HER2 Testing Research Articles

Correlation of Clinicopathologic Features of Filipino Primary Breast Cancer Patients with HER2 Subgroups Classified according to the ASCO/CAP 2018 Breast Cancer HER2 Testing Guidelines

Correlation of Clinicopathologic Features of Filipino Primary Breast Cancer Patients with HER2 Subgroups Classified according to the ASCO/CAP 2018 Breast Cancer HER2 Testing Guidelines

Abstract B106: Assessing racial disparities in the receipt of quality care in the most prevalent cancers in American Indians

Abstract INTRODUCTION Previous SEER-Medicare analyses reported lower receipt of guideline concordant care for American Indian (AI) compared with White (WH) patients across several cancers. While large scale assessments are informative, there is a need to assess cancer outcomes and develop interventions at a level closer to communities. To address this gap, we assessed measures of quality care in AI and WH breast, prostate, and colorectal cancer patients. METHODS We assembled novel cohorts of AI and WH patients from the North Carolina (NC) cancer registry, the state with the largest AI population east of the Mississippi River. Eligible patients were diagnosed with breast, prostate, and colorectal cancers who linked to public and private insurance claims with continuous enrollment (2003-2019). Measures were assessed within 1 year of diagnosis unless stated otherwise. Breast cancer measures included receipt of: (1) HER2 testing within 3 months of diagnosis [NQF #1878]; (2) Tamoxifen/Aromatase Inhibitors for Stage I-III ER/PR+ [NQF #220]; (3) radiation among stage I-III breast conserving surgery or mastectomy patients [NQF #0219]. Stage II-III colorectal cancer measures included receipt of: (1) carcinoembryonic antigen (CEA) testing; (2) surveillance colonoscopy; and (3) computed tomography (CT) among resected patients [NCCN 2.2023 COL-8]. We assessed receipt of prostate-specific antigen (PSA) testing in the first 15 months after prostate cancer diagnosis to monitor disease recurrence. Poisson regression adjusting for sex, urbanicity, insurance type, and age at diagnosis was used to estimate risk ratios (RR) and 95% confidence intervals (CI) comparing the receipt of care between AI and WH patients. RESULTS The sample sizes of AI patients differed across measures, ranging from 104 colorectal to 554 prostate cancer patients. Evidence of disparity was mixed for the breast cancer measures. AI breast cancer patients less frequently received HER2 testing within 3 months of diagnosis (AI=61% vs WH=71%), although adjustment attenuated this association (RR=0.90; CI: 0.81-1.01). Among stage I-III breast cancer patients, AIs more frequently received radiation within 1 year of surgery (AI=75% vs WH=71%) compared with WH patients (RR=1.11; CI: 1.01-1.21). Across colorectal cancer measures, AI patients performed as well or better than WH patients. Notably, AI patients more frequently received CEA testing (AI=71% vs WH=59%), a difference that persisted after adjustment (RR=1.17; CI: 1.03-1.32). AI prostate cancer patients received PSAs less often in the 15 months following diagnosis (AI=82% vs WH=88%) than WH patients (RR=0.96; CI: 0.93-1.00). CONCLUSIONS The magnitude and direction of AI/WH disparities in receipt of quality cancer care differed across measures. Racial misclassification is a challenge in AI health outcomes research, which may misrepresent the experience of AIs. Nevertheless, our findings provide insight into specific areas of breast, prostate, and colorectal cancer care where local tailored interventions can be focused to improve care equity. Citation Format: Bradford E. Jackson, Marc E. Emerson, Lisa P. Spees, Chris D. Baggett, Hayley N. Morris, Ana I. Salas, Angelo Moore, Yadurshini Raveendran, Clare Meernik, Tomi Akinyemiju, Rachel Denlinger-Apte, Ronny A. Bell, Stephanie B. Wheeler. Assessing racial disparities in the receipt of quality care in the most prevalent cancers in American Indians [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B106.

Think "HER2" different: integrative diagnostic approaches for HER2-low breast cancer.

This work explores the complex field of HER2 testing in the HER2-low breast cancer era, with a focus on methodological aspects. We aim to propose clear positions to scientific societies, institutions, pathologists, and oncologists to guide and shape the appropriate diagnostic strategies for HER2-low breast cancer. The fundamental question at hand is whether the necessary tools to effectively translate our knowledge about HER2 into practical diagnostic schemes for the lower spectrum of expression are available. Our investigation is centered on the significance of distinguishing between an immunohistochemistry (IHC) score 0 and score 1+ in light of the clinical implications now apparent, as patients with HER2-low breast cancer become eligible for trastuzumab-deruxtecan treatment. Furthermore, we discuss the definition of HER2-low beyond its conventional boundaries and assess the reliability of established diagnostic procedures designed at a time when therapeutic perspectives were non-existent for these cases. In this regard, we examine potential complementary technologies, such as gene expression analysis and liquid biopsy. Ultimately, we consider the potential role of artificial intelligence (AI) in the field of digital pathology and its integration into HER2 testing, with a particular emphasis on its application in the context of HER2-low breast cancer.

HER2-low metastatic breast cancer: molecular insights and therapeutic strategies

The identification of HER2-low metastatic breast cancer as a novel subgroup with therapeutic implications underscores the intricacies in breast cancer classification. This subset, comprising about 60% of breast cancer cases, presents a challenge due to its heterogeneous nature, characterized by varying HER2 protein expression levels. This heterogeneity complicates diagnosis and treatment decisions. The advent of trastuzumab deruxtecan (T-DXd), a second-generation antibody-drug conjugate (ADC), instills renewed hope for HER2-low breast cancer patients, having demonstrated effectiveness in clinical trials. The article also explores the evolution of HER2 testing guidelines, notably the 2023 ASCO/CAP guidelines that acknowledge the potential benefits of HER2-targeted therapies for this subgroup. In summary, this article emphasizes the significance of collaborative efforts between Pathologists and Oncologists in the era of precision medicine. It also highlights the potential for innovative, tailored therapies for HER2-low breast cancer, promising enhanced treatment outcomes and a broader range of therapeutic options.

HER2 amplification in cases with low HER2 expression by immunohistochemistry (IHC): A Single Institutional Experience

Abstract Introduction/Objective HER2 testing in invasive breast carcinoma (IBC) is the standard of care to determine patient eligibility for HER2 directed therapy with trasuzumab. Initial testing of tissue by HER2 immunohistochemistry (IHC) can be positive, negative, or equivocal. In equivocal cases as well as negative cases in our institution HER2 FISH is also performed. According to ASCO/CAP guidelines a subset of equivocal and negative IHC cases are considered HER2 positive if they meet criteria for increased HER2/CEP17 ratio and HER2 copy number by FISH, allowing more patients to be treated with HER2 directed therapies. HER2 grouping per ASCO is as follows; Group 1: HER2 copy number ≥4 signals/cell, Group 2: <4.0 signals/cell, Group 3: ≥6 signals/cell, Group 4: HER2 copy number ≥4 and <6 signals/cell, Group 5: HER2 copy number <4 signals/cell Methods/Case Report All cases of IBC resection with HER2 IHC and FISH results from Jan 2018-Dec 2021 were included in this study. All cases positive for HER2 by IHC alone (3+ staining) were excluded. The ASCO/CAP 2018 guidelines for HER2 testing in breast cancer were used to evaluate HER2 positivity by FISH and the relation to IHC scores Results (if a Case Study enter NA) A total of 2630 IBC cases with both HER2 IHC and FISH testing were included. Of these, 131 (5.0%) were in FISH group 1, 17 (0.7%) in group 2, 11 (0.4%) in group 3, 161 (6.1%) in group 4, and 2310 (87.8%) in group 5. A total of 142 (5.4%) cases that were HER2 equivocal or negative by IHC were HER2 positive by FISH. Specifically, 0.3% of cases with an IHC score of 0, 1.4% with a score of 1+, and 14.6% of cases with a score of 2+ were positive by FISH. Of the 14.6% IHC 2+ cases that were FISH positive 13.3% were in FISH group 1 (115 cases) and 1.3% (11 cases) in FISH group 3. Of FISH positive cases 1.4% had an IHC score of 0, 9.9% had an IHC score of 1 and 88.7% had a score of 2 Conclusion At our institution 14.6% of IBC with equivocal HER2 staining on IHC, 1.4% of cases with negative (1+) staining and 0.3% of cases with negative (0) were HER2 FISH positive. Since HER2 FISH is not reflexively performed on cases HER2 negative by IHC, this additional 1.7% will qualify for HER2 targeted therapy Interpretation of low HER2 expression by IHC by traditional IHC assay may miss a small percentage of cases eligible for HER2 directed therapy. Accurate interpretation of HER2 low by IHC is critical as recent clinical trials have shown that low HER2 expression with IHC scores of 1+ or 2+ without gene amplification by FISH could benefit from Trastuzumab Deruxtecan

Immunohistochemical Analysis of Breast Cancer at BP Koirala Memorial Cancer Hospital Nepal

Introduction: Immunohistochemistry test is used to characterize intracellular proteins or various cell surfaces in all tissues. It is used to solve diagnostic problems or for determining prognosis and response to therapy in breast pathology. ER, PR and HER2 are well established biomarkers for breast cancer prognosis and for guiding treatment. Materials and methods: This is retrospective study at Department of Pathology of B P Koirala Memorial Cancer Hospital in Bharatpur, Chitwan, Nepal effective from 15 April 2020 to 14 April 2021. All the data were retrieved and analyzed. Results: Total 205 breast cancer cases were analyzed, among them 198 cases were females accounting 96.5 % and 7 cases were males accounting 3.5 %. Altogether 125 (60.9%) cases had immunohistochemistry panel of ER, PR and HER2 tests done. 48% cases were ER positive, 42.4% cases were PR positive, 34.4% were HER2 positive and 9.9% cases were triple negative. Conclusion: Breast cancer is more common in females than in males. Most common affected age group was 41-50 years. Most common histological type was invasive ductal carcinoma NST. In order to improve breast cancer outcomes and survival, early diagnosis, immunohistochemistry hormone analysis and screening tests should be done.

Impact of a board certification system and adherence to the clinical practice guidelines for gastric cancer on risk-adjusted surgical mortality after distal and total gastrectomy in Japan: a questionnaire survey of departments registered in the National Clinical Database.

The relationship between board certification, clinical guideline implementation, and quality of gastric cancer surgery remains unclear. A web-based questionnaire survey was administered to departments registered in the National Clinical Database (NCD) of Japan between October 2014 and January 2015. Quality indicators (QIs) based on the Donabedian model were evaluated. Structural QIs (e.g., affiliations with academic societies and board certifications) and process QIs (adherence to clinical practice guidelines for gastric cancer) were assessed using risk-adjusted odds ratios (AORs) for surgical mortality. Multivariable logistic regression models with a generalized estimating equation were used. A total of 835 departments performing 40,992 distal gastrectomies and 806 departments performing 19,618 total gastrectomies responded. Some certified institutions and physicians showed significant associations, with lower AORs for surgical mortality. Important process QIs included pre- and postoperative abdominal CT scanning, endoscopic resection based on progression, curative resection with D2 dissection for advanced gastric cancer, laparoscopic surgery, and HER2 testing for patients with unresectable recurrent gastric cancer. Multiple structural and process QIs are associated with surgical mortality after gastrectomy in Japan. Measuring and visualizing QIs may enhance healthcare improvements.

Assessment of <i>ERBB2</i> and HER2 expression in metastatic breast cancer using the nCounter® system and a 100-gene scale

Background. Individual molecular characteristics of a tumor can serve as a basis for a tailored approach to therapy, prediction of the disease course and outcome, and timely treatment correction in cancer patients. Tumor genomic profiling allows for a more precise tumor assessment in an individual manner. Accurate identification of the HER2 status of a breast tumor is crucial for clinical decisions and appropriate treatment strategy.Aim. To increase the efficacy of systemic therapy for breast cancer, reduce inappropriate prescribing, and ensure a tailored approach to systemic breast cancer therapy using the information on individual molecular characteristics of the tumor.Materials and methods. We explored the expression of 100 genes involved in breast cancer development in 106 tumor samples from patients with metastatic breast cancer. We used the nCounter technology based on direct digital target detection using color-coded molecular barcodes. We analyzed the expression of 28 genes with a high predictive value for breast cancer.Results. The nCounter technology allowed us to perform semiquantitative assessment of the expression of 28 genes in tumor tissue samples. We compared the expression of ERBB2 and HER2. The HER2 expression between 252.32 and 6000 barcodes was equivalent to HER2 (0) status; between 6000 and 9196.25 barcodes, to HER2 (1+); between 9196.25 and 15022.46, to HER2 (2+/ISH±); and 15022.46 barcodes, to HER2 (3+). In case of HER2 (3+) and ERBB2 below 6000 barcodes, the result was considered false positive. In case of HER2 (0) or (1+) and ERBB2 above 15 000 barcodes, the result was considered false negative. In 18 tumors, the discrepancies in the results meant two principally different breast cancer subtypes requiring different treatments; in 2 cases, the discrepancies were in the level of HER2 expression.Conclusion. HER2 testing should be performed on an excision sample (ideally on the same block that was used for genomic testing). Despite the correlation between the HER2-enriched molecular class and the response to anti-HER2 therapy, the final result on HER2 status in discordant cases should be based on currently approved assays after results validation.

1396P HER2 testing pattern, characteristics of locally advanced or metastatic NSCLC patients by HER2 testing in France

1396P HER2 testing pattern, characteristics of locally advanced or metastatic NSCLC patients by HER2 testing in France

Gastric adenocarcinoma mimicking a submucosal tumor- a diagnostic pitfall in the pediatric population: report of two cases

Pediatric gastric adenocarcinoma (GAC) is sporadic with limited relevant data, and gastric adenocarcinoma, which presents as submucosal, has seldom been reported. The clinical presentation and outcome have not yet been thoroughly understood. Two boys (10 and 14-year-old) were admitted to the hospital with severe malnutrition. Abdominal CT demonstrated the tumor protruding into the stomach, irregular border, and peritoneal metastasis. Gastric biopsies showed pleomorphic cells, variable size, and increased N/C ratio. These cells were arranged into sheet growth patterns, clusters of cells or incomplete tubules with neutrophils infiltrating. The malignant cells showed strong expression of CK, negativity for CD99, NSE, myogenin, CD3, CD20, ALK, and CD30. Both cases were consistent with poorly differentiated gastric adenocarcinomas, diffuse type with lymphovascular invasion. Pediatric GAC presented with a more advanced stage and poor differentiation. However, the clinical presentation is similar to adult GAC. Because of data limitations, the diagnosis and treatment of pediatric GAC remain a significant challenge. GAC should be kept in mind, especially when a submucosal tumor-like lesion appears in the stomach. Additional molecular investigations, including E-cadherin or HER2 testing of the tumor samples, may offer more treatment choices for these patients.

Assessment of <i>ERBB2</i> and HER2 expression in metastatic breast cancer using the nCounter® system and a 100‑gene scale

Background. Individual molecular characteristics of a tumor can serve as a basis for a tailored approach to therapy, prediction of the disease course and outcome, and timely treatment correction in cancer patients. Tumor genomic profiling allows for a more precise tumor assessment in an individual manner. Accurate identification of the HER2 status of a breast tumor is crucial for clinical decisions and appropriate treatment strategy.Aim. To increase the efficacy of systemic therapy for breast cancer, reduce inappropriate prescribing, and ensure a tailored approach to systemic breast cancer therapy using the information on individual molecular characteristics of the tumor.Materials and methods. We explored the expression of 100 genes involved in breast cancer development in 106 tumor samples from patients with metastatic breast cancer. We used the nCounter technology based on direct digital target detection using color‑coded molecular barcodes. We analyzed the expression of 28 genes with a high predictive value for breast cancer.Results. The nCounter technology allowed us to perform semiquantitative assessment of the expression of 28 genes in tumor tissue samples. We compared the expression of ERBB2 and HER2. The HER2 expression between 252.32 and 6000 barcodes was equivalent to HER2 (0) status; between 6000 and 9196.25 barcodes, to HER2 (1+); between 9196.25 and 15022.46, to HER2 (2+ / ISH±); and ≥15022.46 barcodes, to HER2 (3+). In case of HER2 (3+) and ERBB2 below 6000 barcodes, the result was considered false positive. In case of HER2 (0) or (1+) and ERBB2 above 15000 barcodes, the result was considered false negative. In 18 tumors, the discrepancies in the results meant two principally different breast cancer subtypes requiring different treatments; in 2 cases, the discrepancies were in the level of HER2 expression.Conclusion. HER2 testing should be performed on an excision sample (ideally on the same block that was used for genomic testing). Despite the correlation between the HER2‑enriched molecular class and the response to anti‑HER2 therapy, the final result on HER2 status in discordant cases should be based on currently approved assays after results validation.

Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

Since the release of the DESTINY-Breast04 (DB-04) trial findings in June 2022, the field of pathology has seen a renaissance of HER2 as a predictive biomarker in breast cancer. The trial focused on patients with metastatic breast cancer who were classified as "HER2-low," i.e., those with immunohistochemistry (IHC) HER2 1 + or 2 + and negative in situ hybridization (ISH) results. The study revealed that treating these patients with trastuzumab deruxtecan (T-DXd) instead of the oncologist's chosen chemotherapy led to outstanding improvements in survival. This has challenged the existing binary HER2 pathological classification system, which categorized tumors as either positive (overexpression/amplification) or negative, as per the ASCO/CAP 2018 guideline reaffirmed by ASCO/CAP 2023 guideline update. Given that DB-04 excluded patients with HER2 IHC score 0 status, the results of the ongoing DB-06 trial may shed further light on the potential benefits of T-DXd therapy for these patients. Roughly half of all breast cancers are estimated to belong to the HER2-low category, which does not represent a distinct or specific subtype of cancer. Instead, it encompasses a diverse group of tumors that exhibit clinical, morphological, immunohistochemical, and molecular variations. However, HER2-low offers a distinctive biomarker status that identifies a specific therapeutic regimen (i.e.,T-DXd) linked to a favorable prognosis in breast cancer. This unique association emphasizes the importance of accurately identifying these tumors. Differentiating between a HER2 IHC score 0 and score 1 + has not been clinically significant until now. To ensure accurate classification and avoid misdiagnosis, it is necessary to adopt standardized procedures, guidelines, and specialized training for pathologists in interpreting HER2 expression in the lower spectrum. Additionally, the utilization of artificial intelligence holds promise in supporting this endeavor. Here, we address the current state of the art and unresolved issues in assessing HER2-low status, with a particular emphasis on the score 0. We explore the dilemma surrounding the exclusion of HER2-zero patients from potentially beneficial therapy based on traditional HER2 testing. Additionally, we examine the clinical context, considering that DB-04 primarily involved heavily pretreated late-stage metastatic breast cancers. We also delve into emerging evidence suggesting that extrapolating HER2-low status from the original diagnosis may lead to misleading results. Finally, we provide recommendations for conducting high-quality testing and propose a standardized pathology report in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

Biomarker Testing Trends in Patients With Metastatic Colorectal Cancer Who Live in Rural Areas and Urban Clusters in the US.

There is a paucity of data on biomarker testing rates in rural populations with metastatic colorectal cancer (mCRC). To assess biomarker testing practices, oncologists in rural areas and urban clusters in the US were surveyed. A web-based survey was administered to oncologists spending ≥40% of their time practicing in rural areas or urban clusters and who had treated ≥2 patients with stage IV mCRC in the prior month. Ninety-nine oncologists completed the quantitative survey and 17 the qualitative interview. Among respondents, 97% reported ordering biomarker tests. Oncologists reported testing for KRAS, NRAS, BRAF, HER2, and mismatch repair deficiency/microsatellite instability in 72%, 65%, 63%, 56%, and 66% of patients with metastatic disease, respectively. Forty-one percent reported performing reflex testing. The most cited testing barriers were lack of insurance coverage, insufficient tissue samples, and long turnaround times. Further assessment of rural testing practices is needed.

HER2 status as a potential predictive biomarker for ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian carcinoma characterized by unique biological features and highly malignant characteristics including low chemosensitivity. Therefore, new therapeutic targets are needed. These could include the downstream pathways of receptor tyrosine kinases, especially the human epidermal growth factor receptor 2 (HER2). Our main objective was to characterize the HER2 status using immunohistochemistry (IHC) and FISH on 118 OCCCs, also considering the novel paradigm of HER2-zero and HER2-low status. Other aims included determination of the association between HER2 status and survival, HER2 gene DNA and RNA NGS analysis, HER2 gene expression analysis, and correlation between IHC and gene expression in HER2-zero and HER2-low cases. Cases with HER2 overexpression/amplification accounted for 5.1% (6/118), with additional 3% harbouring HER2 gene mutation. The remaining 112 (94.9%) cases were HER2-negative. Of these, 75% were classified as HER2-zero and 25% as HER2-low. This percentage of HER2 aberrations is significant concerning their possible therapeutic influence. Cases from the HER2-zero group showed significantly better survival. Although this relationship lost statistical significance in multivariate analysis, the results have potential therapeutic significance. HER2 gene expression analysis showed a significant correlation with HER2 IHC status in the entire cohort (HER2-positive vs. HER2-negative), while in the cohort of only HER2-negative cases, the results did not reach statistical significance, suggesting that gene expression analysis would not be suitable to confirm the subdivision into HER2-low and HER2-zero. Our results also emphasize the need for standardized HER2 testing in OCCC to determine the best predictor of clinical response.

Next-generation sequencing complements conventional clinical HER2 testing for advanced or recurrent endometrial tumors (183)

Next-generation sequencing complements conventional clinical HER2 testing for advanced or recurrent endometrial tumors (183)

Impact of Anti-EGFR Therapies on HER2-Positive Metastatic Colorectal Cancer: A Systematic Literature Review and Meta-Analysis of Clinical Outcomes.

HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies. Given the lack of comprehensive investigations into this association, we assessed the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes. A systematic review of MEDLINE, Embase, and Cochrane Library (2001-2021) identified studies evaluating progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) in HER2-positive vs. HER2-negative patients with RAS WT mCRC who received anti-EGFR treatments and whose HER2 status was known. Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) were performed using random-effect models with pre-specified sensitivity analyses. Five high-quality retrospective cohort studies were included in the meta-analyses representing 594 patients with mCRC. All patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Meta-analysis of PFS demonstrated a 2.84-fold higher risk of death or progression (95% CI, 1.44-5.60) in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens. The odds of response to anti-EGFR treatment were 2-fold higher in HER2-negative vs. HER2-positive (odds ratio, 1.96 [95% CI, 1.10-3.48]). Differences in OS were not statistically significant. Sensitivity analyses confirmed the robustness of the base-case estimates. While this study could not account for all confounding factors, in patients with RAS WT mCRC who received anti-EGFR therapy, HER2 overexpression/amplification was associated with worse PFS and ORR and may therefore predict poorer outcomes. HER2 testing is important to inform treatment decisions and could optimize outcomes for patients.

HER2 Expression in Circulating Tumor Cells as Prognostic and Predictive Biomarkers for Anti‐HER2 Therapy in Previously Treated Metastatic Colorectal Cancer

AbstractFor human epidermal growth factor receptor 2‐positive metastatic colorectal cancer (HER2+ mCRC), anti‐HER2 therapy shows benefits, while current HER2 testing using tumor biopsy remains controversial. Noninvasive circulating tumor cells (CTCs) may achieve more accurate HER2 diagnosis . Herein, enumeration and HER2 phenotyping on CTCs (HER2(0/1+/2+/3+) CTCs) are assessed using TUMORFISHER for 40 mCRC patients (20 HER2+; 20 HER2‐negative). Positive/negative HER2 phenotypes on CTCs (ctcHER2+/‐) are determined with or without > 5% HER2(2+/3+) CTCs. After anti‐HER2 therapy, HER2+ patients without baseline CTCs show significantly better survivals than those with 1 ≤ CTCs ≤ 51 or ≥ 52 CTCs at baseline (mPFS; 5.6, 4.2, and 2.0 months; p = 0.0021) (mOS; not yet reached, 18.0 and 9.1 months; p = 0.0002). Among HER2+ patients with 1 ≤ CTCs ≤ 51 at baseline, ctcHER2+ has more favorable survivals than ctcHER2– (mPFS; 5.1 and 2.3 months; p = 0.0257) (mOS; not yet reached, 14.7 months; p = 0.0400). HER2+ patients with ≥ 52 CTCs or (with 1 ≤ CTCs ≤ 51 and maintained ctcHER2–) show a higher progression disease rate (60.0%, 0.0%; p = 0.0106). Therefore, CTC enumeration and ctcHER2 phenotyping may be prognostic and predictive biomarkers for HER2+ mCRC with anti‐HER2 therapy.

Comprehensive Analysis of Human Epidermal Growth Factor Receptor 2 Through DNA, mRNA, and Protein in Diverse Malignancies.

Human epidermal growth factor receptor 2 (HER2) expression (protein immunohistochemistry [IHC] or gene amplification [copy-number variation, CNV]) predicts anti-HER2 therapy responsiveness, although recently it was shown that even low HER2-expressing breast cancers benefit from trastuzumab-deruxtecan. Little is known about HER2 transcriptomic (mRNA) expression, and comparisons between genomic, mRNA, and protein HER2 assays. HER2 status was evaluated using clinical-grade IHC (protein), quantitative reverse transcription polymerase chain reaction (mRNA), and next-generation sequencing (NGS; amplifications). Multi-institutional HER2 testing was performed on 5,305 diverse cancers including non-small-cell lung (n = 1,175), breast (n = 1,040), and colon cancers (n = 566; N = 3,926 tested for CNV; N = 1,848, mRNA; N = 2,533, IHC). Overall, 4.1% (161/3,926) had NGS HER2 amplification; 33.3% (615/1,848) had mRNA overexpression; and 9.3% (236/2,533) were IHC-positive. In 723 patients with all three tests (CNV/mRNA/IHC), various amplification/expression patterns occurred: 7.5% (54/723) had all three HER2 tests positive; 62.8% (454/723) had all three tests negative. Discrepant patterns between amplification and overexpression emerged. For instance, 20% (144/723) of patients had mRNA overexpression alone with negative CNV and IHC. A range in values for only mRNA+ cases occurred in different tumor types (eg, 16.9%, breast; 5%, hepatobiliary). There were 53 patients with various tumors from our institution who had all three assays attempted; 22 tested positive for HER2, and seven received anti-HER2 therapy: two patients achieved response: one (esophageal cancer), complete response (≥42 months); one (cholangiocarcinoma), who only had HER2 mRNA positivity (tissue was inadequate for IHC and CNV assessment), partial response (≥24 months) on HER2-based regimens. We demonstrate variability of HER2 (protein and mRNA) expression and amplification using comprehensive assays (CNV, mRNA, and IHC) among diverse cancers. As HER2-targeted therapy indications expand, the relative importance of these modalities merits further evaluation.

Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18

Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC). We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m2 paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%). Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.

GASTric Cancer HER2 Re-Assessment Study 2 (GASTHER2): HER2 Re-assessment for Initially HER2-Negative Advanced Gastric Cancer Patients after Progression on First-Line Treatment.

Heterogeneous human epidermal growth factor receptor 2 (HER2) overexpression in gastric cancer may lead to a misdiagnosis of HER2 status. Accurate assessment of HER2 status is essential for optimal treatment as novel HER2-directed agents are being investigated in various clinical settings. We evaluated the usefulness of HER2 re-assessment following progression on first-line treatment in initially HER2-negative advanced gastric cancer (AGC) patients. We enrolled 177 patients with baseline HER2-negative AGC and performed HER2 re-assessment after progression on first-line treatment from February 2012 to June 2016 at Asan Medical Center, Seoul, Korea. The re-assessed HER2 status was analyzed with baseline HER2 status and clinical characteristics. The median age was 54 years (range, 24 to 80 years), and 123 patients (69.5%) were men. Seven patients (4.0%) were HER2-positive on the re-assessment. Patients with baseline HER2 negativity confirmed by a single test (n=100) had a higher HER2-positive re-assessment rate compared to those who had repeated baseline testing (n=77) (5.0% vs. 2.6%). Among the patients with single baseline HER2 testing, the rate was higher in patients with baseline HER2 immunohistochemistry (IHC) 1+ compared to those with IHC 0 (13.4% vs. 3.6%). Overall, 4.0% of patients with baseline HER2-negative AGC were HER2-positive on re-assessment, and the HER2-positive re-assessment rate was higher among patients who had a single test at baseline. HER2 re assessment may be considered for initially HER2-negative patients to determine their eligibility for HER2-directed therapy, particularly if their HER2 negativity was determined by a single test, especially if they had a single baseline HER2 IHC 1+ test.