Abstract P2-10-16: Quantitative HER3 protein expression and PIK3CA mutation status in matched samples from primary and metastatic breast cancer tissues and correlation with time to recurrence

10557 Background: Selection of patients for treatment with trastuzumab is currently based on the semi-quantitative measurement of HER2 protein expression (IHC) or gene amplification (FISH). We made quantitative measurements of HER2 expression and homodimerization using a novel assay, eTag, and correlated them with overall survival (OS) and time-to-progression (TTP) following trastuzumab treatment in a cohort of patients with metastatic breast cancer (MBC). We also examined the benefit of concomitant chemotherapy (CT) depending on quantitative HER2 expression. Methods: The Jules Bordet cohort (Brussels, Belgium, N=71) had MBC and prior treatment with at least two CT regimens. Patients received trastuzumab alone or combined with predominantly paclitaxel. Independent medical data review and central confirmation of HER2 overexpression by FISH (N=64) or IHC (N=7) were mandatory. The eTag assay was used to quantitate HER2 protein expression and HER2:HER2 dimers in FFPE specimens. eTag measurements were correlated with OS and TTP using Kaplan-Meier and Cox Proportional Hazards regression analyses. Results: Cox analyses identified three independent correlates of OS and TTP: number of metastatic sites (HROS = 2.4/site, 95%CI 1.5–3.9, p = 0.00019), treatment with trastuzumab only (HROS = 2.8, 95%CI 1.1–7.3, p = 0.036), and HER2 expression level (HROS = 0.24/log10(HER2), 95%CI 0.09–0.7, p = 0.0058). Patients with high HER2 (above median expression) experienced better OS than those with low HER2 (HR 0.24, p = 0.0014). Patients with high HER2 expression did not benefit from added CT (HR = 0.95, 95%CI 0.24–3.8, p = 0.94), while patients with low HER2 expression did (trastuzumab alone HR 4.4, 95% CI 1.3–18, p = 0.018). Similar results were observed for HER2:HER2 dimerization. Conclusions: Within a population of patients selected by FISH or IHC to receive trastuzumab, higher HER2 expression or HER2:HER2 dimerization correlated with better outcomes. Patients with high HER2 expression derived no benefit from concomitant CT, while patients with low HER2 expression benefited significantly from the addition of CT to trastuzumab. No significant financial relationships to disclose.

Download Full-text

Quantitative measurements of p95HER2 (p95) and total HER2 (H2T) protein expression in patients with trastuzumab-treated, metastatic breast cancer (MBC): Independent confirmation of clinical cutoffs.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.586 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 586-586 ◽

Cited By ~ 1

Author(s):

W. Biernat ◽

R. Duchnowska ◽

B. Szostakiewicz ◽

J. Sperinde ◽

M. Haddad ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Protein Expression ◽

Metastatic Breast ◽

Quantitative Measurements ◽

Independent Confirmation

Download Full-text

Quantitative HER2 measurement and PI3K mutation profile in matched primary and metastatic breast cancer tissues.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.614 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 614-614

Author(s):

Weidong Huang ◽

Jonathan F. Lara ◽

Richard Michaelson ◽

Xiu Sun ◽

Pierfranco Conte ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Catalytic Domain ◽

Pik3ca Mutation ◽

Metastatic Breast ◽

Her2 Status ◽

Her2 Positive ◽

Pik3ca Mutations ◽

Meta Analyses ◽

Negative Conversion

614 Background: HER2 status of primary breast cancer (PBC) is routinely used to determine systemic treatment for metastatic breast cancer (MBC) patients. Discordance rates of HER2 status between PBC and MBC range from 5.5% to 29% based on published meta-analyses. The clinical benefit of re-assessing HER2 in MBC tissues remains controversial. In this study, we measured quantitative HER2 expression in matched PBC and MBC tissues and correlated changes of HER2 with mutations in the catalytic domain of PI3 kinase(PIK3CA). Methods: Total HER2 protein expression (H2T) was quantified by the HERmark assay in 41 matched PBC and MBC formalin-fixed, paraffin-embedded specimens. PIK3CA mutation status in exons 9 (E545K and E542K) and 20 (H1047R) was determined using a validated pyrosequencing assay. Results: MBC samples included 5 lymph node, 13 viscera, 6 brain, and 17 soft tissue lesions (N=41). 27 (66%) cases showed higher H2T in MBC than in matched PBC; and 14 (34%) cases had higher H2T in PBC than in matched MBC, indicating an overall increase of H2T in matched MBC lesions (fold change 0.25-17.57; p=0.005, paired Wilcoxon rank sum test). HER2 positive conversion (HERmark negative/equivocal in PBC, but positive in matched MBC) was found in 6 (15%) cases, while HER2 negative conversion (HERmark positive in PBC, but negative/equivocal in matched MBC) was seen in 2 (5%) cases. HER2 status was unchanged in 33 (80%) cases. PIK3CA mutations were detected in 13 (32%) of PBC and 19 (46%) of MBC samples. Among the HER2 positive conversion cases, PIK3CA mutation was identified in 50% (3/6) PBC and 67% (4/6) MBC, compared to 0% (0/2, PBC or MBC) in the HER2 negative conversion cases. Among cases with unchanged HER2 status, PIK3CA mutation was observed in 30% (10/33) PBC and 42% (14/33) MBC. Conclusions: Quantitative HER2 assessment revealed a 20% discordance in HER2 status between matched PBC and MBC tissues, with more frequent conversion from low HER2 in PBC to high HER2 in MBC. PIK3CA mutation was observed more frequently in patients who converted from HER2 negative PBC to HER2 positive MBC. These results suggest that re-assessment of biomarkers in MBC tissues may better inform the selection of therapeutic options for patients with MBC.

Download Full-text

Comparisons of survival time in BRCA-positive patients with metastatic breast cancer using electronic health records (EHRs).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13004 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13004-e13004

Author(s):

Yookyung Christy Choi ◽

Jerzy Edward Tyczynski ◽

Dongmu Zhang

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Survival Time ◽

Cancer Diagnosis ◽

Systemic Chemotherapy ◽

Metastatic Breast ◽

Breast Cancer Diagnosis ◽

Study Cohort ◽

Breast Cancer Patients ◽

Mutation Status

e13004 Background: BRCA is a hereditary genetic mutation associated with a higher risk of breast cancer at younger age. Generally, BRCA gene testing is done in perceived high-risk individuals, and different management approaches might be considered given the high risk of breast cancer. This study examines treatment outcomes among BRCA-positive, metastatic breast cancer patients with consideration of prophylactic management by using US nationwide EHR data. Methods: This was a retrospective cohort study using Optum EHRs. The study cohort includes female adults who underwent their first systemic chemotherapy for metastatic breast cancer between 2013-2018 with a BRCA positive test result prior to the systemic chemotherapy, with ≥ 6 months baseline period from the chemotherapy. Physicians’ notes captured in Natural Language Processing (NLP) were further used to construct the cohort. Patients were followed from the earliest breast cancer diagnosis date until a censoring event (death or end of observation period). Death information was provided with national death certificate data. Descriptive statistics were used for patient characteristics and a stepwise Cox Proportional Hazard (CPH) regression model was fit to compare survival time. Results: Of 3624 patients included in the cohort, median age at the earliest breast cancer diagnosis is 50 years old (IQR 43-59), and a total of 540 (14.9%) deaths was observed. Prior to systemic chemotherapy, 1430 (39.5%) received mastectomy/lumpsectomy. 571 (15.8%) received hormone therapy prior to systemic chemotherapy. 646 (17.8%) had a clinical record indicating a triple negative breast cancer (TNBC). 2196 (60.6%) received more than 1 line of chemotherapy. Overall median survival days in the study cohort was 3778 days from the earliest breast cancer diagnosis. Median survival days in those with ER/PR positive and with TNBC status were 4150 days and 3124 days, respectively. From the CPH model, age, tumor mutation status, and prior mastectomy/lumpectomy were identified as significant factors; Hazard Ratio (HR) with each 1 year older in age at diagnosis was 1.02 (95% CL 1.01-1.03), that of TNBC vs ER/PR positive status was 2.27 (95% CL 1.87-2.77) and that of those with prior surgery vs without was 0.567 (95% CL 0.457-0.703). Conclusions: This study demonstrated the utility of EHR database for survival analysis. In metastatic breast cancer patients with a known BRCA-positive status, age at the initial diagnosis, tumor mutation status, and prior mastectomy/lumpectomy were significant factors in survival time.

Download Full-text

Use of alpelisib in the treatment of hormone receptor positive metastatic breast cancer: An institutional experience.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15216 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15216-e15216

Author(s):

Tsering G. Lama Tamang ◽

Daniel Kyung ◽

Lauren Eisenbud ◽

Tianyi Tang ◽

Ritesh Parajuli ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Pik3ca Mutation ◽

Metastatic Breast ◽

Pi3k Pathway ◽

Real World Data ◽

Tumor Registry ◽

Hormone Receptor Positive ◽

Heavily Pretreated ◽

Institutional Experience

e15216 Background: Mutations in PI3K pathway is a known mechanism of resistance to endocrine therapy in breast cancer. Alpelisib is an alpha-specific PI3K inhibitor. Alpelisib with Fulvestrant is approved for treatment (Tx) of PIK3CA mutated HR+ metastatic breast cancer (MBC) that progress on hormonal therapy. Despite its approval by the FDA, real world data on the use of Alpelisib for the management of MBC is lacking. This abstract reviews the safety and efficacy of Alpelisib in the management of patients with MBC. Methods: A retrospective review of the tumor registry database at a single institution was conducted to identify patients with HR+ MBC. Detailed clinical and pathologic data of PIK3CA mutated patients treated with Alpelisib were obtained. Genomic profiling was done with Foundation One. Results: Table highlights the characteristics of the four patients. All were treated with Alpelisib and Fulvestrant after PIK3CA mutation was demonstrated. 3 patients were heavily pretreated with systemic Tx including CDK 4/6 inhibitors. All patients responded to Alpelisib and Fulvestrant despite treatment history. Mucositis, rash, hyperglycemia and pancytopenia were the observed adverse events (A/E). All A/E were adequately managed except in one patient that required discontinuation of Tx. None has clinically progressed. Conclusions: Our data suggests that Alpelisib and Fulvestrant is tolerated and improves outcomes in patients with HR+ MBC. Alpelisib and Fulvestrant could be an effective therapy in patients who have also progressed on systemic chemotherapy including CDK 4/6 inhibitors. Although our sample size is small, we hope that our experience could guide clinicians in the management of patients with HR+ MBC who harbor the PIK3CA mutation and are being treated with Alpelisib. [Table: see text]

Download Full-text