Background:To examine the impact of a frequent her2 gene polymorphism (Ile655Val) on tumor growth and on the pharmacodynamics of treatment by trastuzumab.Patients and methods: Experimental study: The growth characteristics of cells expressing the Ile or Val isoform were examined in vitro and after injection into nude mice. The effect of trastuzumab was determined in both experimental models. Clinical study: 61 patients with advanced breast cancers and treated by trastuzumab were genotyped for HER2 by PCR-RFLP. The influence of HER2 genotype on the trastuzumab treatment was examined. Conclusions: This study establishes a clear-cut difference between the two HER2 isoforms regarding their tumorogenic potential with an advantage for the Val/HER2 isoform. In breast cancer patients treated with trastuzumab, the presence of a Val allele may constitute a risk factor for cardiac toxicity.

Preoperative breast cancer diagnosis on core biopsies has become a standard of care in many countries. Controversies exist concerning the accuracy of HER2 testing on biopsies as compared with surgical specimens, and few data exist concerning the use of emerging technologies such as bright-field in-situ hybridization in such a setting. A French multicenter, cross-sectional, histopathological study assessed the concordance of HER2 status determined by immunohistochemistry and silver (SISH) or chromogenic in-situ hybridization (CISH) on core-needle biopsies with HER2 status determined by fluorescence in-situ hybridization (FISH) on surgical specimens. The concordance between biopsy and operative results was also assessed for each method. We studied 260 breast tumors from 24 centers between April 2003 and August 2009. Excellent concordance (j: 0.92-0.97) was shown between immunohistochemistry and FISH with low discordance rates (2-4%), high specificity (97-98%) and sensitivity values (95-99%), with no significant difference according to the immunohistochemistry interpretation guidelines used. The correlation between SISH and CISH on biopsies and FISH on surgical samples was strong (j: 0.96 and 0.94, respectively), with no significant difference between false negative rates or sensitivity and specificity values (2 and 5%, 99 and 96%, 98 and 98%, respectively). Whatever the evaluation technique, excellent concordance between biopsies and surgical specimens was observed (j X0.97; discordance rates between 1 and 2%), with high sensitivity (98-99%) and specificity (98-100%). Based on these results, when FISH cannot be used, SISH and/or CISH could be proposed as an alternative method to determine HER2 status and to confirm any ambiguous immunohistochemistry results, either for preoperative percutaneous biopsies or for surgical specimens. They could also be used for quality controls and immunohistochemistry calibration.

Background:The role of consolidation therapy with 90 Y-ibritumomab tiuxetan ( 90 YIT) for patients with follicular lymphoma (FL) after receiving second or third line immunochemotherapy has not been established. Aims: Thus, we conducted a multicenter phase II trial evaluating the efficacy and toxicities of bendamustine and rituximab (BR) followed by 90 YIT for patients with relapsed FL. Methods: This study included patients who had biopsy-proven, relapsed FL (Grade 1/2 or 3a); one or two prior therapies; age of 20-74 years; ECOG performance status of 0-2; measurable lesion(s); no severe organ dysfunction; 3 months or longer life expectancy; and written informed consent. BR consisted of rituximab (375 mg/m 2 , day 1) and bendamustine (90 mg/m 2 , day 2 and 3), and repeated every 4 weeks up to 4-6 cycles. As the consolidation therapy, 14.8 MBq/kg of 90 YIT was administered to patients who achieved complete response (CR) or partial response after BR therapy. The primary endpoint was 2-year progression-free survival (PFS) after the consolidation with 90 YIT. The secondary endpoints were response rates after BR therapy, response rates after consolidation with 90 YIT, 2-year overall survival (OS) rate after the consolidation with 90 YIT, and toxicities. Results: A total of 30 patients were registered between 2013 and 2015. Of these patients, 6 were excluded from the study because of pathological diagnoses other than FL in the central review (n = 3), unmet criteria (n = 2), and the other advanced cancer found (n = 1), respectively. Thus, 24 patients with a median 60 years of age (range 47-74 years) and a median of 6.7 years (range 1.6-14.8 years) of duration from the initial diagnosis were evaluated. Among them, R-CHOP based chemotherapy was the most common initial treatment (92%). The FLIPI2 score at the time of registration was high in 3, intermediate in 7, and low in 14 patients, respectively. After re-induction treatment with BR, 22 patients (92%) ultimately received consolidation with 90 YIT, resulting in an overall response rate of 95% and a CR rate of 91%, respectively. Within the 2-year observation period, 10 patients relapsed and 3 of them had a histological transformation to diffuse large B-cell lymphoma. Severe non-hematological toxicities were rare and no treatment-related mortality was observed. Within the observation period, one patient died of disease progression. Second primary malignancies were not observed. Consequently, the 2-year PFS and OS rates after the consolidation were 58%, and 94%, respectively.

warfarin therapy with a supratherapeutic INR (ibrutinib was dose reduced to once every 3 days, and warfarin was discontinued and not restarted prior to the patient expiring) and one patient had a spontaneous subdural hematoma while on concomitant rivaroxaban and aspirin therapy (ibrutinib, anticoagulation, and antiplatelet agents were discontinued permanently). In the 13 patients with minor bleeding events, the site of bleeding was: 6 genitourinary, 4 skin, 1 soft tissue, 1 tympanic, and 1 GI. Anticoagulation was discontinued permanently in 7 pts, continued at the same dose in 5 pts, and held for one month in 1 pt. Ibrutinib was discontinued permanently in 1 pt, continued at the same dose in 8 pts, held temporarily in 2 pts, and dose reduced in 2 pts. Anticoagulation therapy was effective for patients who received it given that no patient experienced a thrombotic stroke or subsequent venous thromboembolism while on anticoagulation therapy.

26 Background: HER2 is an important prognostic and also a predictive biomarker for trastuzumab response in gastric cancer. Therefore, HER2 status should be tested in all gastro-esophageal junction (GEJ) and gastric cancer (GC) patients. ToGA phase III study showed a benefit in overall survival of trastuzumab added to standard chemotherapy in patients with HER2-positive advanced GEJ/GC. The objective of the HER-EAGLE study was to assess the incidence of HER2 positivity in GEJ/GC cancer. Methods: HER-EAGLE was an international epidemiological, non-interventional study assessing HER2 status by IHC/ISH in tumor samples from any stage in patients with GEJ/GC. Samples were obtained by excision or core biopsy and routinely analyzed via validated Ventana or Dako methods and scoring criteria used in ToGA: HER2-positive if IHC 3+ or IHC 2+ (FISH/SISH confirmed; HER2/CEP17 ratio ≥ 2.0); HER2-negative if IHC 0 or IHC 1+ or IHC 2+ if FISH/SISH negative ratio < 2.0. Overall and subgroup estimates calculated with 95% CI. Data from the French cohort are presented. Results: The HER-EAGLE French cohort included 267 patients (68.6% males) from 7 centers (May 2007 to March 2012), with 150 biopsies (56.2%) and 117 excisions (43.8%). Tumor locations were 65.9% stomach and 34.1% GEJ, and adenocarcinoma types were according to Lauren classification: 170 intestinal (63.7%), 72 diffused (27%), 22 mixed (8.2%) and 3 not available (1.1%). HER2 status was: 36 cases IHC 3+ (13.5%), 51 IHC 2+ (19.1%) whereof 18 ISH positive (35.3%), 35 IHC 1+ (13.1%) and 145 IHC 0 (54.3%). Overall HER2 positivity (IHC 3+ or IHC 2+/ISH+) was 20.2%. Heterogeneity for HER2 staining was observed in 81 samples (30.3%). No statistical difference was found according to cancer stage. HER2 positivity was higher in GEJ (31.9%) than in GC (14.2%), p<0,001, and higher in intestinal (28.2%) compared to diffused adenocarcinomas (5.6%), p<0,001. Conclusions: HER-EAGLE French cohort results confirmed the feasibility of HER2 testing in GEJ/GC in routine practice. The incidence of HER2 overexpression was similar to the literature review, and it was higher in GEJ and intestinal adenocarcinomas type.