Prevalence of HER2 Positivity and Its Clinicopathological Correlation in Locally Advanced/Metastatic Gastric Cancer Patients in Malaysia

Purpose

Human epidermal growth factor receptor 2 (Erbb2/HER2) overexpression, which was previously detected in invasive breast cancer, has now been implicated in advanced gastric cancer (GC) and gastroesophageal junction cancer (GEC). A study was conducted to determine the rate of HER2 positivity in patients with locally advanced or metastatic GC and GEC in Malaysia and to assess the impact of various demographic and clinical parameters on HER2 positivity.

Methods

A total of 228 adult patients with GC or GEC were enrolled from Subang Jaya Medical Centre, Malaysia, for retrospective (210) and prospective study. All patients were subjected to the HER2 immunohistochemistry test using an FDA-approved, standardized test kit. Carcinomas scoring 2+ on immunohistochemistry were further tested with HER2 in situ hybridization (ISH) using an FDA-approved test kit.

Results

The overall rate of HER2 positivity in the population studied was 24.6% (n = 56). The rate was significantly higher in men than in women (29.6 vs. 16.3%; p = 0.024). HER2 overexpression was significantly more common in diffuse type than in intestinal type of tumors (39.8 vs. 14.9%; p < 0.001). In our study, out of 56 samples, 44 (78.6%) were considered for gene amplification testing, out of which 40 (90.1%) samples showed gene amplification. There was no statistically significant correlation between HER2 positivity and patient age, race, tumor location, tumor differentiation, and TNM staging.

Conclusions

HER2 overexpression was evident in nearly 25% of the Malaysian patients with locally advanced or metastatic gastric cancer. The overexpression correlated significantly with male gender and diffuse-type tumors. The majority of the IHC-positive tumors demonstrated c-erb2 gene amplification and this finding reached statistical significance.

     

Immuno-Histochemical Assessment of HER2NEU Expression in Gastric Adenocarcinoma in North Karnataka,India

Background and Objectives: Gastric cancer is the fourth most common cancer worldwide and ranks fifth in India.Surgical resection is curative in early stage gastric cancers. Most of the gastric cancers are diagnosed at an advancedstage necessitating multimodality treatment strategies. Based on the ToGA trial, the international regulatory agencieshave recently approved trastuzumab in locally advanced and metastatic gastric and gastroesophageal adenocarcinomasexpressing HER2. Since there are limited studies from India and no published data available from this part of NorthKarnataka, we undertook this study to evaluate the frequency of expression of HER2 in gastric and gastroesophagealadenocarcinomas and to correlate it with various clinicopathological variables. Methodology: The study was conductedin the Department of Pathology, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka from May 2012to January 2016. The samples included both endoscopic biopsies and gastrectomies. Histopathological slides from 70cases were reviewed. Immunohistochemical staining for HER2 was performed in all the cases and Hoffman’s gastriccancer scoring system was employed. The results of HER2 expression was correlated with various clinicopathologicalparameters. Results: HER2 positivity was seen in 16/70 cases (23%). 6 cases (8.5%) were equivocal and 48/70 cases(68.5%) were HER2 negative. HER2 positivity was more common in GEJ cancers and intestinal type of adenocarcinoma.However, it did not correlate with age, gender, grade and stage. Conclusion: HER2 positivity was noted in 23% of thecases. 23.4% of intestinal type and 21.7% of diffuse type were HER2 positive. HER2 positivity did not significantlydepend on age, gender, tumour type, grade and stage. Hence, HER2 remains as an independent biomarker and should betested in all patients of gastric cancer regardless of the clinicopathological findings for offering a personalized treatment.     

Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)

PurposeThe intratumoural heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is a major challenge when identifying patients who might benefit from HER2-targeting therapy. We investigated the significance of re-evaluation of HER2 status in primary sites and metastatic or recurrent sites in advanced gastric cancer patients whose primary tumours were initially HER2-negative.Patients and methodsIn part I of this study, we evaluated the significance of repeat endoscopic biopsy in unresectable or metastatic gastric cancer patients whose tumours were initially HER2-negative. In part II, we examined the HER2 positivity rate in metastatic or recurrent sites in patients whose primary tumours were HER2-negative in biopsy or surgical specimens.ResultsIn part I (n = 183), we identified patients with HER2-positive tumours for a rescued HER2 positivity rate of 8.7% (95% confidence interval [CI], 4.6–12.8%) that was associated with tumour location (diffuse stomach versus other = 0% versus 11.7%, P = 0.013), Bormann type (IV versus others = 0% versus 11.7%, P = 0.013), and initial biopsy HER2 immunohistochemistry score (0 versus 1 versus 2 = 6.7% versus 15.4% versus 25.0%, P = 0.028). Part II (n = 175) resulted in HER2 positivity of 5.7% (95% CI 2.3–9.1%) that was significantly associated with metastatic site (liver versus others = 17.2% versus 3.4%, P = 0.012). When compared with a historical control that showed HER2 positivity on initial assessment, patients who had rescued HER2 positivity had similar treatment benefits from trastuzumab-containing first-line chemotherapy.ConclusionRepeat HER2 assessment in primary and metastatic or recurrent sites is recommended in patients with advanced gastric cancer whose primary tumour is initially HER2-negative.     

Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma

Background:

Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma.

Methods:

The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours.

Results:

Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis.

Conclusion:

The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process.     

Modified Docetaxel and Cisplatin in Combination with Capecitabine (DCX) as a First-Line Treatment in HER2-Negative Advanced Gastric Cancer

Background: Docetaxel and cisplatin in combination with fluorouracil (DCF) regimen is accepted to be oneof the standard regimens in the treatment of advanced gastric cancer. However, substantial toxicity has limitedits use in daily clinical practice. Therefore, modification of DCF regimens, including introduction of capecitabinehas been investigated to improve the safety profiles. In the present study, the efficacy and toxicity of a regimenwith a modified dose of docetaxel and cisplatin in combination with oral capecitabine (DCX) was evaluated inuntreated patients with HER2-negative advanced gastric cancer. Materials and Methods: Fifty-four patientswith HER2-negative locally advanced or metastatic gastric cancer were included in this cohort. Patients receiveddocetaxel 60 mg/m2 plus cisplatin 60 mg/m2 (day 1) combined with capecitabine 1650 mg/m2 (days 1–14) every3 weeks. Treatment response, survival, and toxicity were retrospectively analyzed. Results: The median age was54 years (range: 24–76). The majority of patients (70%) had metastatic disease, while 11 patients (21%) hadrecurrent disease and underwent curative gastrectomy, and 5 patients (9%) had locally advanced disease (LAD).The median number of DCX cycles was 4. There were 28 partial responses and 11 complete responses, with anoverall response rate of 72%. Curative surgery could be performed in four patients among five with LAD. Atthe median follow-up of 10 months, the median progression-free survival (PFS) and overall survival (OS) of theentire cohort of patients were 7.4 and 12.1 months, respectively. Dose modification was done in 12 patients dueto toxicity in 8 and noncompliance in 4 patients. The most common hematological toxicity was neutropenia,which occurred at grade 3-4 intensity in 10 of 54 patients (27.7%). Febrile neutropenia was diagnosed only intwo cases. Conclusions: DCX regimen offers prominent anti-tumor activity and considered to be effective firstlinetreatment with manageable toxicity for patients with HER2-negative advanced gastric cancer.     

Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis

BackgroundTo determine whether human epidermal growth factor receptor 2 (HER2) status is an independent prognostic factor in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma.Patients and methodsFormalin-fixed paraffin-embedded tumor samples from 381 metastatic gastric/GEJ cancer patients enrolled at Krankenhaus Nordwest and Memorial Sloan–Kettering Cancer Centers on six first-line trials of chemotherapy without trastuzumab were examined for HER2 by immunohistochemistry (IHC) and in situ hybridization (ISH). IHC 3+ or ISH-positive tumors were considered HER2 positive.ResultsSeventy-eight of 381 patients (20%) had HER2-positive disease. In the multivariate logistic model, there were significantly higher rates of HER2 positivity in patients with liver metastasis (liver metastasis 31%; no liver metastasis 11%; P = 0.025) and intestinal histology (intestinal 33%; diffuse/mixed 8%; P = 0.001). No significant differences in HER2 positivity were found between resections and biopsies or primaries and metastases. Patients with HER2-positive gastric cancer had longer median overall survival compared with HER2-negative gastric cancer patients (13.9 versus 11.4 months, P = 0.047), but multivariate analysis indicated that HER2 status was not an independent prognostic factor (hazard ratio 0.79; 0.44–1.14; P = 0.194).ConclusionsApproximately 20% of Western patients with metastatic gastric cancer are HER2 positive. Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GEJ.     

Systemic chemotherapy does not increase the risk of gastrointestinal perforation.

BACKGROUND: Gastrointestinal perforation is a rare complication of gastric cancer. Although there is the perception of chemotherapy aggravating the perforation risk, the rate of perforation in patients with gastric cancer receiving chemotherapy is unknown. This study describes the incidence and clinical course of patients with gastric or gastroesophageal junction (GEJ) carcinoma who experience a perforation while receiving chemotherapy. PATIENTS AND METHODS: The records of patients with gastric or GEJ adenocarcinoma over a 6-year period who received chemotherapy for locally advanced or metastatic disease were reviewed. Extracted information included demographics, treatment received, and overall survival was calculated. RESULTS: 1032 patients at MSKCC received systemic cytotoxic chemotherapy for locally advanced or metastatic gastric or GEJ carcinoma; 11 patients experienced a perforation (1.1%, 95% CI 0.5-1.9%); 5/11 (45%) patients received further chemotherapy and had a median survival of 5.6 months. CONCLUSIONS: The rate of perforation in patients with advanced GEJ/gastric adenocarcinoma receiving chemotherapy is 1.1%, which is the same rate as in surgical series of patients presenting with perforation. Chemotherapy does not significantly add to the risk of gastrointestinal perforation.     

HER2 and gastric cancer: a novel therapeutic target for trastuzumab

HER2 protein overexpression by immunohistochemistry (IHC) and/or erB2 gene amplification by in situ hybridization (ISH) was detected in 4-28% of gastric or gastro-oesophageal junction (GOJ) cancers. Most studies have shown that HER2-overexpressing gastric cancers were worse prognosis. Trastuzumab is a humanized monoclonal antibody directed against HER2 with known efficacy in patients with HER2+ early or metastatic breast cancer. The international randomized trial ToGA study showed the superiority of the combination of trastuzumab with chemotherapy doublet fluoropyrimidine (5-FU or capecitabine) plus cisplatin (FP) every three weeks compared with chemotherapy alone in terms of overall survival : 13.8 versus 11.1 months (HR: 0.74, 95% CI: 0.60-0.91, P = 0.0046) in HER2+ advanced gastric cancers. The benefit was even greater in the subgroup with HER2 overexpression (16% of the screened population) as defined by IHC3+ or IHC2+ confirmed by positive ISH test. Trastuzumab plus FP chemotherapy has become the standard treatment for patients with HER2+ non-pretreated metastatic adenocarcinoma of the stomach or GOJ cancer. All these cancers should be tested for HER2 on paraffin block resection or biopsy specimens of the primary tumour or metastases. Endoscopic gastric biopsies should be multiple. The IHC should be the initial test. The standardized immunohistochemical scoring system differs from that recommended for breast cancer given the heterogeneity of HER2 expression and the frequency of incomplete membranous staining in gastric cancers. Equivocal IHC2+ tumours should be tested by ISH with two tools: fluorescence in situ hybridization (FISH) or bright field in situ hybridization (SISH). The perspectives are the assessment of trastuzumab in the perioperative and adjuvant setting, the development of novel anti-HER2 drugs and research into mechanisms of resistance and predictive molecular markers.     

Phase II study of cisplatin, etoposide and paclitaxel in locally advanced or metastatic adenocarcinoma of gastric/gastroesophageal junction

BACKGROUND: Unresectable and metastatic gastric cancers carry a poor and dismal prognosis. Several phase II studies have identified effective anticancer drugs. AIMS: To evaluate safety and efficacy of low-dose cisplatin, etoposide and paclitaxel (CEP) based combination chemotherapy in locally advanced or metastatic adenocarcinoma of gastric/gastroesophageal junction. SETTING AND DESIGN: Prospective single-arm phase II study. MATERIALS AND METHODS: Thirty-three patients were enrolled onto this study, out of which, all but one received cisplatin 15 mg/m 2, etoposide 40 mg/m 2 and paclitaxel 50 mg/m 2, given on day 1 and 4 every week for three weeks in a 28-day cycle. Survival analysis was done using SPSS program. RESULTS: Median age of group was 56 years. Twenty-five were males. Twenty-nine had metastatic/inoperable disease and four patients had recurrent disease. Liver was the commonest metastatic site seen in 15 patients. With a median of 2 cycles per patient, a total of 76 cycles was administered. Grade III or IV toxicity were seen in 11 (35%) patients; diarrhea, 5 patients; vomiting, 3 patients; and neutropenia, 7 patients, 5 of whom also had fever). One patient died of neutropenic fever. Best responses, seen in 32 evaluable patients, were 2 CR (6.1%), 21 PR (63%) and 3 SD (9.2%). Four patients were considered operable after chemotherapy. With median follow-up of 11 months in surviving patients, median OS was 10 months and PFS was 8 months. Median OS was 13 months in responders versus 8 months in nonresponders (P =0.04). Seven patients survived> 12 months. CONCLUSION: Combination of low-dose CEP shows good clinical response and an acceptable toxicity profile in advanced or metastatic adenocarcinoma of gastric/gastroesophageal cancers. Whether addition of 5 FU or capecitabine adds to the benefit should be explored. This may be tested with other standard/conventional protocols in a randomized fashion.     

Trastuzumab: a new treatment option for HER2-positive metastatic gastric and gastroesophageal junction cancer

In patients with metastatic gastric cancer, median overall survival with standard chemotherapy remains under 1 year. As such, effective new treatments with acceptable tolerability are urgently needed. Amplification/overexpression of HER2 is reported in approximately 20% of gastric tumors, providing a rationale to investigate trastuzumab, a monoclonal antibody against HER2, in this setting. In the Phase III international Trastuzumab for Gastric Cancer (ToGA) study, the addition of trastuzumab to chemotherapy significantly improved overall survival without compromising safety in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer. The purpose of this review is to discuss clinical data supporting the role of trastuzumab in metastatic gastric cancer, and consider the optimization of gastric cancer-specific HER2 testing and analysis.     

Potential prognostic significance of p185(HER2) overexpression with loss of PTEN expression in gastric carcinomas

AIMS AND BACKGROUND: The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185(HER2)) that has partial homology with the epidermal growth factor receptor and shares intrinsic tyrosine kinase activity. The phosphatase and tensin homolog mutated on chromosome ten (PTEN) gene product is a protein tyrosine phosphatase that participates in modulating the phosphoinositide 3-kinase pathway which has antagonizing activity to protein tyrosine kinase. The authors investigated the correlation between clinicopathologic variables including survival and the overexpression of the p185(HER2) with loss of PTEN expression in gastric adenocarcinoma patients. METHODS: The protein expression of p185(HER2) and PTEN was examined by immunohistochemical stain in paraffin-embedded tissues of 94 (M:F, 52:42) gastric adenocarcinoma patients by using monoclonal antibody, and the results were related to clinicopathological variables and survival. RESULTS: p185(HER2) overexpression correlated positively with lymph node metastasis, distant metastasis, AJCC classification, higher relapse rate. Patients with overexpression of p185(HER2) were found to have significantly lower disease-free survival (P = 0.003) and overall survival (P = 0.0004). Loss of PTEN expression correlated positively with depth of invasion (T stage) and was more frequent in the advanced stage. The patient group with p185(HER2) overexpression and loss of PTEN expression showed significantly shorter disease-free and overall survival (P = 0.03, P = 0.01) than the other groups. CONCLUSIONS: Our observations suggest potential prognostic significance of p185(HER2) overexpression with PTEN loss in gastric adenocarcinoma patients. This opens up the possibility of considering p185(HER2)and PTEN as a therapeutic target in gastric cancer.     

Optimal management of gastroesophageal junction cancer

Although recent decades have witnessed incremental improvements in the treatment of gastroesophageal junction (GEJ) carcinoma, outcomes remain modest. For locally advanced esophageal cancer, the addition of chemotherapy and/or radiation to surgery is considered the standard of care. Chemotherapy remains the primary treatment for metastatic disease and improves survival over best supportive care. However, the prognosis for patients with GEJ cancers, which are treated along the same paradigms as esophageal and gastric carcinomas, remain poor because of the emergence of chemoresistance and limited targeted therapeutic approaches, which include agents that target the HER2 and vascular endothelial growth factor pathways. Evaluation of immune checkpoint inhibitors in the chemorefractory setting have confirmed the activity of immunotherapy in esophagogastric cancer. Ongoing immunotherapeutic strategies are being evaluated in both the locally advanced and metastatic settings. This review focuses on the treatment of locally advanced and metastatic GEJ carcinomas, which encompass all tumors that have an epicenter within 5 cm proximal or distal to the anatomical Z-line (Siewert classification). Because the vast majority of GEJ tumors are adenocarcinoma, the management of adenocarcinoma is the focus of this review. Evolving approaches and areas of clinical equipoise are discussed.     

Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer

Introduction

HER2 over-expression and/or amplification are present in 9-38% of gastric or gastroesophageal junction (GEJ) cancers and are correlated to poor outcome. We conducted a multicentre phase II trial to evaluate trastuzumab in combination with cisplatin in patients with untreated HER2-positive advanced gastric or GEJ cancer.

Materials and methods

Chemo-naïve patients with measurable, non-resectable, advanced or metastatic gastric or GEJ adenocarcinoma, with HER2 over-expression and/or amplification (IHC 3+, or IHC 2+ and FISH+), age ≥18 years, ECOG ≤2, left ventricle ejection fraction ≥50% and adequate organ function were eligible. Treatment consisted of trastuzumab (8 mg/kg on cycle 1 day 1 as loading; 6 mg/kg in subsequent cycles) and cisplatin (75 mg/m²), both intravenously on day 1, every 21 days.

Results

Twenty-two out of 228 patients (10%) were HER2-positive and were included in this phase II trial. The median age was 66 years and ECOG 0/1 was 41%/59%. The median number of cycles was 4 (range 1–41). The confirmed ORR was 32% and disease control was achieved in 64% of patients. Median time to progression was 5.1 months. Grade 3 adverse events included asthenia (27%), neutropenia (18%), anorexia (14%), diarrhoea (9%) and abdominal pain (9%). There were no grade 4 toxicities or treatment-related deaths. Higher baseline HER extracellular domain (ECD) levels were associated with better outcome in terms of response and survival.

Conclusions

Trastuzumab in combination with cisplatin is an active regimen and has a favourable toxicity profile in advanced HER2-positive gastric or gastroesophageal cancers.     

Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma

Novel systemic treatments are needed in pancreatic cancer. The authors sought to establish the frequency of overexpression of the HER-2/neu oncogene in patients with pancreatic adenocarcinoma to determine the potential role of trastuzumab (Herceptin) as a therapeutic agent in this disease. Tumor specimens from patients with pancreatic adenocarcinoma were analyzed by staining for p185HER2 protein using the DAKO immunohistochemical assay. Patients with and without HER-2/neu overexpression by immunohistochemistry were compared with respect to clinical and pathologic characteristics. HER-2/neu gene amplification was also evaluated by fluorescence in situ hybridization (FISH). Thirty-two of 154 patients (21%) had pancreatic adenocarcinoma that demonstrated HER-2/neu overexpression by immunohistochemistry. At initial diagnosis, 16% of resectable cancers, 17% of locally advanced cancers, and 26% of metastatic cancers were determined to have HER-2/neu overexpression. Three of 11 (27%) patients with HER-2/neu overexpression by immunohistochemistry had gene amplification by FISH. HER-2/neu overexpression occurs in a subset of pancreatic cancer. Evaluation of the efficacy of trastuzumab for patients with pancreatic cancer who overexpress HER-2/neu appears indicated.     

HER2 Status in Gastric Cancer: Comparison between Primary and Distant Metastatic Disease

HER2 (human epidermal growth factor receptor-2) assessment in histological samples of gastric cancer is essential to determine which patients might benefit from trastuzumab therapy. HER2 is often evaluated in primary tumor even if trastuzumab therapy is used to treat metastatic disease. However, the exact relationship in terms of HER2 status between primary and metastatic tumors has not been fully clarified. We aimed to evaluate the HER2 status concordance between primary gastric cancer and corresponding distant metastasis. HER2 status was evaluated by IHC (immunohistochemistry) and/or FISH ( fluorescence in situ hybridization) in 41 patients in primary gastric cancer and in paired metastasis. HER2 was assessed according scoring criteria applied in clinical approach. HER2 positivity was found in 14,6 % primary tumors and in 24,4%corresponding metastasis. HER2 concordance rate between primary and metastasis was 80,5 % (K-value = 0,388). Eight/41 (19,5 %)cases resulted discordant: 6 patients with metastatic HER2 positive lesions were found HER2 negative in primary cancers while 2 patient HER2 positive in primary lesion showed a negative conversion in metastasis. Our results showed a good concordance in terms of HER2 status between primary and metastatic lesions, as well as in biopsy and surgical removed specimens. However, the higher rate of HER2 positive status found in metastatic lesions underlined the importance of HER2 assessment in all samples obtained from different sites of gastric cancer disease.     

The emerging role of Lapatinib in HER2-positive breast cancer

In breast cancer, overexpression of HER2 is associated with an aggressive tumor phenotype and poor prognosis. Lapatinib has demonstrated benefit in combination with capecitabine in patients with HER2-positive locally advanced and metastatic breast cancer that has progressed after prior treatment with an anthracycline, a taxane, and trastuzumab. It has also demonstrated benefit with paclitaxel in patients with metastatic disease not previously treated with chemotherapy. This review discusses results from clinical trials suggesting an advantage with the use of lapatinib with other treatment modalities in the setting of metastatic and locally advanced disease.     

HER2 testing in gastric cancer: molecular morphology and storage time-related changes in archival samples

Seventy-two archival specimens of advanced gastric adenocarcinoma were analyzed by fluorescence in situ hybridization and immunohistochemistry for HER2 gene status. Gene amplification and concomitant protein overexpression were detected in 15.2% of cases. Intratumor topographical variability of HER2 amplification was observed, indicative of the late involvement of HER gene in gastric tumorigenesis. No significant correlations were found between HER2 status and histopathologic type, grade of differentiation, and Goseki classification of carcinomas, suggesting that HER2 gene is variably linked with the morphogenesis of gastric adenocarcinoma. A significant decrease of the incidence of HER2 amplified carcinomas in function of the duration of the storage of paraffin blocks was observed: 42-33% for tumor specimens paraffin-embedded in 2002-2001; 8.3%, 15.7%, 11.1% for the years 2000, 1999, 1998, respectively; 0% for cases embedded during 1997. According to these results, the reliability of the FISH and immunohistochemical assays decreases after prolonged storage of paraffin-embedded specimens.     

Predictors of positive radial margin status in a population-based cohort of patients with rectal cancer

Background

Surgical margin status is an important predictor of risk of relapse among patients with rectal cancer.

Methods

Patients referred to the British Columbia Cancer Agency for consideration of adjuvant therapy for rectal adenocarcinoma were included. Predictors of margin positivity were determined from uni- and multivariate analysis.

Results

Among 340 patients, 83% had negative resection margins. In 268 patients with resectable tumours, a significantly higher rate of margin positivity was observed in low rectal tumours (32.2%) as compared with mid-rectal (3.9%) and high rectal (14.3%) tumours. Among 59 patients with locally advanced rectal cancer treated with preoperative radiation (with or without chemotherapy), 32% with low tumours had margin positivity. Of patients with T4 tumours, 50% (11/22) had a positive resection margin.

Conclusions

In a population cohort, distal-third rectal location, locally advanced presentation, and T4 cancer represent subgroups for whom further improvement in therapy is required.     

HER2 loss in HER2‐positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research

Mechanisms of acquired resistance to trastuzumab‐based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post‐progression in patients receiving chemotherapy and trastuzumab for advanced HER2‐positive [immunohistochemistry (IHC) 3+ or 2+ with in‐situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over‐expression were defined as post‐trastuzumab IHC score <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post‐progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over‐expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over‐expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab‐based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti‐HER2 second‐line strategies in initially HER2‐positive disease.     

Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study.

PURPOSE: Based on preclinical in vitro synergy data, this study evaluated the activity and toxicity of a gemcitabine/oxaliplatin combination in patients with metastatic and locally advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Previously untreated metastatic and locally advanced unresectable pancreatic adenocarcinoma patients were enrolled onto this multicenter phase II study. Patients received gemcitabine 1,000 mg/m(2) as a 10-mg/m(2)/min infusion on day 1 and oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 2 every 2 weeks. Patients with metastatic disease were treated until evidence of progressive disease, whereas patients with locally advanced disease received six cycles in the absence of progression, followed when appropriate by concomitant radiochemotherapy. RESULTS: Among 64 eligible patients included in eight centers, 30 had locally advanced and 34 had metastatic disease. Response rate for the 62 patients with measurable disease was 30.6% (95% confidence interval, 19.7% to 42.3%), 31.0% for locally advanced and 30.3% for metastatic patients. Among 58 assessable patients, 40% had clinical benefit. Median progression-free survival and median overall survival (OS) were 5.3 and 9.2 months, respectively, with 36% of patients alive at 1 year. Median OS for patients with metastatic disease and locally advanced disease were 8.7 and 11.5 months, respectively. With 574 treatment cycles (median per patient, nine; range, zero to 27), grade 3/4 toxicity per patient was 11% for neutropenia and thrombocytopenia, 14% for nausea or vomiting, 6.2% for diarrhea, and 11% for peripheral neuropathy, with no toxic deaths. CONCLUSION: Palliative effects, response rate, and survival observed with this well-tolerated gemcitabine/oxaliplatin combination deserve additional evaluation. A comparative study of combination therapy versus gemcitabine alone is ongoing.