Dataset Information

Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients.

ABSTRACT:

Background

During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.

Methods

aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).

Results

As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).

Conclusions

HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.

Trial registration

NCT05735392 retrospectively registered on January 31, 2023 https://www.

Clinicaltrials

gov/search?term=NCT05735392.

SUBMITTER: Giordani E

PROVIDER: S-EPMC11218356 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Publications

Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients.

Giordani Elena E Allegretti Matteo M Sinibaldi Alberto A Michelotti Francesco F Ferretti Gianluigi G Ricciardi Elena E Ziccheddu Giovanna G Valenti Fabio F Di Martino Simona S Ercolani Cristiana C Giannarelli Diana D Arpino Grazia G Gori Stefania S Omarini Claudia C Zambelli Alberto A Bria Emilio E Paris Ida I Buglioni Simonetta S Giacomini Patrizio P Fabi Alessandra A

Journal of experimental & clinical cancer research : CR 20240629 1

<h4>Background</h4>During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.<h4>Methods</h4>aHER2 and sHER2 were as ...[more]

PMID: 38951853

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Project description:Background:Breast cancer is highly prevalent worldwide and leads to high health-care costs. HER2-positive subtype represents 30% of all breast cancers and is associated with a poor prognosis. Patients treated with anti-HER2 therapies frequently develop resistance and require pharmacological treatment change. Liquid biopsy is a minimally invasive and an easily accessible technique, with high sensitivity and specificity, to detect molecular treatment resistance even before the onset of clinical manifestations and can thus be used to reduce unnecessary anti-HER2 treatment costs. Objective:To evaluate the cost-effectiveness of using liquid biopsy (ctDNA detection) to determine treatment change in women with HER2-positive advanced breast cancer in Colombia. Methodology:We performed an economic evaluation using decision tree modeling and deterministic analyses based on literature search for first and second lines of treatment (trastuzumab, pertuzumab, docetaxel, and TDM1); resistance; outcomes; and sensitivity and specificity of tests detecting molecular resistance. The effectiveness was measured using quality-adjusted life year (QALY) score, and costs were obtained from databases with national validity, suppliers, the Colombian Drug Price Information System (SISMED), and local studies. Results:The use of liquid biopsy (ctDNA detection) with conventional treatment was more expensive and less effective than conventional treatment without liquid biopsy (US $177,985.35 and 0.533889206 QALY, respectively). The incremental cost with liquid biopsy was US $7,333.17 and the incremental effectiveness was 0.00042256 QALY relative to the conventional method. Conclusion:Including liquid biopsy in the treatment of HER2-positive advanced breast cancer was considered currently inapplicable in Colombia because it was not cost effective. Our results open a window of opportunity to improve the development and implementation of ctDNA testing in Colombia, potentially reducing current costs. More evidence is required on the utility of this test, depending on the financial capacity of Colombia and other countries.

Project description:Metastatic breast cancer (mBC) patients have a high risk of progression and face poor prognosis overall, with about one third (34%) surviving five years or more. In rare instances (2-4% of cases) patients with mBC have ERBB2 (HER2) activating mutations but are ERBB2 non-amplified. Neratinib is a potent, irreversible inhibitor that binds HER2 and inhibits downstream signaling. We used the previously validated high-definition single cell assay (HDSCA) workflow to investigate the clinical significance of the liquid biopsy in ERBB2 mutant, non-amplified, post-menopausal mBC patients starting neratinib and fulvestrant combination therapy. Characterization with a comprehensive liquid biopsy methodology (HDSCA) included genomic analysis of both the cell-free DNA (cfDNA) and single circulating tumor cells (CTCs) to monitor tumor evolution and identify potential mutational variants unique to the patient's clinical response. A limited series of five sequentially enrolled patients presented here were from the MutHER ( https://www.clinicaltrials.gov , NCT01670877) or SUMMIT ( https://www.clinicaltrials.gov , NCT01953926) trials. Patients had an average of 5.4 lines of therapy before enrollment, variable hormone receptor status, and ERBB2 mutations at diagnosis and during treatment. CTC enumeration alone was not sufficient to predict clinical response. Treatment pressure was shown to lead to an observable change in CTC morphology and genomic instability (GI), suggesting these parameters may inform prognosis. Single cell copy number alteration (CNA) analysis indicated that the persistence or development of a clonal population of CTCs during treatment was associated with a worse response. Hierarchical clustering analysis of the single cells across all patients and timepoints identified distinct aberrant regions shared among patients, comprised of 26 genes that are similarly affected and may be related to drug resistance. Additionally, the genomic analysis of the cfDNA, identified new mutations in ERBB2, PIK3CA, and TP53 that arose likely due to treatment pressure in a patient with poor response, further providing insights on the dynamics of the cancer genome over the course of therapy. The data presented in this small cohort study demonstrates the feasibility of real-time molecular profiling of the cellular and acellular fractions of the liquid biopsy using the HDSCA methodology. Additional studies are necessary to determine the potential use of morphometric and genomic analysis as a prognostic tool to advance personalized oncology.

Dataset Information

Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients.

Background

Methods

Results

Conclusions

Trial registration

Clinicaltrials

Publications

Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients.

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