Introduction  Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality worldwide. Within this context, a subset of CRCs shows overexpression of the human epidermal growth factor receptor 2 (HER2/neu), a characteristic also seen in other malignancies like breast and gastric cancers. The success of targeting the HER2 pathway in these cancers has prompted investigations into the potential use of similar interventions in CRC. Aims This research aims to assess HER2/neu expression in CRCs and its correlation with the CRC stage and histopathology, as well as to evaluate the demographic characteristics of CRC patients. Materials and methods  This prospective observational study was conducted on a cohort of 40 CRC patients, using histopathology and immunohistochemistry (IHC) sections from the Department of Pathology. Clinical and demographic data were collected over a 24-month period, and routine tissue processing and IHC staining were performed on colectomy tissues. Immunostaining with the HER2/neu marker was conducted for detailed analysis. Data were analyzed using IBM SPSS Statistics for Windows, Version 27.0 (Released 2020; IBM Corp., Armonk, NY, United States). Results  Among the 40 CRC cases studied, six cases (15%) exhibited robust membranous positivity, while eight cases (20%) showed moderate focal membranous positivity. Twenty-six cases (65%), however, demonstrated no HER2/neu staining positivity. A significant correlation was found between the histological grade of the tumor and HER2/neu expression (p = 0.0001). Additionally, HER2/neu expression was significantly correlated with lymphovascular invasion (p < 0.0001) and lymph node status (p < 0.047). Conclusion  This study found a strong correlation between the tumor's stage, grade, lymph node status, and lymphovascular invasion and HER2/neu expression. Therefore, HER2/neu can be a predictive and therapeutic marker in colorectal cancers. This underscores the potential importance of incorporating these parameters in the clinical evaluation and targeted treatment strategies for CRC patients.

Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors.

We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials.

Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting.

These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.

The prognosis of metastatic colorectal cancer (mCRC) is poor. Cetuximab and panitumumab, 2 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs), improve the overall survival of patients with RAS wild-type mCRC. However, not all patients with RAS wild-type mCRC will respond to anti-EGFR mAbs. Several retrospective trials suggest that human epidermal growth factor receptor 2 (HER2) amplification could be a predictive biomarker of resistance to anti-EGFR mAbs in patients with metastatic RAS and RAF wild-type mCRC. Dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab has shown promising preliminary anti-tumoral efficacy in RAS wild-type mCRC. Although these findings need to be confirmed in randomized trials, the data strongly support that HER2 is an actionable gene in CRC and provide the scientific rationale to test HER2 status on a routine basis in this disease. In this review, we discuss the predictive value of HER2 activation in CRC as well as its potential role as a treatment target.

Introduction: Metastatic colorectal cancer (CRC) remains a dilemma for cancer researchers with an increasing incidence in the younger patient population. Until the last decade, limited therapeutic options were available for metastatic CRC patients leading to relatively poor clinical outcomes.Areas covered: With advances in genome sequencing technology and reductions in the cost of next-generation sequencing, molecular profiling has become more accessible for cancer researchers and clinical investigators, which has furthered our understanding of the molecular behavior of CRC. This progress has recently translated into significant advances in molecular-based therapeutics and led to the development of new target-specific agents in metastatic CRC patients. In this review article, we extensively elaborate on genomic alterations seen in CRC patients including, but not limited to, EGFR, MMR, BRAF, HER2, NTRKs, FGFR, BRCA1/2, PALB2, POLE, and POLD1 genes, all of which are potentially actionable by either an FDA-approved agent or in a clinical trial setting.Expert opinion: We strongly recommend molecular profiling in metastatic CRC patients during the early course of their disease, as this may provide therapeutic and prognostic information that can guide clinicians to practice precision medicine. Patients with potentially actionable genes should be considered for targeting agents based on molecular alterations.

Colorectal cancer (CRC) is one of the most common malignant tumors; it is a focus of research globally, but the identification of clinically actionable oncogenic drivers remains elusive. Human epidermal growth factor receptor 2 (HER2) activation is present in approximately 5% of CRC and has acquired resistance to epidermal growth factor receptor (EGFR)-targeted therapy. Early clinical trials suggest an emerging role for personalized HER2-targeted therapy in a subset of metastatic CRC.

This manuscript reviews the relevance of HER2 activation in CRC and its potential role as a target for therapy. A literature search was conducted in June 2018 of MEDLINE and EMBASE databases for published preclinical and clinical studies; abstracts of international cancer meetings (AACR, ASCO, and ESMO) were also reviewed.

HER2 is activated in a small but relevant proportion of CRC patients (particularly left-side, RAS wild-type, anti-EGFR resistant tumors). Dual HER2 blockade with monoclonal antibodies (mAbs) (trastuzumab and pertuzumab) or the combination of mAbs with tyrosine kinase inhibitors (trastuzumab and lapatinib) induces durable tumor responses in about one-third of HER2-positive CRC refractory to standard systemic therapy. Although immature, these results are remarkable and anticipate an expanding role for HER2 as a therapeutic target in CRC.

An increasing number of patients with metastatic colorectal cancer (mCRC) are able to receive 3 or more lines of therapy. Treatments in this setting can include regorafenib (an oral multikinase inhibitor), trifluridine/tipiracil hydrochloride (TAS-102), antibodies that target epidermal growth factor receptor for patients with RAS wild-type tumors (if no prior exposure), and, where approved, anti-programmed cell death protein 1 inhibitors for patients with microsatellite instability-high mCRC. Although guidelines describe the available treatment options, few insights are provided to guide selection and sequencing. In this article, we share expert opinion from diverse geographic regions, to offer guidance for best practice when selecting and managing third-line treatment for mCRC. Various factors, including performance status, age, and tumor sidedness, can be used to guide treatment selection. Biomarkers, such as RAS, BRAF, and microsatellite instability, can be useful for treatment stratification. Management of adverse events, to maintain quality of life, is a key consideration and is crucial to best practice in this setting. Common toxicities associated with third-line treatments are hand-foot skin reaction, fatigue, diarrhea, and cytopenias. Patients who receive third-line and later-line treatments should be monitored for these events, especially during the first 2 cycles. Dose modifications can also be used to manage toxicities and to minimize the effect on quality of life, while maximizing treatment benefit. Clinical trials of emerging agents, new treatment combinations, and novel therapies continue the efforts to improve outcomes for patients with mCRC. Sharing expert opinions on best practice for treatment selection and management can ultimately improve outcomes for patients with mCRC.

Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.

Gastrointestinal (GI) cancers altogether represent the most common cancer type. HER2 is found to be present in nearly all histologic types of GI cancers in variable degrees of expression. Over the last decade, substantial advances have been made in targeting HER2-positive cancers. Areas covered: The present review summarizes the current progress and future directions for HER2 targeted therapies in GI cancers, including esophagogastric, pancreaticobiliary, and colon cancers. To date trastuzumab is the only anti-HER2 therapy approved for metastatic esophagogastric adenocarcinoma. Efforts are ongoing to expand the therapeutic role of HER2 to other GI cancers and overcome mechanisms of drug resistance. Novel agents and combinations are being tested in most HER2 positive GI cancers including early stage disease. These are of recent interest in colorectal cancer with studies indicating that HER2 overexpression might increase resistance to anti-EGFR therapy and may be potentially targeted. Expert commentary: With the current ability to sequence tumors and detect genetic alterations, emphasis should be put on genomically-selected pan-tumor targeted therapies. HER2 is a perfect example of a promising drug target in GI cancers.

Choosing the optimal treatment approach for patients with metastatic colorectal cancer (mCRC) demands that oncologists assess both clinical and genomic variables and individualize care based upon the findings. Clinically, choices depend on assessing the side of the colon in which the primary tumor originates, the sites and burden of metastatic disease, the patient's performance status, and their individual comorbidities. Genomic assessment of the tumor to discern the mutational status of genes such as RAS/RAF, HER2, and TRK, as well as assessing whether tumors have defective mismatch repair (dMMR) or high microsatellite instability (MSI-H), all factor in to potential treatment options and can determine clinical trial eligibility. Metastasectomy may be an option for patients with a low burden of disease and accessible liver- or lung-limited metastases. In some unresectable cases, systemic therapy with a FOLFOX- or FOLFIRI-based regimen with or without a biologic agent can lead to sufficient disease reduction to make a patient eligible for resection of metastatic disease. Tumor sidedness and RAS mutational status guide which biologic we add to the initial chemotherapy backbone, with patients with left-sided, RAS wild-type (WT) tumors receiving anti-epidermal growth factor receptor (EGFR)-directed therapy and patients with right-sided tumors or those with RAS mutations receiving bevacizumab. In patients with tumors that manifest microsatellite instability or deficient mismatch repair, we typically administer checkpoint inhibitors such as pembrolizumab or nivolumab after progression on irinotecan- or oxaliplatin-based therapies. In patients with progressive disease, we routinely send tumor tissue for next generation sequencing (NGS) to assess for the presence of actionable genomic alterations such as HER2, BRAF, and TRK fusions and offer them the option of enrollment on clinical trials with agents targeting those or other identified alterations.