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Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients
Elena Giordani1, Matteo Allegretti1, Alberto Sinibaldi2
1Translational Oncology Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
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.
Insights
HER2-positive breast cancer patients treated with T-DM1 showed a surprising gain in soluble HER2 (sHER2) protein levels, even as HER2 DNA decreased. This sHER2 gain correlated with longer progression-free survival, suggesting a potential biomarker for treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- HER2-positive breast cancers often lose HER2 DNA amplification during targeted therapy.
- HER2 protein levels can paradoxically increase despite DNA loss.
- Longitudinal assessment of HER2 DNA and protein stoichiometry is crucial for understanding treatment response.
Purpose of the Study:
- To longitudinally and systematically evaluate complex changes in HER2 DNA and protein levels (HER2-2D) using liquid biopsy.
- To assess the correlation between HER2 DNA copy numbers and soluble HER2 (sHER2) levels during T-DM1 treatment.
- To investigate the clinical significance of HER2-2D changes in advanced HER2-positive breast cancer patients.
Main Methods:
- Assessed HER2 DNA (aHER2) by digital PCR and soluble HER2 (sHER2) by ELISA in 37 advanced HER2-positive breast cancer patients.
- Measurements were taken before and after standard-of-care treatment with Trastuzumab-emtansine (T-DM1).
- Correlated aHER2/sHER2 kinetics with tumor re-biopsies and in vitro cell line experiments.
Main Results:
- T-DM1 treatment suppressed aHER2, but 81% of patients showed a concurrent gain in sHER2.
- sHER2 gain was observed in tumor re-biopsies despite copy-number-neutrality.
- sHER2 gain was associated with significantly longer progression-free survival (PFS) compared to sHER2 loss.
- Excluding bypass alterations, sHER2 gain showed an even stronger association with improved PFS.
Conclusions:
- HER2 gain, reflected as sHER2 gain in blood, is adaptively selected in tumors during anti-HER2 therapy.
- sHER2 gain may indicate a favorable host response to cytotoxic ADCs like T-DM1.
- HER2-2D analysis via liquid biopsy could help tailor anti-HER2 treatments, especially for tumors with low aHER2/sHER2.
- Alternative oncogenic drivers may emerge and bypass HER2 during treatment.
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