Use Of HER2-targeted Therapies Research Articles

Frequency of HER2-Low in breast cancer biopsies in Chile.

e13163 Background: In breast cancer (BC), human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker. Traditionally, the use of HER2-targeted therapies is reserved for BC that overexpress HER2, defined as immunohistochemical (IHC) expression of 3+ or 2+ with amplification of the gene encoding HER2, detected by in situ hybridization (ISH). Recently, the term HER2-Low, defined as the IHC expression of 1+ or 2+ with negative ISH, has gained relevance as a new predictive biomarker for the use of trastuzumab-deruxtecan. The frequency of HER2-Low BC in the Chilean population is unknown. The objective of this study is to show the frequency of HER2-Low BC in a Chilean center. Methods: Descriptive cross-sectional analysis of clinical records and biopsies of localized or metastatic invasive breast carcinoma performed at Clínica Santa María between January 2020 and December 2023. The IHC expression of the estrogen receptor (ER), progesterone receptor (PR), Ki-67, HER2, histological grade (G) and HER2 in situ hybridization (ISH) when appropriate. The frequency and characteristics of HER2-Low cases are described and compared with the surrogate clinicopathological subtypes luminal A, luminal B (HER2-Positive and Negative), HER2-Positive and Triple Negative (TN), according to the St Gallen Consensus Conference 2013. Results: Between January 2020 and December 2023, a total of 339 biopsies with invasive BC were identified, from which 104 (36.0%) met the definition of HER2-Low. The frequency of luminal B and luminal A that met the definition of HER2-Low was 54 (51.9%) and 40 (38.5%), respectively. Of the 253 biopsies classified as luminal, 94 (37.2%) met the definition of HER2-Low, while of the 36 biopsies classified as TN, 10 (27.8%) did. Luminal B HER2-Negative and TN surrogate subtypes that met the definition of HER2-Low had a higher frequency of G3 than their non-HER2-Low counterpart. Conclusions: In the population analyzed, a considerable percentage of cases meet the definition of HER2-Low. This has relevant therapeutic implications. Distribution of biopsies that meet HER2-Low criteria according to surrogate clinicopathological subtype of breast cancer. [Table: see text]

Abstract P1-18-09: Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program

Abstract Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. It is well-known that de novo metastatic HER2+ breast cancer patients have better outcomes that women with metastatic relapse. This could be related both to a lead time bias, as well as to an ATRESS (adjuvant therapy-related shortening of survival) phenomenon [1]. Indeed, cancer treatments induce increased both clonal selection, as well as globally tumor resistance and agressivity [2]. However, there is relatively limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2 targeted treatments on patterns of recurrence and outcomes of HER2+ MBC. Thus, the purpose of this study was to determine how and how long anti-HER2 targeted treatment in early setting impact outcomes of patients with HER2+ recurring BC. Methods: Since 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2017 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to 1st metastasis [TTM]) in patients with HER2+ MBC pretreated with trastuzumab in the (neo)adjuvant setting (aT) compared with trastuzumab-naïve patients and patients with de novo HER2+ MBC. Multivariate analyses adjusted for baseline demographic, prognostic factors, adjuvant treatment received and time to MBC. Results: Among the 23698 pts of the ESME database, 4145 were women treated in 1st line of a HER2+ MBC: 1716 pts (41%) had de novo and 2429 pts (59%) recurrent and 65% had Hormone Receptor (HR) + MBC; 53%, 26% and 21% had respectively 1, 2, or > 2 metastatic sites (64% visceral and 11% brain). With a median follow-up of 60.7 m, median OS is 42.4 m (95% CI: 40.1-45.0) for patients who relapsed. OS is significantly longer in de novo MBC: 64.7 m (95% CI: 60.2-73) (HRadjusted=0.68, 95% CI: 0.62-0.76, p < 0.0001). Among pts with recurrent MBC, 56% (1343) had received adjuvant trastuzumab (aT). As 1st-line therapy for MBC, 86 % of pts received HER2-targeted agents (74% T-based, 24% T-pertuzumab-based). Median TTM was 46.9 months (m): 57.6 m in HR+ and 30.2 m in HR-. Among pts with HR- diseases, 38% relapsed during the first 2 years of follow-up and 30% after 4 years (14.8%% and 56.9% in HR+ respectively). Among pts with recurrent MBC, crude median OS is inferior in pts who received aT, as compared to those who did not: 37.2 m (95% CI: 34.4-40.3) vs. 53.5 m (95% CI: 47.6-60.1), but this difference does not persist after adjustment for age, performans status, disease-free interval and number and type of metastatic sites in the multivariate model (HR=1.05, 95% CI: 0.91-1.22). A short disease-free interval (6-24 months compared to >48) remains, however, a strong adverse prognostic factor (HR=2.1, 95% CI: 1.82-2.50). Conclusions: The receipt of adjuvant trastuzumab does not predict for worse outcomes when adjusted to the other prognostic factors, among patients who relapsed during the 2008-2017 period. An ATRESS phenomenon is not suggested, although we cannot rule it out for those who relapsed within the initial 2 years. The much better prognosis of de novo MBC may be largely linked to lead time biases. Citation Format: Fanny Le Du, Matthieu Carton, Mahasti Saghatchian, David Perol, Barbara Pistilli, Etienne Brain, Delphine Loirat, Laurence Vanlemmens, Thomas Vermeulin, Christelle Levy, Anthony Goncalves, Mony Ung, Marie Robert, Anne Jaffre, Mathieu Robain, Suzette Delaloge, Véronique Dieras. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-09.

Trastuzumab emtansine for HER2-positive metastatic breast cancer: Outcomes from a whole-of-population Australian cohort

PurposeWe aim to describe the treatment patterns and overall survival (OS) outcomes in patients receiving trastuzumab emtansine (T-DM1) for HER2-positive metastatic breast cancer (HER2+MBC) in routine clinical care. MethodsRetrospective, whole-of-population cohort study of people initiating T-DM1 for HER2+MBC between October 2015 and May 2019 in Australia. We used dispensing claims to estimate time-to-T-DM1 initiation, duration of treatment, and treatments administered prior to and following T-DM1 therapy. We estimated OS from T-DM1 initiation and stratified results based on whether patients received first- or second-line T-DM1 treatment. We benchmarked outcomes to those reported in the pivotal, EMILIA trial. Results345 patients initiated T-DM1: 309 as second-line therapy for HER2+MBC and 36 as first-line therapy. 51% of patients had received endocrine therapy and 98% of second-line patients received pertuzumab prior to starting T-DM1. The median age was 57 years (53 in EMILIA); median time-to-T-DM1 initiation from start of HER2-targeted therapy for HER2+MBC was 11.6 months (IQR: 7.9–16.6); median duration of T-DM1 treatment was 6.5 months (3.1–13.5; 7.6 months in EMILIA), and median OS was 19.3 months (7.9–29.5; 29.9 months in EMILIA). ConclusionsOur findings highlight differences in patient characteristics (older, more previous pertuzumab therapy) and outcomes (shorter OS) from the T-DM1 pivotal trial and provide real-world estimates that can inform patient, clinician and policy, decisions around the use of HER2-targeted therapies in routine clinical care.

Access to HER2-targeted therapy at a tertiary care center in India: An evolution.

In a previous retrospective audit from our institution we reported that patients had limited access to HER2-targeted therapy due to financial constraints. Subsequently, the advent of biosimilar versions of trastuzumab and philanthropic support has potentially changed this situation. Herein, we reanalyzed and reported access to HER2-targeted therapy in a more recent cohort of patients. Medical records of new breast cancer patients registered in one calendar year were retrospectively reviewed, supplemented by online pharmacy data to extract information on receptor status, use of HER2-targeted therapy, and other relevant variables. Since not all HER2 immunohistochemistry (IHC) 2+ tumors underwent fluorescent in-situ hybridization (FISH) testing, we estimated the probable HER2 amplified from this group based on a FISH amplified fraction in those HER2 2+ tumors who did undergo FISH. Between January 2016 and December 2016, 4717 new BC patients were registered at our institution, of whom 729 (20.04%) had HER2 IHC 3+ tumors while 641 (17.62%) had HER2 IHC 2+ tumors. The final number of HER2 overexpressing/amplified tumors was estimated to be 928 (729 HER2 IHC 3+, 105 known FISH amplified, and 94 estimated FISH amplified), of whom 831 received treatment at our institution. Overall 474 (57.03%, 95% confidence interval [CI] 53.6-60.4) of these 831 patients received trastuzumab for durations ranging from 12 weeks to 12 months in the (neo)adjuvant setting or other durations in metastatic setting compared to 8.61% (95% CI 6.2-11.6) usage of HER2-targeted therapy in the 2008 cohort. Access to HER2-targeted therapy has substantially increased among patients treated at a public hospital in the past decade, likely due to the advent of biosimilars, the use of shorter duration adjuvant regimens, and philanthropic support. However, further efforts are required to achieve universal access to this potentially life-saving treatment.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5years. Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. Median follow-up as of June 2020 is 42months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function.

12069 Background: HER2-targeted therapies are associated with cardiotoxicity, mostly asymptomatic and reversible. The impact of withholding these therapies on breast cancer outcomes is unknown. SAFE-HEaRt trial was the first study to evaluate the safety of HER2-targeted agents in patients with reduced left ventricular ejection fraction (LVEF) receiving concomitant cardioprotective medications and close cardiac monitoring. We report the 3-year follow-up (f/u) results. Methods: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with asymptomatic LVEF 40-49%, were started on beta blockers (ß-blockers) and/or ACE inhibitors/ARBs, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. Results: Patients were accrued from 10/2013 to 12/2017 and median f/u as of 2/7/20 is 37 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. 24 patients were reconsented for long-term f/u. There were 23 evaluable patients (1 lost for f/u). Off study, 2 patients continued treatment with trastuzumab, 3 with trastuzumab and pertuzumab, and 3 with TDM-1 for metastatic disease. 1 of the 2 patients who had developed a CE with symptomatic heart failure (HF) died of progressive oncological disease, and the second had LVEF recovery on cardiac medications after completion of adjuvant HER2-targeted therapy. Almost 5 years later, she had an asymptomatic decline in her LVEF to 35% after deciding to stop her ß-blocker and ARB. Of the remaining 21 patients, 15 had recovery of their LVEF to ≥50%, 9 of whom remain on cardiac medications. 5 patients had stable LVEF 40-49% and remain asymptomatic on cardiac medications. Only 1 patient had symptoms suggestive of HF, with last documented LVEF stable at 45-50%, but she has not sought medical care for the last 15 months since relocating to another country. There were no new CE and no cardiac deaths. Mean LVEF was 45% at baseline, 46% at end of treatment, and 51.5% at long term f/u. Conclusions: Long-term f/u of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is essential for improved patient outcomes. Clinical trial information: NCT04143594 .

Abstract P4-05-10: Comparative analysis of genomic landscape reveals heterogeneity in HER2-positive primary breast cancers and residual disease following neoadjuvant therapy

Abstract Background: Neoadjuvant therapy is currently standard of care for patients with HER2-positive (HER2+) breast cancer. Patients with residual disease after neoadjuvant therapy have a higher risk of metastatic recurrence compared to patients achieving pathologic complete response (pCR). While both primary breast cancer and residual disease may harbor cancer cell subpopulations with high metastatic potential, residual disease after neoadjuvant targeted therapy may include larger subpopulations of therapy-resistant cells. A better understanding of the differences in genomic aberrations in residual disease following neoadjuvant therapy in comparison to primary breast cancer is essential to choice of novel post-neoadjuvant treatment strategy for HER2+ patients with residual disease. Methods: We are currently building a large ethnically diverse, breast cancer cohort with integrated genomic data. We analyzed clinical data of stage 1-3, HER2+ breast cancer. pCR after neoadjuvant therapy was defined as ypT0N0 or ypTisNo. Using the xT 595-gene panel (Tempus Labs, Inc.) with matched tumor-normal samples in a subset of the cohort, we evaluated genomic heterogeneity between HER2+ primary breast cancers and residual disease following neoadjuvant therapy. Results: There were 469 HER2+ early stage invasive breast cancer patients in the study cohort with a median follow-up of 6.0 years. The mean age at diagnosis was 53.6 (SD=13.4) years. 52.7% are European Americans and 39.2% are African Americans. 61.8% were hormone receptor-positive (HR+)/HER2+ and 37.7% were HR-/HER2+. Although patients undergoing neoadjuvant chemotherapy (n=191) had lager tumor and more nodal positive disease compared to patients undergoing adjuvant therapy (n=213), the two groups have similar recurrence-free survival rate (adjusted hazard ratio 0.88, 95% CI 0.50-1.55). In patients undergoing neoadjuvant therapy, 72 (37.7%) achieved pCR. Women with HR-/HER2+ tumors had higher pCR rate (58.9%), compared with 24.6% in women with HR+/HER2+ tumors (p<0.001). pCR was a very strong predictor for recurrence: the 5-year recurrence-free survival was 0.97 for patients with pCR in contrast to 0.75 for patients without pCR. Of the 38 patients whose tumor DNAs were sequenced to date, there were 23 primary tumors and 15 residual tumors. Compared to primary HER2+ tumors, residual tumors had lower frequency of somatic alterations in ERBB2 (33% vs. 74%, p=0.02), CDK12 (13% vs. 48%, p=0.039), and ATM (0% vs. 26%, p=0.063) compared to the primary tumors. The overall tumor mutational burden was 2.1 m/MB (range: 0.4-42.5) in primary tumors and 2.9 m/MB (0-12.5) in residual tumors (p=0.94). Median ERBB2 copy number is 10 (range: 2-20) in primary tumors and 3 (2-20) in residual tumors. Alterations in the CDK4 pathway (CDK4, CCND1, CDKN2A, and RB1) were more frequently detected among tumors with loss of ERBB2 amplification (50%) than tumors with ERBB2 amplification (10%, p=0.011), suggesting they may be mutually exclusive. In particular, 4 of the residual tumors had mutations in the CDK4 pathway and none co-occurred with ERBB2 amplification. Conclusions: These preliminary data support the importance of integrating genomic sequencing of residual tumors to identify potentially non-HER2 druggable targets as a post-neoadjuvant treatment strategy. Alternative approaches including addition of novel therapies such as CDK4 inhibitors may have the potential to reduce costs associated with extended use of HER2-targeted therapies when unlikely to improve overall survival for non-HER2 amplified tumors. Citation Format: Masaya Hattori, Dezheng Huo, Nike Beaubier, Padma Sheila Rajagopal, Toshio Yoshimatsu, Yonglan Zheng, Elisabeth Sveen, Galina Khramtsova, Fang Liu, Taylor Abboushi, Kevin White, Olufunmilayo Olopade. Comparative analysis of genomic landscape reveals heterogeneity in HER2-positive primary breast cancers and residual disease following neoadjuvant therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-10.

Abstract P1-19-34: The role of hormone receptor (HR) status on initial treatment choices and outcomes for human epidermal growth factor receptor (HER)-2 positive advanced breast cancer: A study of the southeast Netherlands advanced breast cancer (SONABRE) registry

Abstract Background Previously, we reported that patients with HR+/HER2+ advanced breast cancer diagnosed in 2007-2009 had a better overall survival (OS) than patients with HR-/HER2+ advanced breast cancer (SONABRE Registry, Lobbezoo et al. BCRT 2013). This differential outcome suggests an impact of biology and/or used systemic therapies. The objective of the current study was to present initial palliative systemic therapy choices and its impact on OS and progression-free survival (PFS) in patients diagnosed with HER2+ advanced breast cancer in the Netherlands in 2007-2017, stratified by HR status. Patients and methods From our ongoing SONABRE Registry, we selected all consecutive patients diagnosed with HER2+ advanced breast cancer in six hospitals in the Netherlands in 2007-2017. OS and PFS by HR status were obtained using the Kaplan-Meier method and compared by the log-rank test. The multivariable Cox proportional hazards model for OS and PFS on initial systemic therapy were stratified by HR status and included the potential prognostic variables age, cardiovascular disease, metastatic-free interval, initial metastatic sites, (neo-) adjuvant therapy and (type of) initial palliative systemic therapy. Results Of the 376 patients included, 221 (59%) patients were diagnosed with HR+/HER2+ and 155 (41%) with HR-/HER2+ advanced breast cancer. Patients with HR+/HER2+ disease were most frequently diagnosed with bone metastases (74%), whereas the majority of patients with HR-/HER2+ disease were diagnosed with visceral metastases (66%) as initial dominant metastatic site. Of patients with HR+/HER2+ disease, 95% received at least one line of palliative systemic therapy among which 56% initially included HER2-targeted based therapy. Among patients with HR-/HER2+ disease, 77% received systemic therapy of which 87% initially included HER2-targeted based therapy. Median OS was 29 months (95% CI: 24-34) for HR+/HER2+ and 17 months (95% CI: 14-22) for HR-/HER2+ disease (logrank p=0.03). In patients with HR+/HER2+ disease, initial endocrine therapy without HER2-targeted therapy (n=80) did not significantly impact OS (hazard ratio: 1.12, 95% CI: 0.75-1.68), even though it was associated with a shorter initial PFS (hazard ratio: 1.48, 95% CI: 0.94-2.34) when compared with initial HER2-targeted therapy plus chemotherapy (n=81). On the other hand, in patients with HR-/HER2+ disease, receiving initial chemotherapy without HER2-targeted therapy (n=15) was associated with a shorter OS (hazard ratio:2.15, 95% CI 1.11-4.16) and PFS (hazard ratio =3.15, 95% CI 1.37-7.24) when compared with receiving initial HER2-targeted therapy plus chemotherapy (n=97). Conclusions In this extended real-life study with a long follow-up, we confirmed our previous findings that among patients with HER2+ advanced breast cancer the HR+ subtype had a more favorable outcome. We were able to show a differential metastatic pattern by HR status underlining its biological relevance. Immediate use of HER2-targeted therapy had no statistically significant positive effect on OS in the HR+ subtype, in contrast to the positive effect of immediate HER2-targeting therapy in the HR- subtype. Translational studies are warranted to shed more light on the cross-talk between the HR and HER2 pathways to improve selection for HER2-targeted therapies. Citation Format: Sandra M.E. Geurts, Khava I.E. Ibragimova, Nathalie JA Teeuwen, Frans Erdkamp, Birgit EPJ Vriens, Marien O den Boer, M Wouter Dercksen, Manon JAE Pepels, Maaike de Boer, Vivianne CG Tjan-Heijnen. The role of hormone receptor (HR) status on initial treatment choices and outcomes for human epidermal growth factor receptor (HER)-2 positive advanced breast cancer: A study of the southeast Netherlands advanced breast cancer (SONABRE) registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-34.

Possibilities of therapeutic use of HER2-inhibitorsin metastatic colorectal cancer: a case report

Current landscape of personalized and molecular-driven approach to cancer treatment contributes to a rapid growth of novel biomarkers used for a targeted therapy. Amplification or over-expression of HER2 has been shown to play an important role in the development and progression of some cancers. Recent studies have shown that over-expression of HER2 is found in up to 5% of colorectal cancers (CRC). These findings led to active research of therapeutic use of HER2-targeted therapy in a subset of patients with metastatic CRC, especially in patients with wild-type RAS, who progressed on anti-EGFR targeted therapy. According to data from several published studies, the rate of objective responses, progression-free and overall survival in this subset of patients matches or exceeds same rates that are achieved while using BRAF-targeted therapies in BRAF-mutated metastatic CRC patients and immunotherapy used in subjects diagnosed with MSI-H tumors. Currently, there is no conclusive data on potential of HER2-targeted therapy in RAS-mutated CRC patients. In this paper, we report a case of durable objective response obtained on trastuzumab therapy in patient with metastatic CRC, mutation in 12 th exon of KRAS gene and over-expression of HER2 in 40% of tumor cells, after progression on several lines of chemotherapy and anti-angiogenic targeted therapy.

A Study of Hormone Receptor Status in Breast Carcinoma and use of HER2-Targeted Therapy in a Tertiary Care Center of India

Abstract Aims: The aim is to study the hormone receptor status, association of HER2 expression with prognostic factors and use of HER2-targeted therapy in North Indian breast cancer patients. Subjects and Methods: Immunohistochemistry reports of 288 breast cancer patients registered in the department of Radiotherapy, SMS Medical College, Jaipur in 2015–2016 were analyzed for estrogen receptor (ER), progesterone receptor (PR), and c-erb B-2 protein (HER2/neu) expression. Equivocal HER2 (2+) was further confirmed by fluorescent in situ hybridization (FISH). Number of patients receiving HER2/neu-targeted therapy was also studied. Results: For ER, positive status was more common (56%), whereas for PR and HER2/neu, negative status was more common (59% and 60% resp.). HER2 status was unknown for 25% patients. The percentage of equivocal HER2 (immunohistochemistry 2+) cases showing amplification on FISH was also high (56.7%). The percentage of eligible cases for targeted therapy actually receiving it was low (28%). The percentage of triple negative phenotype (ER-/PR-/HER2-) was high (29.8%). Triple-negative breast cancer phenotype was more common in young-aged premenopausal women but was not statistically significant. All HER2/neu + cases were infiltrating ductal carcinoma. HER2/neu expression was significantly higher with large tumor size (P = 0.001), high tumor grade (P < 0.001), advanced stage (P = 0.001), greater number of positive lymph nodes (P = 0.02), and ER/PR negativity (P < 0.001). Conclusions: Most of the breast cancer patients are ER and/or PR positive and HER2/neu negative. The percentage of triple-negative phenotype is higher. More than half of HER2/neu 2+ cases show amplification on FISH assay. The percentage of eligible patients actually receiving targeted therapy is low. HER2/neu protein expression is significantly higher with adverse features such as large tumor size, high grade, advanced stage, greater number of positive lymph nodes, and ER/PR negativity.

HER2 testing in gastric cancer diagnosis: insights on variables influencing HER2-positivity from a large, multicenter, observational study in Germany.

HER2 testing in metastatic gastric or gastroesophageal junction cancer (mGC/mGEJC) is standard practice. Variations in HER2-positivity rates suggest factors affecting test quality; however, the influence of patient-, tumor-, and laboratory-related factors on HER2-positivity rates remains unknown. This observational, prospective study collected routine HER2 testing data from 50 pathology centers in Germany (January 2013-December 2015). For each sample, HER2 status, primary tumor location, method of sample retrieval, and other patient- and tumor-related parameters were recorded. A model for predicting the probability of HER2-positivity was developed using stepwise multiple logistic regression to identify influencing factors. Documented positivity rates and corresponding predicted HER2-positivity probabilities were compared to identify institutes with deviations in HER2-positivity. Data from 2761 mGC/mGEJC routine diagnostic specimens included 2033 with HER2 test results (1554 mGC, 479 mGEJC); overall HER2-positivity rates across centers were 19.8% and 30.5%, respectively. HER2-positivity correlated most with Lauren classification, then HER2 testing rate, primary tumor location, sample type, and testing method (all p < 0.05). Three institutes had model-predicted HER2-positivity rates outside the 95% confidence interval of their documented rate, which could not be explained by sample and center characteristics. Results demonstrated the high quality of routine HER2 testing in the mGC/mGEJC cohort analyzed. This is the first study investigating parameters impacting on HER2-positivity rates in mGC/mGEJC in routine practice and suggests that assessment of HER2 testing quality should consider primary tumor location, testing method and rate, and tumor characteristics. Accurate identification of patients with HER2-positive mGC/mGEJC is essential for appropriate use of HER2-targeted therapies.

Abstract P6-16-08: Using continuing professional development (CPD) as an investigative tool to improve clinical practice and interdisciplinary team treatment

Abstract Background: Continued and rapid evolution of diagnosis and staging methods along with the development of new treatments has changed the decision-making process for cancer patients into a more complex task. In breast cancer, quality measures related to sentinel lymph node biopsy (SLNB), axillary dissection (AD), HER2 testing and use of HER2-targeted therapy, provide parameters for assessing care quality. We assessed the influence of quality improvement education (QIE) on alignment with BC quality indicators. Methods: 39 members of the interprofessional team at Inova (an integrated care network of 5 hospitals) participated in the QIE components. For a baseline Inova provided deidentified electronic medical records (EMR) data that included a total of 67 breast cancer patients treated between 12/1/16 – 2/28/17. The patients diagnosed with HER2+ breast cancer records were retrospectively reviewed for adherence to quality measures pertaining to HER2 testing, SLNB, AD, and treatment. Follow-up reviews were completed 6 months after the launch of the online component, which included 142 patients. Results: Patient and disease characteristics were generally similar across the 2 cohorts. At baseline, treatment selection for patients with advanced stage cancer was consistent. The original goal of the activity was to assess adherence to quality measures in breast cancer treatment, in our assessment stage the team discovered potential undersampling of sentinel lymph nodes in patients who underwent neoadjuvant chemotherapy for clinically node-positive, with 3 of 8 patients (37.5%) having only 1 or 2 lymph nodes sampled. The educational programming improved recognition of the risk of false negative rates of sampling under 2 lymph nodes in this setting. In addition, the Inova team recommended that the triage protocol be changed to include the medical oncologist earlier in the treatment decision making process in tandem with the surgeon. In the post-program patient data, 26 patients with clinically N1/N2 disease had neoadjuvant therapy and a SLN biopsy. Of these, 3 (11.5%) had only 1 lymph node sampled, suggesting an increased adherence to recommended sampling. The educational program also improved participant knowledge of the phase III APHINITY trial efficacy findings, which was consistent with an increase in the use of pertuzumab-containing adjuvant therapy for early breast cancer (use of TCHP, 0% vs 46% in the pre-program and post-program charts, respectively). In addition, participants in the educational programming increased awareness of the need for reflex testing in the event of an equivocal HER2 IHC result. In the post-program follow-up, no cases of equivocal HER2 IHC staining lacked reflex testing with FISH. Taken together, these findings are consistent with practice change following interventional medical education for incorporating best practices and emerging clinical data in the management of HER2-positive breast cancer. Citation Format: Harnden K, Hester D. Using continuing professional development (CPD) as an investigative tool to improve clinical practice and interdisciplinary team treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-16-08.

Abstract P5-20-03: Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcome in 2863 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program

Abstract Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. However, there is relatively limited real-world information on the impact of adjuvant Trastuzumab (aT) on patterns of recurrence and outcome of HER2+ MBC. Methods: In 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2014 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to next treatment [TNT]) in patients with HER2+ MBC pretreated with trastuzumab in the adjuvant setting (aT) compared with trastuzumab-naïve patients (nT) and patients with de novo HER2+ MBC (dn). Multivariate analyses adjusted for baseline demographic, prognostic factors and year of diagnosis (prior or after 2005, when aT was approved and widely administered in France for early HER2+ breast cancer). Results: Among the 15170 pts of the ESME database, 2863 (19%) were HER2+: 1093 pts (38%) had de novo and 1765 pts (62%) recurrent MBC; 63% were Hormone Receptor (HR) +; 54%, 25% and 21% had respectively 1, 2, or &amp;gt; 2 metastatic sites (68% visceral and 12% brain). Median time to 1st metastasis was 43.4 months (m) (95% CI: 24.6-84.4): 54 m in HR+ and 30 m in HR-. Among pts with recurrent MBC, 55% (995) had received aT. As 1st-line therapy for MBC, 90 % of pts received HER2-targeted agents (73% T-based). With a median follow-up of 46 m, median OS is 45 m (95% CI: 42.5-48). OS is significantly higher in de novo compared to recurrent MBC: 54 m (95% CI: 50.2-60.4) vs. 38.4 m (95% CI: 36.7-41.9), (p &amp;lt; 0.0001). Among pts with recurrent cancers, median OS is inferior in pts who had received aT, as compared to those who had not: 33.4 m (95% CI: 29.6-36.7) vs. 49.5 m (95% CI: 44.3-56.8), (p &amp;lt; 0.0001). Statistically significant differences persist after adjustment for age at MBC, disease-free interval, metastatic sites and RH status in the multivariate model (HR=1.45, 95% CI: 1.26-1.67) but not after adjustment for year of diagnosis (prior or after 2005) (HR=0.90, 95% CI: 0.70-1.15). Conclusions: These large-scale real-world data in patients with HER2+ MBC provide evidence that the survival outcome remain similar in patients with failure of adjuvant trastuzumab compared with trastuzumab-naïve patients after adjustment for year of diagnosis. De novo HER2+ MBC pts have the best outcomes. Data on clinical characteristics of metastasis and time to next treatment for the three subgroups will be presented at the meeting. Citation Format: Saghatchian M, Carton M, Piot I, Pérol D, Pistilli B, Brain E, Ghouadni A, Ricci F, Vanlemmens L, Loeb A, Levy C, Goncalves A, Dalenc F, Lefeuvre-Plesse C, Campone M, Jaffre A, Gourgou S, Cailliot C, Robain M, Dieras V. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcome in 2863 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-03.

Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer.

The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer has changed dramatically with the introduction and widespread use of HER2-targeted therapies. There is, however, relatively limited real-world information about the effectiveness and safety of trastuzumab emtansine (T-DM1) in Hong Kong Chinese patients. We assessed the efficacy and toxicity profiles among local patients with HER2-positive advanced breast cancer who had received T-DM1 therapy in the second-line setting and beyond. This retrospective study involved five local centres that provide service for over 80% of the breast cancer population in Hong Kong. The study period was from December 2013 to December 2015. Patients were included if they had recurrent or metastatic histologically confirmed HER2+ breast cancer who had progressed after at least one line of anti-HER2 therapy including trastuzumab. Patients were excluded if they received T-DM1 as first-line treatment for recurrent or metastatic HER2+ breast cancer. Patient charts including biochemical and haematological profiles were reviewed for background information, T-DM1 response, and toxicity data. Adverse events were documented during chemotherapy and 28 days after the last dose of medication. Among 37 patients being included in this study, 28 (75.7%) had two or more lines of anti-HER2 agents and 26 (70.3%) had received two or more lines of palliative chemotherapy. Response assessment revealed that three (8.1%) patients had a complete response, eight (21.6%) a partial response, 11 (29.7%) a stable disease, and 12 (32.4%) a progressive disease; three patients could not be assessed. The median duration of response was 17.3 (95% confidence interval, 8.4-24.8) months. The clinical benefit rate (complete response + partial response + stable disease, ≥12 weeks) was 37.8% (95% confidence interval, 22.2%-53.5%). The median progression-free survival was 6.0 (95% confidence interval, 3.3- 9.8) months and the median overall survival had not been reached by the data cut-off date. Grade 3 or 4 toxicities included thrombocytopaenia (13.5%), raised alanine transaminase (8.1%), anaemia (5.4%), and hypokalaemia (2.7%). No patient died as a result of toxicities. In patients with HER2-positive advanced breast cancer who have been heavily pretreated with anti-HER2 agents and cytotoxic chemotherapy, T-DM1 is well tolerated and provided a meaningful progression-free survival of 6 months and an overall survival that has not been reached. Further studies to identify appropriate patient subgroups are warranted.

Characteristics and Prognostic Factors for Patients With HER2-overexpressing Breast Cancer and Brain Metastases in the Era of HER2-targeted Therapy: An Argument for Earlier Detection

BackgroundAlthough brain metastases (BM) are associated with poor prognosis, patients with human epidermal growth factor receptor 2 (HER2) overexpressing (HER2+) breast cancer (BC) with BM who are treated with anti-HER2 therapy have a relatively longer survival after BM diagnosis compared with other subtypes and HER2+ patients previously untreated with anti-HER2 therapy. It is unclear if previously reported prognostic factors are applicable to patients with HER2+ BC in the era of HER2-targeted therapy. Patients and MethodsWe evaluated 100 consecutive patients with HER2+ BC with BM who underwent radiation therapy as primary BM treatment from January 2001 to December 2011 at Memorial Sloan Kettering Cancer Center by retrospective review. Patient characteristics at the time of BM diagnosis and their associations with time from BM to death were evaluated by Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. ResultsSignificantly better survival from BM was noted for patients with higher performance status, fewer BM lesions, continued use of HER2-targeted therapy after BM diagnosis, and better controlled extracranial metastatic disease. Absence of neurologic symptoms at BM diagnosis was significantly associated with fewer lesions, decreased use of whole brain radiotherapy, and longer survival in univariate and multivariate analysis (multivariate hazard ratio, 3.69; 95% confidence interval, 1.69-8.07). ConclusionOur finding supports the continued use of HER2-targeted therapy after BM diagnosis. In addition, future research on the clinical impact of detecting asymptomatic BM in patients with HER2+ BC, in terms of improving prognosis, quality of life, and avoidance of whole brain radiotherapy, is warranted.

Real-world practice patterns in community U.S. oncology practices: A quality improvement approach in HER2-positive breast cancer.

e18196 Background: In breast cancer (BC), quality measures related to care coordination (CC), HER2 testing (testing) and use of HER2-targeted therapy (Tx), provide parameters for assessing care quality. We assessed the influence of quality improvement education (QIE) on alignment with BC quality indicators. Methods: 20 community oncologists participated in an IRB-approved QIE program. At baseline, 200 randomly selected charts of women with HER2+ invasive BC were retrospectively reviewed for adherence to quality measures pertaining to testing, Tx and CC. The cohort participated in accredited QIE activities for developing action plans for improvement. Follow-up chart reviews were completed 6 months after the QIE. Results: Patient and disease characteristics were generally similar across the 2 cohorts. At baseline, documentation of cancer staging was 90%, ECOG functional status assessment was 67% and cardiac testing was 33%. Treatment in the adjuvant setting was most common, followed by neoadjuvant, and metastatic. Documentation of CC varied greatly across specialties, and was highest for primary care physicians. At follow-up, randomly selected charts (n=60 to date) revealed increases in documentation of patient assessments and care coordination. A shift towards increased treatment in the neoadjuvant setting was also observed. Conclusions: QIE interventions that engaged oncology teams showed a positive impact on documentation across several parameters. A complete analysis of follow-up charts (n=200) will be presented. [Table: see text]

Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: protocol detailing observations in a whole of population cohort

BackgroundThe management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited...

Abstract P5-09-01: Simulation in continuing professional development in oncologic care: Advancing evidence-based decisions in the management of HER2-positive metastatic breast cancer

Abstract Background: Breast cancer is the second leading cause of cancer death among women. The growth factor receptor HER2 is overexpressed in 20% to 30% of invasive breast cancers, and use of HER2-targeted therapies have improved responses and survival in patients with metastatic breast cancer (MBC). However, the choice of the most appropriate agents and their sequencing is crucial to maximizing beneficial patient outcomes. A study was conducted to determine if simulation-based educational interventions to address underlying clinical practice gaps could improve competence and performance of oncologists in the management of HER2-positive breast cancer. Methods: A cohort of US-practicing oncologists who participated in online simulation-based education was evaluated. The interventions consisted of two cases presented in a platform that allowed physician learners to assess the patient and choose from an extensive database of diagnostic possibilities matching the scope and depth of actual practice. Clinical decisions made by participants were analyzed using a sophisticated decision engine, and instantaneous clinical guidance was provided at each decision point employing current evidence-based and expert faculty recommendations. Participant decisions were collected after clinical guidance and compared with each user's baseline data using a 2-tailed paired T-test to provide P values for assessing the impact of simulation-based education on the clinical decisions made by participants as of 12/4/2014. Results: The assessment sample consisted of 123 oncologists who made clinical decisions within the simulation and proceeded to the concluding debrief section. As a result of clinical guidance provided through simulation, significant improvements were observed in several areas of management of patients with HER2-positive MBC, specifically: •35% improvement (P&amp;lt;.001) in the selection of the preferred treatment regimen (trastuzumab, pertuzumab, with a taxel) in the first-line setting •21% improvement (P=.003) in evidence-based treatment selection for individuals whose disease progressed on first-line therapy •A 35% decrease was seen in the number of participants who selected trastuzumab for individuals whose disease progressed on first-line therapy, which demonstrated an improvement in oncologists ability to select the most appropriate selection based on the current evidence-base •39% (P&amp;lt;.001) improvement in the number of oncologists who ordered adverse event counseling for the patient •Similarly, 33% more participants (P&amp;lt;.001) referred a patient for psychosocial counseling after clinical guidance The data gathered during simulation also provided insights into the remaining gaps, including the choice of the most appropriate, evidence-based first line HER2-targeted regimen in patients with MBC. Conclusion: This study showed improvements in evidence-based practice patterns of oncologists who were selecting therapeutic protocols for patients with HER2-positive MBC, thus demonstrating that simulation-based instruction can result in an increase in evidence-based clinical decisions and, therefore, may play a role in improving the quality of care and patient outcomes. Citation Format: Herrmann TL, Blevins D, Warters M, Peters P. Simulation in continuing professional development in oncologic care: Advancing evidence-based decisions in the management of HER2-positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-09-01.

HER2 FISH classification of equivocal HER2 IHC breast cancers with use of the 2013 ASCO/CAP practice guideline.

The status of human epidermal growth factor receptor 2 (HER2, ERBB2) determines the eligibility of breast cancer patients to receive HER2-targeted therapy. The majority of HER2 testing in the U.S. is performed using a combination of immunohistochemistry (IHC) screening followed by fluorescence in situ hybridization (FISH) for IHC equivocal cases. In 2013, the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) updated the guideline for HER2 testing. This study evaluates the impact of the 2013 ASCO/CAP updated guideline on final HER2 FISH classification of breast cancers with an equivocal IHC result. For each case, we reported a FISH result according to the 2013 updated guideline and recorded a separated result using the 2007 guideline for investigational purpose. McNemar's test and Bowker's symmetry test were used to compare the classifications by the two guidelines. Among 172 HER2 IHC 2+ equivocal cases, use of the 2103 guideline changed classifications in 36 cases (21%) when compared with the results expected by use of the 2007 guideline, and yielded a higher proportion of positive (28.5 vs. 23.3%) and equivocal (16.3 vs. 4.1%), and a lower proportion of negative (55.2 vs. 72.7%) cases (p<0.001). The major classification change with use of the updated guideline is from the HER2 FISH negative to equivocal in 26 cases (15%). Our study has shown that implementation of the 2013 ASCO/CAP updated guideline has significant impact on HER2 classification for breast cancers with an equivocal HER2 IHC result and therefore increased the use of HER2-targeted therapy. Our data have also shown that reflex FISH is effective for final classification of the IHC equivocal cases and that polysomy 17 (CEP17 copy number ≥3/cell) is present in a significantly higher proportion of cases with an equivocal HER2 FISH classification.

Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment.

BackgroundHuman epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome.MethodsIn order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib).ResultsFollowing 12 hours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons.ConclusionThis proteomic study highlights several proteins that are closely associated with early HER2-inhibitor response and will provide a valuable resource for further investigation of ways to improve efficacy of breast-cancer treatment.