TEST:

HER2DX

P=N/A, N=60, Recruiting, European Institute of Oncology

"Reveal Genomics, S.L...and the Istituto Europeo di Oncologia (IEO) today announced the start of an impact study of the HER2DX® test, the first genomic test in the world specialized in HER2+ breast cancer...The project, entitled "Prospective observational monocentric study to evaluate the impact of the HER2DX® assay on treatment decisions in patients with early-stage HER2+ breast cancer: HER2-BREAST-DX," aims to determine the impact of applying the test in medical decisions regarding treatment for patients diagnosed with localized HER2+ breast cancer (stage I-IIIA). These patients are candidates for either neoadjuvant treatment (prior to surgery) or adjuvant treatment (post-surgery). The project therefore seeks to advance the personalization of treatments."

The HER2DX assay revealed that all HER2+ DCIS cases were categorized as low-risk, with most cases showing high ERBB2 expression and a high predicted response to anti-HER2-based therapy. These findings underscore the underlying biology of HER2+ DCIS and its tumor immune microenvironment, indicating that HER2+ DCIS shares similar tumor biology with low-risk HER2+ breast cancer.

This is a retrospective study of paired samples from patients (pts) with hormone receptor-positive and HER2-negative (HR+/HER2-) EBC treated at Hospital Clinic of Barcelona between 2014 and 2023 and from the letrozole arm of SOLTI-1501 VENTANA trial (Adamo et al...All pts received POET for 2 to 12 weeks prior to surgery, with tamoxifen or aromatase inhibitors (AI), administered according to menopausal status... POET is a simple and secure treatment that can be administrated before surgery in HR+/HER2- EBC. The molecular profiling and dynamic evaluation of biological changes induced by POET could offer opportunities for a better understanding of the tumor´s sensitivity to endocrine therapy and could help guide and optimize treatment strategies in HR+/HER2- EBC.

ESMO Breast 2024) and following T-DM1 monotherapy in the second-line setting or beyond (Brasó-Maristany et al. The HER2DX ERBB2 mRNA score is strongly associated with long-term survival outcomes in metastatic HER2+ breast cancer treated with first-line THP. Notably, HER2DX identified patients with ERBB2-low disease, as the subgroup with the poorest outcomes in both PFS and OS. Further analyses will be presented at the conference.

While immune markers such as TILs and PD-L1 scores are not typically measured in HER2-positive breast cancers, this data opens up the possibility of rationally leveraging targeted therapies in this subset of immune and HER2-sensitive breast cancers, thus potentially avoiding chemotherapy in the future for this biologically selected group. This regimen holds promise as an effective, relatively non-toxic, and biologically-driven alternative to standard chemotherapy for patients with HER2- enriched subset of early breast cancer.

While most early-stage HER2-positive breast cancer patients benefit from combining trastuzumab monoclonal antibody with chemotherapy, the therapeutic response to various drug combinations varies across the HER2+ patient population...It offers recommendations on follow-up intervals, treatment plans, and the duration of drug therapy. This review examines the literature and analyzes studies applying HER2DX to guide the comprehensive treatment and predict prognosis in HER2+ breast cancer patients, aiming to promote the widespread use of HER2DX in individualized treatment.

P3 | N=808 | CLEOPATRA (NCT00567190) | Sponsor: Genentech, Inc. | "REVEAL GENOMICS S.L...released further evidence supporting HER2DX, the world’s first specialized genomic test for HER2+ breast cancer. These results were obtained in collaboration with F. Hoffmann-La Roche Ltd (Basel, Switzerland) after analyzing HER2DX in tumor samples from the CLEOPATRA phase III clinical trial (NCT00567190)....For the first time, the investigators evaluated the ability of the HER2DX ERBB2 mRNA score to predict long-term survival outcomes in 214 patients treated with THP in the pivotal CLEOPATRA phase III trial3. The results showed a strong association of HER2DX ERBB2 mRNA score with PFS and OS....Detailed results of this study will be presented at an upcoming medical congress and submitted for publication."

Multigene prognostic assays have become essential tools in the management of EBC, providing crucial information for risk stratification.

Our findings demonstrate the significant impact of HER2DX on clinical management decisions in early HER2+ BC, prompting oncologist to modify treatment strategies based on its results.

Thirdly, the model was externally validated in 418 patients with stage 1-3 eTNBC undergoing neoadjuvant taxane-based chemotherapy without anthracycline/cyclophosphamide and pembrolizumab from 2 external cohorts: i) WSG-ADAPT-TN phase II study (NCT01815242) and ii) MMJ-CAR-2014-01 study (NCT01560663). TNBC-DX genomic test predicts response to neoadjuvant taxane-carboplatin chemotherapy in eTNBC, and helps forecast the patient´s long-term survival in the absence of neoadjuvant anthracycline, cyclophosphamide, and immunotherapy.

HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.

Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

"REVEAL GENOMICS, S.L... announced the results of the study 'HER2DX ERBB2 mRNA assay Following Trastuzumab-Based Chemotherapy in HER2-Positive Advanced Gastric Cancer' presented at ESMO Gastrointestinal Cancers Congress 2024 in Munich, showing that HER2DX genomic test demonstrates significant potential in refining patient selection for trastuzumab-based chemotherapy in HER2-positive advanced gastric cancer."

Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

"REVEAL GENOMICS, S.L...has announced the start of a prospective study in collaboration with the Dana-Farber Cancer Institute (Dana-Farber). This trial will evaluate the turnaround time of the HER2DX genomic test to determine its feasibility in clinical practice in the US....The study will also examine how the HER2DX test results influence therapeutic decisions by Dana-Farber physicians for patients with stage I-III HER2+ breast cancer, and the confidence levels of both patients and physicians before and after the test."

P=N/A; N=304; Not yet recruiting; Sponsor:Fundacio Clinic Barcelona

"REVEAL GENOMICS...announced the forthcoming prospective validation of its groundbreaking diagnostic tool HER2DX® within the framework of the ongoing CompassHER2 pCR Trial."

The HER2DX ERBB2 mRNA assay demonstrates significant potential in refining patient selection for T-CT in HER2-positive AGC. Further research of the assay with novel anti-HER2 treatments seems warranted.

The TROP2 antibody-drug conjugate sacituzumab govitecan (SG) demonstrated antitumor activity with a 5.5-month median PFS in endocrine refractory HR+ mBC... Analyzing biomarkers of interest in pts with HR+ mBC unveiled diverse patterns, without associations with OS. Patient characteristics.

In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.

P=NA | N=NA | "MEDSIR...presenting the results of two sub-studies focused on biomarkers: transFal, focused on patients with HR+/HER2- advanced breast cancer and METSGain, centered on patients with early breast cancer....Notably, high expression of Ki67 and CDK6, along with elevated ctDNA density at baseline, were correlated with shorter progression-free survival and overall survival. These findings illuminate potential avenues for understanding and overcoming resistance to CDK4/6 inhibitors, marking a significant step forward in personalized cancer treatment....Notably, patients with high-risk scores at surgery and less molecular changes after anti-HER2 therapy were more likely to develop metastasis, further highlighting the potential of HER2DX tool developed by REVEAL GENOMICS S.L. in guiding treatment decisions for HER2+ early breast cancer patients."

Conclusions Implementation of the HER2DX test is feasible and is being used across a wide range of clinical scenarios. The moderate alignment of HER2DX scores with standard clinical-pathological metrics, fitting expected patterns, provides new and meaningful insights for healthcare providers and pts.

Methods HER2DX was assessed on pre-treatment baseline FFPE tumor biopsies from 147 patients (pts) with stage I-III BC treated with trastuzumab-based CT at Hospital Clinic Barcelona...Conclusions The HER2DX pCR score outperforms MRI response as a predictor of pCR in HER2+ BC undergoing anti-HER2-based neoadjuvant chemotherapy. It reliably predicts pCR rates regardless of MRI response status, emphasizing its effectiveness in guiding neoadjuvant treatment optimization.

In pts who de-escalated the antiHER2, 23/29 received less antiHER2 (i.e. avoidance of pertuzumab or neratinib) and 6/29 shortened the duration of trastuzumab. In a scale from 1 (very unconfident) to 5 (completely confident), the mean confidence of physicians improved after the test (3.8 vs 4.6, p=0.002). Conclusions In this first prospective study, HER2DX impacted clinical care in early-stage HER2+ BC and improved the level of confidence of physicians.

Background In first-line metastatic HER2+ BC, the standard regimen of taxane-trastuzumab-pertuzumab (THP) is increasingly challenged by new therapies like antibody-drug conjugates. Conclusions The HER2DX ERBB2 mRNA score shows a significant association with improved survival in metastatic HER2+ BC patients treated initially with THP. Additional validation of the HER2DX ERBB2 score and integration of prognostic clinical factors might refine and optimize treatment strategies in this clinical setting.

Methods We analyzed standardized HER2DX pCR-scores from pts with stage I-III HER2+ BC receiving trastuzumab-based CT at the Hospital Clinic of Barcelona between Nov/21 - Jan/24...Conclusions The HER2DX pCR-score is significantly associated with pCR in pts with early-stage HER2+ BC undergoing anti-HER2-based NACT in a real-world setting. A low HER2DX pCR-score is consistently correlated with a reduced likelihood of achieving pCR, independently of the use of multiagent CT and clinico-pathological factors.

Background The 27-gene HER2DX test predicts pathological complete response (pCR) following neoadjuvant trastuzumab-based chemotherapy for HER2-positive (HER2+) breast cancer...The association remained consistent across all subgroups, regardless of tumor and nodal stage, pCR, and hormone receptor status (Table). Table: 1MO HER2DX risk-score continuous [HR, 95%CI] HER2DX risk-group [HR, 95%CI] Overall (n=2,031) 1.29 (1.16 – 1.42) 2.25 (1.43 – 3.54) Tumor stage T1 (n=1,005) 1.19 (1.07 – 1.34) 2.59 (1.35 – 4.95) T2-T3-T4 (n=1,026) 1.20 (1.10 – 1.30) 2.06 (1.32 – 3.23) Nodal stage N0 (n=1,192) 1.30 (1.16 – 1.46) 2.62 (1.54 – 4.45) N1-N2-N3 (n=576) 1.33 (1.06 – 1.65) No events in the low-risk Hormone receptor status Positive (n=1,334) 1.24 (1.15 – 1.34) 2.73 (1.73 – 4.32) Negative (n=697) 1.19 (1.08 – 1.32) 2.41 (1.37 – 4.22) Outcomes at surgery pCR (n=341) 1.18 (0.97 – 1.43) 1.91 (0.75 – 4.87) Residual disease (n=462) (1.09 – 1.33) 2.94 (1.66 – 5.18) No neoadjuvant treatment (n=1,228) 1.23 (1.13 – 1.34) 2.34 (1.39 – 3.94) Conclusions In patients with early-stage HER2+ breast cancer, HER2DX provides prognostic information on long-term outcomes beyond clinical-pathological variables and pCR status.

The HER2DX assay is highly reproducible and robust for the quantification of recurrence risk, pCR likelihood, and ERBB2 mRNA expression in early-stage HER2-positive breast cancer.

These data suggest that HER2DX risk-score in RD provides additional information on the likelihood of developing distant recurrences. In RD, high expression of immune and luminal genes was associated with a reduced risk, while high expression of proliferation genes was associated with a higher risk. Molecular changes after anti-HER2 therapy were mainly observed in RD of pts that did not relapse.

In patients with early-stage HER2+ breast cancer, HER2DX risk-score provides prognostic information beyond clinicopathological variables, including treatment regimen with or without trastuzumab.

"REVEAL GENOMICS, S.L...has announced the start of the DEFINITIVE study, led by FRCB-IDIBAPS, representing the first prospective trial for HER2DX. This landmark study will be pivotal in bolstering the clinical validations already acquired for HER2DX. The study seeks to secure the prospective validation for endorsement by clinical guidelines and ensure recognition and reimbursement across Europe."

Sponsored by CHUGAI PHARMACEUTICAL CO., LTD.

Sponsored by CHUGAI PHARMACEUTICAL CO., LTD.

Background : The PREDIX HER2 trial (n=202) compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (DHP) vs. trastuzumab emtansine (T-DM1) in HER2-positive breast cancer, resulting in similar pathologic complete response (pCR) rates. Conclusion : Using multiomics analysis in a randomized trial, we show that T-DM1 and standard dual HER2 blockade harbor strikingly distinctive biomarkers of response. Further validation in prospective biomarker-driven studies, integrated multimodal predictive models and studies with novel antibody-drug conjugates are warranted.

Background: The PREDIX HER2 trial, compared six courses of docetaxel, trastuzumab, and pertuzumab (DTP) vs. trastuzumab emtansine (T-DM1) as neoadjuvant treatment for HER2-positive breast cancer (BC). This study demonstrates that antibody–drug conjugates and standard treatment harbor strikingly distinctive biomarkers across tumor ecosystem. Further external validation and integrated ML model comprising all unimodal models are ongoing.

This study assessed the impact of HER2 heterogeneity on treatment response in stage II-III HER2+ breast cancer patients treated with neoadjuvant T-DM1 and pertuzumab. The HER2DX genomic assay demonstrates low variability within HER2+ breast cancer, supporting its reliability as a consistent tool for assessing prognosis, the probability of pCR and ERBB2 quantitative expression.

Standardized HER2DX was evaluated centrally using RNA from baseline FFPE tumor biopsies from the WSG-ADAPT-TN study (NCT01815242), a multicenter phase II trial that randomized 336 patients with stage I–III early TNBC to 12-weeks of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 d1,8 every 3 weeks (arm A) versus nab-paclitaxel 125 mg/m2 plus carboplatin AUC2 day 1,8 every 3 weeks (arm B). The HER2DX genomic test in TNBC provides valuable insights into the response and survival following neoadjuvant taxane-based chemotherapy in the absence of immunotherapy. The development of a tailored genomic assay for TNBC is currently in progress.

The inferior pCR rates among cases classified as ITH-HER2 translated into numerically inferior outcomes for both EFS and iDFS. The number of events is small; therefore, our results are exploratory. Selecting pts whose tumors lack ITH-HER2 can increase the chances of achieving RCB 0/I with neoadjuvant TDM1 + pertuzumab.

The integration of intrinsic molecular subtypes with stage or HER2DX risk-score predicts site-specific metastatic risk in HER2-positive BC, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.

P2 | "In IgG-high tumors, the proportion of TLS+ tumors was 61.6% compared to 38.4% TLS-negative (p<0.001) Conclusions The B-cell/IGG signature is a GE pattern strongly associated with TLS across cancer types, even independently of TILs. This signature could serve as a valuable tool for precisely measuring TLS and predicting clinical outcomes and response to immunotherapy in cancer patients."

Patients (pts) with newly diagnosed stage I-IIIA HER2+ BC and PET evaluable lesions were randomized (1:4) to receive either docetaxel (T), carboplatin (C), and HP (group A) or HP ± endocrine therapy (ET) (group B). Conclusions HER2DX predicts pCR following neoadjuvant HP-based therapy (with or without chemotherapy) and identifies pts with a higher risk of recurrence. This assay might help individualize HP-based therapy in early HER2+ BC.