The Prevalence of HER2 Positivity In HER2 Borderline Tumors In Iranian Breast Cancer Patients And Predictive Variables

Background: Human epidermal growth receptor-2 (HER2) gene amplification is an important predictive and prognostic factor in breast cancer treatment. However, the expression of HER2 by immunohistochemistry (IHC) is determined as borderline in some cases and confirmation of the HER2 status by in situ hybridization either fluorescent (FISH) or bright field chromogenic (CISH) is necessary for correct treatment decision-making. Considering the high cost of FISH and CISH, we aimed to investigate whether the HER2 status could be predicted by other histological and cellular characteristics of the tumor by evaluating the association of these characteristics with the actual tumor HER2 status. Methods: Data of 438 breast cancer patients with IHC-determined HER-2 borderline disease was evaluated retrospectively. FISH or CISH results, pathologic tumor size and type, node involvement, Ki67%, presence of estrogen and progesterone receptor (ER, PR), HER2 status, lymphovascular invasion (LVI), perineural invasion (PNI), and stage were retrieved from clinic records. Results: Seventy-four (16.9%) patients had positive results for HER2 status with FISH or CISH. Logistic regression analysis showed that the pathologic size had a positive association with HER2 positivity with an OR equal to 1.03 (Odds ratio (OR):1.03, 95% CI: 1.01-1.05). In addition, the adjusted OR illustrated a statistically significant association between HER2 positivity and PR negativity (OR=2.14, 95% CI: 1.14-4.02). The invasive lobular carcinoma histology had a reverse association with HER2 positive status, with a borderline significance level (OR=0.15, 95% CI: 0.02-1.18).Conclusion: We could not find an applicable model to predict the actual status of HER2 in borderline cases and still, we have to recommend further assay by FISH or CISH in these patients.

Prevalence of HER2 overexpression and amplification in cervical cancer: A systematic review and meta-analysis

The reported rates of HER2 positivity in cervical cancer (CC) range from 0% to 87%. The importance of HER2 as an actionable target in CC would depend on HER2 positivity prevalence. Our aim was to provide precise estimates of HER2 overexpression and amplification in CC, globally and by relevant subgroups. We conducted a PRISMA compliant meta-analytic systematic review. We searched Medline, EMBASE, Cochrane database, and grey literature for articles reporting the proportion of HER2 positivity in CC. Studies assessing HER2 status by immunohistochemistry or in situ hybridization in invasive disease were eligible. We performed descriptive analyses of all 65 included studies. Out of these, we selected 26 studies that used standardized American Society of Clinical Oncology / College of American Pathologists (ASCO/CAP) Guidelines compliant methodology. We conducted several meta-analyses of proportions to estimate the pooled prevalence of HER2 positivity and subgroup analyses using geographic region, histology, tumor stage, primary antibody brand, study size, and publication year as moderators. The estimated pooled prevalence of HER2 overexpression was 5.7% (CI 95%: 1.5% to 11.7%) I2 = 87% in ASCO/CAP compliant studies and 27.0%, (CI 95%: 19.9% to 34.8%) I2 = 96% in ASCO/CAP non-compliant ones, p < 0.001. The estimated pooled prevalence of HER2 amplification was 1.2% (CI 95%: 0.0% to 5.8%) I2 = 0% and 24.9% (CI 95%: 12.6% to 39.6%) I2 = 86%, respectively, p = 0.004. No other factor was significantly associated with HER2 positivity rates. Our results suggest that a small, but still meaningful proportion of CC is expected to be HER2-positive. High heterogeneity was the main limitation of the study. Variations in previously reported HER2 positivity rates are mainly related to methodological issues.

Differential Second Primary Malignancy Occurrence After Breast Cancer According to HER2 Status: a SEER Population-Based Analysis

Background: The survival improvement in breast cancer (BC) renders the long-termsurvivorsan increasedprobability of second primary malignancy (SPM), and thus excess mortality. Although previous evidence has indicated various predictorsofSPM, little is known whether SPM incidencevaries by HER2 status of first BC. Methods: Based on BC patients registered between 2010-2018 in the NCI SEER database, we utilized standardized incidence ratio (SIR) and Poisson regression to quantify SPM occurrence compared with the general population. Then, adjusted for competing death risk, cumulative incidence function and Gray’s test were adopted to estimate the probability of SPM. Subsequent proportional subdistribution hazards regression was executedto identify the HER2 status impact on SPM risk. Finally, survival analysiswas performed.Results: A total of 409,796 first BC patients were includedand 18,283 were identified with at least one SPM. The SIR of SPM after HER2+ BC was significantly lower than HER2- BC (1.03 vs 1.13; RR, 0.92; 95% CI, 0.88-0.96; p<0.001). But the predominantly declining SPM risk was only observed for second BC (RR, 0.89; 95% CI, 0.82-0.96; p=0.003) and lung and bronchus cancer (RR, 0.84; 95% CI, 0.74-0.95; p=0.007). Further competing risk analysis verified the protective effect of HER2 positivity status on SPM occurrence.The 5-year cumulative incidence of SPM following HER2+ and HER2- BC were 5.16% and 4.09%, respectively (p<0.001). In addition, among patients suffering from SPM,HER2 positivity status contributed tobetter overall survival. Conclusion: After considering intrinsic incremental risk with age and adjusting for competing risk of death, our study demonstrated that HER2+ BC patients had lower SPM occurrence, remarkable for second BC and lung and bronchus cancer. The disparity implies the relation between SPM occurrence and therapeutic along with genetic factors underlying BC HER2 status.

HER2 Positivity in Histological Subtypes of Salivary Gland Carcinoma: A Systematic Review and Meta-Analysis

BackgroundHER2 aberrations in salivary gland carcinomas (SGC) as well as benefit of HER2 directed therapy have been reported in small studies. However, reliable estimates of the prevalence of HER2 positivity in SGC and its various histological subtypes are lacking.ObjectiveTo assess the prevalence of HER2 positivity in histological subtypes of salivary gland carcinomas (SGC).MethodsStudies were identified by a systematic review of the literature. Data on in situ hybridization (ISH) and immunohistochemistry (IHC) were extracted to derive pooled prevalence estimates calculated by a random effects model. Characteristics of the studies were extracted for subgroup analysis.ResultsFifty studies including 3372 patients were identified, providing data on sixteen histological subtypes. Based on the meta-analysis, the estimated prevalence of HER2 positivity were 43% (95% CI: 36% – 51%) in salivary duct carcinoma (SDC), 39% (95% CI: 32% – 45%) in carcinoma ex pleomorphic adenoma (CEP), 17% (95% CI: 7.5% – 33%) in squamous cell carcinoma (SCC), 13% (95% CI: 7.6% – 21%) in adenocarcinoma NOS (ADC), 6.7% (95% CI: 0.17%-32%) in poorly differentiated carcinoma, 5.5% (95% CI: 2.9% – 9.6%) in mucoepidermoid carcinoma, 4.3% (95% CI: 1.4% – 13%) in myoepithelial carcinoma, 1.8% (95% CI: 0.04%-9.6%) in epithelial-myoepithelial carcinoma, 0.45% (95% CI: 0.0097% – 18%) in acinic cell carcinoma and 0.15% (0.037% – 5.4%) in adenoid cystic carcinoma. Estimates for five additional subtypes were assessed.ConclusionPrevalence of HER 2 positivity in SGC varies greatly based on histological subtype, with SDC, CEP, SCC, and ADC displaying the highest rates.

HER2 in uterine serous carcinoma: Testing platforms and implications for targeted therapy.

5580 Background: HER2 is an emerging prognostic and therapeutic target in uterine serous carcinoma (USC). Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to assess the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of USC specific testing guidelines. We also evaluated the rate of downstream mutations that may affect response to HER2 directed therapy. Methods: A total of 2,192 USC tumors were analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), a subset of 1,423 tumors were also tested by IHC and CISH (Caris Life Sciences, Phoenix, AZ). HER2 positivity through IHC (4B5, Ventana) and CISH (INFORM DUAL HER2 ISH Assay, Ventana) was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. PD-L1 expression was tested by IHC using SP142 (Spring Biosciences) (positive cut-off >1%). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cut-off > 10 mutations per Mb). Statistical significance was determined using chi-square. Results: Rates of HER2 positivity were comparable using the 2018 and 2007 breast cancer guidelines (19.5% vs 17.5%; p=0.25). Based on 2018 guidelines, the concordance between IHC and CISH was 98.9%. Specifically, 229/1423 patients (16%) were IHC+/CISH+, 5 patients (0.4%) were IHC+/CISH- and 11 patients (0.8%) were IHC-/CISH+ (Table). Common pathway alterations in HER2+ USC include TP53, RTK RAS, PI3K, NOTCH, chromatin remodeling and cell cycle genes. Single gene alterations in HER2+ tumors that may implicate HER2 therapy resistance (based on pathway analyses in other tumor types) included PI3K (36%), KRAS (2.6%), and PTEN (2.1%). HER2+ tumors had low immunotherapy biomarker profiles (0.3% MSI-H, 0.8% TMB, 17.1% PD-L1). Conclusions: High concordance rates were observed between CISH and IHC. Ultimately these testing platforms need to be validated by response to HER2 targeted therapies in order to develop USC specific HER2 testing guidelines.[Table: see text]

Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study

We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice.

Prevalence of HER2 overexpression and amplification in uterine cervical cancer: a systematic review and a meta-analysis.

BackgroundThe reported rates of HER2 positivity in uterine cervical cancer (CC) range from 0–87%. The organization of clinical studies of HER2 targeting agents in CC requires a better knowledge of HER2 positivity prevalence. We aimed to provide precise estimates of HER2 overexpression and amplification in CC.MethodsWe conducted a PRISMA compliant meta-analytic systematic review. We searched electronic databases for articles reporting the proportion of HER2 positivity by immunohistochemistry or in situ hybridization in CC. We performed descriptive analyses of all 65 included studies. Of these, we selected 26 studies that used standardized American Society of Clinical Oncology / College of American Pathologists (ASCO/CAP) Guidelines compliant methodology. We conducted several meta-analyses of proportions to estimate the pooled prevalence of HER2 positivity and subgroup analyses using geographic region, histology, tumor stage, primary antibody brand, study size, and publication year as moderators.ResultsThe estimated pooled prevalence of HER2 overexpression was 5.7% (CI 95%: 1.5–11.7%) in ASCO/CAP compliant studies and 27.0%, (CI 95%: 19.9–34.8%) in ASCO/CAP non-compliant ones, p < 0.001. The estimated pooled prevalence of HER2 amplification was 1.2% (CI 95%: 0.0–5.8%) and 24.9% (CI 95%: 12.6–39.6%), respectively, p = 0.004. No other factor was significantly associated with HER2 positivity rates.ConclusionA small proportion of CC is expected to be HER2 positive. Variations in previously reported HER2 positivity rates are mainly related to methodological issues.