Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies.
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ABSTRACT:
SUBMITTER: Vicario R
PROVIDER: S-EPMC4467984 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: HER2 antagonists have marked activity and are approved for the treatment of HER2 overexpressing breast and gastric cancers. Recent studies have shown that ERBB2 (HER2) gene amplification and overexpression may also be actionable in other tumor types. Inter- and intratumoral heterogeneity in HER2 status, however, poses a significant challenge in identifying patients that may benefit from HER2-targeted therapies. ERBB2 amplification as identified by circulating cell-free DNA (cfDNA), which circumvents tissue heterogeneity issues, is emerging as a robust biomarker predictive of response to anti-HER2 agents. Here, the prevalence and genomic landscape of ERBB2 alterations detectable by next-generation sequencing (NGS) of cfDNA was evaluated in a large cohort of Asian patients with advanced solid tumors. Methods: Results were queried for consecutive patients (n = 469) tested by a comprehensive 70/73-gene cfDNA NGS assay (Guardant360®) between November 2015 and June 2018. Patients with ERBB2 gene alterations including copy number amplifications (CNAs), single nucleotide variants (SNVs), and insertion-deletions (indels) were identified. Results: ERBB2 alterations were detected in 52 patients (11.1%); ERBB2 SNVs, CNAs, and indels were found in 27 (5.8%), 27 (5.8%), and 10 (2.1%) patients, respectively. ERBB2 amplification was most frequently identified in gastric (21.4%; 6/28), colorectal (11.1%; 5/45), lung (3.9%; 9/231), and breast (3.2%; 1/31) cancer patients. ERBB2 amplification was often mutually exclusive with other oncogenic alterations in gastric (83.3%; 5/6) and colorectal (60%; 3/5) cancer patients. ERBB2 copy number gains were also highest in gastric and colorectal cancers (median 4.8 and 6.6, respectively). We further report two cases of advanced gastric cancer patients, one treatment naïve, and the other having failed four lines of therapy, whose ERBB2 CNAs were identified by cfDNA and derived clinical benefit from HER2-based therapies. Conclusion: Our data indicate that ERBB2 amplification is a common event in solid tumors among Asian cancer patients. High ERBB2 incidence and copy number gains were observed in gastric and colorectal cancer patients, often in the absence of other oncogenic mutations, underscoring its likely role as the driver alteration in those settings. Finally, we show the potential of comprehensive cfDNA testing in identifying patients who are most likely to benefit from HER2-targeted therapies.
| S-EPMC6458313 | biostudies-literature
Project description:Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs.
| S-EPMC3570596 | biostudies-literature
Project description:Background and purposeDespite their use to treat cancers with specific genetic aberrations, targeted therapies elicit heterogeneous responses. Sources of variability are critical to targeted therapy drug development, yet there exists no method to discern their relative contribution to response heterogeneity.Experimental approachWe use HER2-amplified breast cancer and two agents, neratinib and lapatinib, to develop a platform for dissecting sources of variability in patient response. The platform comprises four components: pharmacokinetics, tumor burden and growth kinetics, clonal composition, and sensitivity to treatment. Pharmacokinetics are simulated using population models to capture variable systemic exposure. Tumor burden and growth kinetics are derived from clinical data comprising over 800,000 women. The fraction of sensitive and resistant tumor cells is informed by HER2 immunohistochemistry. Growth rate-corrected drug potency is used to predict response. We integrate these factors and simulate clinical outcomes for virtual patients. The relative contributions of these factors to response heterogeneity arecompared.Key resultsThe platform was verified with clinical data, including response rate and progression-free survival (PFS). For both neratinib and lapatinib, the growth rate of resistant clones influenced PFS to a higher degree than systemic drug exposure. Variability in exposure at labeled doses did not significantly influence response. Sensitivity to drug strongly influenced responses to neratinib. Variability in patient HER2 immunohistochemistry scores influenced responses to lapatinib. Exploratory twice daily dosing improved PFS for neratinib but not lapatinib.Conclusion and implicationsThe platform can dissect sources of variability in response to target therapy, which may facilitate decision-making during drug development.
| S-EPMC10290754 | biostudies-literature
Project description:Background: HER2 serves as an important therapeutic target in gastroesophageal cancer. Differences in HER2 gene signal distribution patterns can be observed at the tissue level, but how it influences the HER2 amplification status has not been studied so far. Here, we investigated the link between HER2 amplification and the different types of gene signal distribution. Methods: Tumor samples from 140 patients with gastroesophageal adenocarcinoma where analyzed using the HER2 IQFISH pharmDx™ assay. Specimens covered non-amplified and amplified cases with a preselected high proportion of HER2 amplified cases. Based on the HER2/CEN-17 ratio, specimens were categorized into amplified or non-amplified. The signal distribution patterns were divided into homogeneous, heterogeneous focal or heterogeneous mosaic. The study was conducted based on anonymized specimens with limited access to clinicopathological data. Results: Among the 140 analyzed specimens 83 had a heterogeneous HER2 signal distribution, with 62 being focal and 21 of the mosaic type. The remaining 57 specimens had a homogeneous signal distribution. HER2 amplification was observed in 63 of the 140 specimens, and nearly all (93.7%) were found among specimens with a heterogeneous focal signal distribution (p<0.0001). The mean HER2/CEN-17 ratio for the focal heterogeneous group was 8.75 (CI95%: 6.87 - 10.63), compared to 1.53 (CI95%: 1.45 - 1.61) and 1.70 (CI95%: 1.22 - 2.18) for the heterogeneous mosaic and homogeneous groups, respectively, (p<0.0001). Conclusions: A clear relationship between HER2 amplification and the focal heterogeneous signal distribution was demonstrated in tumor specimens from patients with gastroesophageal cancer. Furthermore, we raise the hypothesis that the signal distribution patterns observed with FISH might be related to different subpopulations of HER2 positive tumor cells.
| S-EPMC5535706 | biostudies-other
Project description:Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2(+)/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2(+)/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2(+)/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA(H1047R) accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.
| S-EPMC3761610 | biostudies-literature
Project description:The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody-drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors.
| S-EPMC9496705 | biostudies-literature
Project description:Despite impressive clinical benefit obtained with anti-HER2 targeted therapies, in advances stages, especially in the metastatic setting, HER2 positive tumors remain incurable. Therefore, it is important to develop novel strategies to fight these tumors, especially when they become resistant to available therapies. We show here that the anti-HER3 antibody drug conjugate EV20/MMAF exerted potent antitumoral properties against several models of primary and secondary resistance to common anti-HER2 available therapies, including trastuzumab, lapatinib, neratinib and trastuzumab-emtansine. HER3 was expressed in these HER2+ breast cancer cells and knock down experiments demonstrated that HER3 expression was required for the action of EV20/MMAF. In mice injected with trastuzumab-resistant HER2+ cells, a single dose of EV20/MMAF caused complete and long-lasting tumor regression. Mechanistically, EV20/MMAF bound to cell surface HER3 and became internalized to the lysosomes. Treatment with EV20/MMAF caused cell cycle arrest in mitosis and promoted cell death through mitotic catastrophe. These findings encourage the clinical testing of EV20/MMAF for several indications in the HER2+ cancer clinic, including situations in which HER2+ tumors become refractory to approved anti-HER2 therapies.
| S-SCDT-EMM-2019-11498 | biostudies-other
Project description:BACKGROUND:Targeted treatments may greatly affect the natural history of urothelial carcinoma based on their pharmacokinetics. A phase II trial has explored the combination of cytotoxic chemotherapy with the anti-HER-2 monoclonal antibody trastuzumab in selected patients with metastatic bladder cancer, but it failed. CASE SUMMARY:Here, we report a case of recurrent urothelial bladder carcinoma (UBC) in a patient who has undergone three operations, and further illuminate its diagnosis and treatment. The diagnosis of UBC was rendered according to the pathological indices. Next-generation sequencing on formalin fixed paraffin-embedded (FFPE) tissue was also performed and suggested HER2 gene amplification in the FFPE tissue. Based on HER2 gene amplification in FFPE, the patient was treated with chemotherapy in combination with trastuzumab after his third surgery. Fortunately, the patient got a clinically complete remission to trastuzumab for 34 mo. CONCLUSION:There is not enough clinical evidence for incorporating trastuzumab in routine treatment of UBC. This case hinted that recurrent UBC patients with HER2 gene amplification may benefit from targeted trastuzumab. Further studies are needed to further investigate the status of HER2 gene and better determine trastuzumab in the management of UBC.
| S-EPMC7031824 | biostudies-literature
Project description:Despite impressive clinical benefit obtained with anti-HER2-targeted therapies, in advances stages, especially in the metastatic setting, HER2-positive tumors remain incurable. Therefore, it is important to develop novel strategies to fight these tumors, especially when they become resistant to available therapies. We show here that the anti-HER3 antibody-drug conjugate EV20/MMAF exerted potent anti-tumoral properties against several models of primary resistance and secondary resistance to common anti-HER2 available therapies, including trastuzumab, lapatinib, neratinib, and trastuzumab-emtansine. HER3 was expressed in these HER2+ breast cancer cells and knockdown experiments demonstrated that HER3 expression was required for the action of EV20/MMAF. In mice injected with trastuzumab-resistant HER2+ cells, a single dose of EV20/MMAF caused complete and long-lasting tumor regression. Mechanistically, EV20/MMAF bound to cell surface HER3 and became internalized to the lysosomes. Treatment with EV20/MMAF caused cell cycle arrest in mitosis and promoted cell death through mitotic catastrophe. These findings encourage the clinical testing of EV20/MMAF for several indications in the HER2+ cancer clinic, including situations in which HER2+ tumors become refractory to approved anti-HER2 therapies.
| S-EPMC7207167 | biostudies-literature
Project description:PurposeHER2 overexpression has been identified in approximately 14% of bladder adenocarcinomas. However, until now, there has been no approved standard targeted therapy for bladder adenocarcinoma patients harboring HER2 genetic alteration.Case presentationWe presented a case of a 64-year-old man who was diagnosed with bladder adenocarcinoma, and lung metastasis was confirmed less than one year after initial bladder surgery. The patient received systemic chemotherapy and antiangiogenetic treatment, but the tumor continued to progress. The patient underwent next-generation sequencing (NGS) to seek potential treatment opportunities. HER2 amplification, approximately 7 times, was discovered together with the S310F mutation (mutant abundance 90%). The patient then received late-line treatment with trastuzumab and albumin-bound paclitaxel. A partial response was confirmed two months later. Trastuzumab-based therapy was continued for 8 cycles, and the progression-free survival period was 6 months. NGS was performed on a rebiopsy, and the result showed no amplification of HER2, and the S310F mutant abundance was reduced to 27.9%.ConclusionThis is the first case report describing a bladder adenocarcinoma patient harboring HER2 amplification who responded to trastuzumab. NGS is of great potential in the selection of bladder adenocarcinoma patients suitable for anti-HER2 therapy. The genetic change after treatment also implied possible mechanisms of resistance to trastuzumab-based therapy, which requires more investigation.
| S-EPMC7244354 | biostudies-literature