In 1992, preoperative radiotherapy was considered in France as the standard treatment for T3-4 rectal cancers. The present randomized trial compares preoperative radiotherapy with chemoradiotherapy.
...Patients were eligible if they presented a resectable T3-4, Nx, M0 rectal adenocarcinoma accessible to digital rectal examination. Preoperative radiotherapy with 45 Gy in 25 fractions during 5 weeks was delivered. Concurrent chemotherapy with fluorouracil 350 mg/m2/d during 5 days, together with leucovorin, was administered during the first and fifth week in the experimental arm. Surgery was planned 3 to 10 weeks after the end of radiotherapy. All patients should receive adjuvant chemotherapy with the same fluorouracil/leucovorin regimen. The primary end point of the trial was overall survival.
A total of 733 patients were eligible. Grade 3 or 4 acute toxicity was more frequent with chemoradiotherapy (14.6% v 2.7%; P < .05). There was no difference in sphincter preservation. Complete sterilization of the operative specimen was more frequent with chemoradiotherapy (11.4% v 3.6%; P < .05). The 5-year incidence of local recurrence was lower with chemoradiotherapy (8.1% v 16.5%; P < .05). Overall 5-year survival in the two groups did not differ.
Preoperative chemoradiotherapy despite a moderate increase in acute toxicity and no impact on overall survival significantly improves local control and is recommended for T3-4, N0-2, M0 adenocarcinoma of the middle and distal rectum.
Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general ...population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer.
This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates.
In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent–weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use.
Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5–9 years hazard ratio, 0.67; 95% confidence interval, 0.40–1.12; >10 years hazard ratio, 0.37; 95% confidence interval, 0.19–0.73; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use hazard ratio, 0.24; 95% confidence interval, 0.14–0.43; BRCA1 >15 years since last use hazard ratio, 0.56; 95% confidence interval, 0.18–0.59). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size.
For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations ...may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified.
We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes.
Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval CI: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site.
The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.
Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage ...1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 × 10−8) and 1.14 (trend; P = 1.32 × 10−5), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 × 10−4). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 × 10−11). This locus has also been implicated in prostate cancer.
Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we ...analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients' clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients' survival.
Gene fusions provide access to new therapeutic opportunities for patients treated for a colorectal cancer (CRC). However, they do not excess 1% of patients. A better identification of patients in ...whom gene fusions are highly prevalent is a major issue in a therapeutic and medico-economics perspective. This study assesses the rates of gene fusions in CRC patients with MSI/RAS-BRAFWT in our routine practice detected with a commercially available NGS-based fusion panel. Among the 130 MSI CRC tumors, 43 (33%) were KRAS-NRAS-BRAFWT. A gene fusion was detected in 7 (25.9%) of the 27 MSI/RAS-BRAFWT samples, which had RNA suitable for analysis after quality control. These fusions involved mainly NTRK1/3 (n = 5), as well as ALK (n = 1) and BRAF (n = 1). In the present study, we confirm that patients with MSI/RAS-BRAFWT CRCs represent a subpopulation in which targetable gene fusions are overrepresented. Our results support the use of a two-step algorithm for molecular screening, in which metastatic CRC patients would have routine MSI and RAS/BRAF testing, and then only those with MSI/RAS-BRAFWT would be screened with dedicated NGS RNA panel for gene fusions.
•Gene fusions do not excess 1% of patients with colorectal cancer (CRC).•Gene fusions are overrepresented in patients with MSI/RAS-BRAFWT CRC.•Most of gene fusions provide access to new therapeutic opportunities.•Our results support the use of a two-step algorithm for molecular screening.
Aims:
The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study ...showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies.
Patients & methods:
Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen.
Results:
In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months 95% confidence interval (CI) 10.6–16.1 11.0 months (9.3–16.0) in -HPV02, and 15.6 months (11.2–34.5) in -HPV01, (p = 0.06). The median overall survival was 39.2 months (26.0–109.1) 36.3 in -HPV02 (25.2–NR), and 61.1 months (21.4–120.0) in -HPV01 (p = 0.62). Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF (n = 54) and mDCF (n = 58) in terms of OS (p = 0.57) and PFS (p = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed.
Conclusion:
Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.
The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer ...(HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management.
To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material.
We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies.
Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.
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