Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case

Abstract

BackgroundConstitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients.Patient and methodsHER2 gene amplification and HER2 protein overexpression analysis were performed in tumour tissue by fluorescence in situ hybridisation and immunohistochemistry. HER2 positivity was defined according to HERACLES CRC-specific HER2 scoring criteria. DNA analysis for multiple assessment of gene mutations or amplifications was carried out with the next-generation sequencing (NGS) Ion AmpliSeq Colon and Lung Cancer Panel and by using a more extensive targeted high-multiplex PCR-based NGS panel (OncoMine Comprehensive Assay).ResultsWe report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control. HER gene amplification was confirmed by NGS on two different metastatic lesions during the evolution of the disease.ConclusionThe clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy.

Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer

“…MyPathway, a phase 2a basket study of solid tumors with Her2 amplification, included a trastuzumab and pertuzumab arm and demonstrated an even more promising ORR of 52% in Her2‐amplified/KRAS wild‐type patients and no response in KRAS‐mutated patients. Ongoing clinical trials such as RESCUE continue to explore the potential role of HER2‐targeted therapy in mCRC …”

“…Ongoing clinical trials such as RESCUE continue to explore the potential role of HER2-targeted therapy in mCRC. 63…”

First‐line therapy for metastatic colorectal cancer: Current perspectives and future directions

“…An alternative, dual HER‐2 targeting strategy of trastuzumab and pertuzumab, has also been explored in a phase 2 basket study called “MyPathway” and a similar response rate (38%) was reported . The antibody‐drug conjugate TDM‐1 did demonstrate activity in the setting of trastuzumab resistant‐HER‐2 amplified mCRC …”

Implementation of genomic medicine for gastrointestinal tumors

“…Naturally, the detection rate of clinically relevant point mutations and small insertions/deletions is augmented by the increase of genes in the panels, hybrid capture‐based sequencing, whole exome sequencing, and whole genome sequencing . Determination of other types of alterations such as CNV and structural variations will further increase the number of patients who will benefit from the sequencing . A recent survey showed that physicians who used the Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT), a next‐generation hybridization capture sequencing, changed clinical management in 21% (331/1593) of their patients according to the sequencing result .…”