Loss of HER2 amplification and disease prognosis after neoadjuvant treatment of HER2 amplified breast cancer

Branco, Francisco; Silva, F.; André, Sylvie; Catarino, Ana; Madureira, Renata Cunha; Pinto, João; Godinho, João; Simões, Pedro; Freitas, Antônio Carlos de; Casa‐Nova, Mafalda; Nave, Mónica; Augusto, José; Passos‐Coelho, José Luís

doi:10.1016/s0959-8049(18)30510-0

Cited by 8 publications

(14 citation statements)

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“…The mechanism of HER2 discordance with dual‐agent HER2‐targeted treatment compared to trastuzumab alone is not well‐understood. It has been shown that combination therapy with trastuzumab and pertuzumab results in increased disruption of HER2 receptor dimers and leads to a dose‐dependent downregulation of HER2 receptor levels, which may result in reduced HER2 expression 8 . In addition, given that trastuzumab and pertuzumab results in a synergistic effect on increased breast cancer cell death 8 and that intratumoral heterogeneity of HER2 gene expression exists, 28 treatment with dual‐agent HER2‐targeted therapy may result in increased clonal selection for HER‐negative tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, it appears that clinically meaningful differences in IDFS were not observed for patients with HER2 concordant disease and HER2 discordant disease after neoadjuvant treatment. Previous studies are inconsistent regarding whether the loss of HER2 amplification after neoadjuvant treatment is associated with worse outcomes 7–9,11–15,17–20 . For example, Branco et al report the 5‐year IDFS and 5‐year OS of patients who retained HER2 amplification after neoadjuvant treatment is 70% and 84%, respectively, and 21% and 50% for patients whose residual tumors lost HER2 amplification ( p = 0.02 and p < 0.001) 8 .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies that have investigated the impact of neoadjuvant HER2‐targeted treatment with trastuzumab alone plus chemotherapy report a HER2 discordance rate ranging from 7% to 43% from the time of core biopsy to surgery 7–19 . However, there are few studies that report the discordance rate after neoadjuvant dual HER2‐targeted treatment plus chemotherapy, the current standard‐of‐care.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, 21 (10.7%) patients in this study did not receive chemotherapy with HER2‐directed therapy in the neoadjuvant regimen. Lastly, Branco and colleagues performed a retrospective study of 108 HER2‐positive breast cancer patients and reported a HER2 discordance rate of 13.3% in patients treated with neoadjuvant therapy with residual disease; however, only three patients (including those with a pCR) received neoadjuvant dual HER2‐targeted treatment 8 …”

Section: Discussionmentioning

confidence: 99%

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Incidence and prognostic impact of HER2‐positivity loss after dual HER2‐directed neoadjuvant therapy for HER2+ breast cancer

et al. 2023

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Background Loss of HER2 “positivity” can occur in patients with residual disease after neoadjuvant treatment, but the incidence of HER2‐positivity loss after neoadjuvant dual HER2‐targeted treatment plus chemotherapy, the current standard‐of‐care for most early stage HER2‐positive breast cancers, is not well described. Previous studies that report the HER2 discordance rate after neoadjuvant treatment also do not include the novel HER2‐low category. In this retrospective study, we determine the incidence and prognostic impact of HER2‐positivity loss, including the evolution to HER2‐low disease, after neoadjuvant dual HER2‐targeted therapy with chemotherapy. Methods Clinicopathologic data for patients with stage I‐III HER2+ breast cancer diagnosed between 2015 and 2019 were reviewed in this single institution retrospective study. Patients who received dual HER2‐targeted treatment with chemotherapy were included, and HER2 status before and after neoadjuvant therapy was interrogated. Results A total of 163 female patients were included in the analysis with a median age of 50 years. A pathologic complete response (pCR as defined by ypT0/is) was achieved in 102 (62.5%) of 163 evaluable patients. Among the 61 patients with residual disease after neoadjuvant therapy, 36 (59.0%) had HER2‐positive and 25 (41.0%) had HER2‐negative residual disease. Of the 25 patients with HER2‐negative residual disease, 22 (88%) of patients were classified as HER2‐low. After a median follow‐up of 3.3 years, patients who retained HER2‐positivity after neoadjuvant treatment had a 3‐year IDFS rate of 91% (95% CI, 91%–100%), while patients who lost HER2‐positivity had a 3‐year IDFS rate of 82% (95% CI, 67%–100%). Conclusion Almost half of patients with residual disease following neoadjuvant dual HER2‐targeted therapy plus chemotherapy lost HER2‐positivity. The loss of HER2‐positivity may not confer negative prognostic impact, although the results were limited by short follow‐up time. Further research on the HER2 status after neoadjuvant treatment may help guide treatment decisions in the adjuvant setting.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Incidence and prognostic impact of HER2‐positivity loss after dual HER2‐directed neoadjuvant therapy for HER2+ breast cancer

et al. 2023

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“…By proposing the analysis of EV as a circulating component in combination with cfDNA, the ONCE protocol enables the detection of ERBB2/HER2 biomarker in patients where the relevant biomarker signal presents at the transcriptional level would be missed by analysis of cfDNA only. Indeed, we showed that the ONCE protocol might be an informative approach to monitor ERBB2 in breast cancer patients without genomic ERBB2 amplification or patients that are HER2 positive at diagnosis and turn negative after multiple cycles of therapy (Bon et al., 2020; Branco et al., 2019).…”

Section: Discussionmentioning

confidence: 99%

Integrating extracellular vesicle and circulating cell‐free DNA analysis using a single plasma aliquot improves the detection of HER2 positivity in breast cancer patients

Mugoni,

Ciani,

Quaini

et al. 2023

J of Extracellular Bio

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Multi‐analyte liquid biopsies represent an emerging opportunity for non‐invasive cancer assessment. We developed ONCE (One Aliquot for Circulating Elements), an approach for the isolation of extracellular vesicles (EV) and cell‐free DNA (cfDNA) from a single aliquot of blood. We assessed ONCE performance to classify HER2‐positive early‐stage breast cancer (BrCa) patients by combining EV‐associated RNA (EV‐RNA) and cfDNA signals on n = 64 healthy donors (HD) and non–metastatic BrCa patients. Specifically, we isolated EV‐enriched samples by a charge‐based (CB) method and investigated EV‐RNA and cfDNA by next‐generation sequencing (NGS) and by digital droplet PCR (ddPCR). Sequencing of cfDNA and EV‐RNA from HER2‐ and HER2+ patients demonstrated concordance with in situ molecular analyses of matched tissues. Combined analysis of the two circulating analytes by ddPCR showed increased sensitivity in ERBB2/HER2 detection compared to single nucleic acid components. Multi‐analyte liquid biopsy prediction performance was comparable to tissue‐based sequencing results from TCGA. Also, imaging flow cytometry analysis revealed HER2 protein on the surface of EV isolated from the HER2+ BrCa plasma, thus corroborating the potential relevance of studying EV as companion analyte to cfDNA. This data confirms the relevance of combining cfDNA and EV‐RNA for HER2 cancer assessment and supports ONCE as a valuable tool for multi‐analytes liquid biopsies’ clinical implementation.

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Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer

Ivanova,

Porta,

D’Ercole

et al. 2023

Virchows Arch

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Since the release of the DESTINY-Breast04 (DB-04) trial findings in June 2022, the field of pathology has seen a renaissance of HER2 as a predictive biomarker in breast cancer. The trial focused on patients with metastatic breast cancer who were classified as “HER2-low,” i.e., those with immunohistochemistry (IHC) HER2 1 + or 2 + and negative in situ hybridization (ISH) results. The study revealed that treating these patients with trastuzumab deruxtecan (T-DXd) instead of the oncologist’s chosen chemotherapy led to outstanding improvements in survival. This has challenged the existing binary HER2 pathological classification system, which categorized tumors as either positive (overexpression/amplification) or negative, as per the ASCO/CAP 2018 guideline reaffirmed by ASCO/CAP 2023 guideline update. Given that DB-04 excluded patients with HER2 IHC score 0 status, the results of the ongoing DB-06 trial may shed further light on the potential benefits of T-DXd therapy for these patients. Roughly half of all breast cancers are estimated to belong to the HER2-low category, which does not represent a distinct or specific subtype of cancer. Instead, it encompasses a diverse group of tumors that exhibit clinical, morphological, immunohistochemical, and molecular variations. However, HER2-low offers a distinctive biomarker status that identifies a specific therapeutic regimen (i.e., T-DXd) linked to a favorable prognosis in breast cancer. This unique association emphasizes the importance of accurately identifying these tumors. Differentiating between a HER2 IHC score 0 and score 1 + has not been clinically significant until now. To ensure accurate classification and avoid misdiagnosis, it is necessary to adopt standardized procedures, guidelines, and specialized training for pathologists in interpreting HER2 expression in the lower spectrum. Additionally, the utilization of artificial intelligence holds promise in supporting this endeavor. Here, we address the current state of the art and unresolved issues in assessing HER2-low status, with a particular emphasis on the score 0. We explore the dilemma surrounding the exclusion of HER2-zero patients from potentially beneficial therapy based on traditional HER2 testing. Additionally, we examine the clinical context, considering that DB-04 primarily involved heavily pretreated late-stage metastatic breast cancers. We also delve into emerging evidence suggesting that extrapolating HER2-low status from the original diagnosis may lead to misleading results. Finally, we provide recommendations for conducting high-quality testing and propose a standardized pathology report in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

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Loss of HER2 amplification and disease prognosis after neoadjuvant treatment of HER2 amplified breast cancer

Cited by 8 publications

References 0 publications

Incidence and prognostic impact of HER2‐positivity loss after dual HER2‐directed neoadjuvant therapy for HER2+ breast cancer

Incidence and prognostic impact of HER2‐positivity loss after dual HER2‐directed neoadjuvant therapy for HER2+ breast cancer

Integrating extracellular vesicle and circulating cell‐free DNA analysis using a single plasma aliquot improves the detection of HER2 positivity in breast cancer patients

Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer

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