Neoadjuvant anti-HER2 Therapy Research Articles

Abstract CT064: Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived, and was followed for more than 6 months (p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events observed were considered related to the immunotherapy. Method: This Phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Study Size - Interim Analysis: Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: 1) HER2/neu positive and HLA-A*02; 2) Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy; 3) Exclude Stage IV; and 4) Completed at least 90% of planned trastuzumab-based therapy. Trial Objectives: 1) To determine if GP2 therapy increases IBCFS; 2) To assess the safety profile of GP2; and 3) To monitor immunologic responses to treatment and assess relationship to efficacy and safety. Study Status: The study has been initiated at a number of sites in the US. The study is also expected to be opened in Spain, Germany, and France. Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal S. Patel, Jaye L. Thompson, Mira S. Patel, F. Joseph Daugherty, Mothaffar F. Rimawi. Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT064.

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2-Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti-Human Epidermal Growth Factor Receptor 2 Therapy.

Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)-positive, early breast cancer. We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations). Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor-negative disease, and when using a more stringent definition of pCR (ypT0 ypN0). Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.

Abstract OT2-10-06: Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived and was followed for more than 6 months (p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed considered related to the immunotherapy. Method: This Phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Study Size – Interim Analysis: Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: 1. HER2/neu positive and HLA-A*02 2. Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy 3. Exclude Stage IV 4. Completed at least 90% of planned trastuzumab-based therapy Trial Objectives: 1. To determine if GP2 therapy increases IBCFS 2. To assess the safety profile of GP2 3. To monitor immunologic responses to treatment and assess relationship to efficacy and safety Contact information: Snehal Patel Greenwich LifeSciences, Inc. Stafford, TX Email: snehal.patel@greenwichlifesciences.com Website: greenwichlifesciences.com Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal Patel, Jaye Thompson, Mira Patel, F. Joseph Daugherty, C. Kent Osborne, Mothaffar Rimawi. Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-10-06.

Abstract P4-07-62: Real-World, Single-Center Experience on the Outcomes of Neoadjuvant Chemotherapy and Trastuzumab alone or in Combination with Pertuzumab in Human Epidermal Growth Factor Receptor 2 Breast Cancer Patients

Abstract Background: Neoadjuvant chemotherapy is the standard of care for early stage breast cancer. Human epidermal growth factor receptor 2 (HER2) positive disease constitutes a large proportion of breast cancer patients, and HER2 overexpression is associated with poor prognosis. The induction of HER2+ targeted therapies, such as trastuzumab and pertuzumab, has resulted in improved outcomes in HER2+ breast cancers. Neoadjuvant chemotherapy in combination with HER2 targeted therapies aims at achieving pathological complete response (pCR) and an improved survival. Methods: We performed a retrospective review of HER2+ breast cancer patients who were treated at Medanta – The Medicity Hospital, Gurugram, Haryana, India, between 2011 and 2021. A total of 108 HER2+ breast cancer patients who received neoadjuvant chemotherapy with platinum, anthracycline or taxane-based regimens, along with trastuzumab alone or in combination with pertuzumab, were included. Results: Of 108 enrolled patients, 66 and 42 patients received single-blockade (trastuzumab) and dual-blockade (trastuzumab and pertuzumab) neoadjuvant anti-HER2 therapy, respectively. The majority of patients were aged < 60 years. The patient populations were comparable in terms of clinical stage, hormone receptor status, histopathology category (IDC being most common) and Ki67 status for single- and dual-blockade groups. All patients had IHC3+/FISH+ HER2 expression. No significant (p=0.896) difference was observed for breast conserving surgery between the groups. A higher pCR rate after surgery was reported in the dual-blockade group versus single-blockade group (50% vs. 39.2%; p=0.271). The median follow-up duration was 21.9 and 15.2 months in the single-blockade and dual-blockade groups, respectively. For dual- vs. single- blockade groups, the 1-year OS rates were 100% vs. 100%, and 3-year OS rates were 100% vs. 98.48%. For dual- vs. single- blockade groups, the 1-year DFS rates were 100% vs. 95.45%, and 3-year DFS rates were 92.85% vs. 80.3%. Conclusion: Neoadjuvant chemotherapy with dual HER2-blockade had higher pCR and survival rates compared with the single HER2-blockade strategy in HER2 positive breast cancer. Table. Patient characteristics BCS, breast conserving surgery; ER, estrogen receptor; PR, progesterone receptor; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma. Citation Format: Ashok K. Vaid, Devender Sharma, Jyoti Wadhwa, Rajeev Agarwal, Kanchan Kaur, Shina Goyal, Dheeraj Gautam, Jyoti Arora, Sabhyata Gupta, Ashok Sen, Ruchika K. Goel, Shagun Mahajan. Real-World, Single-Center Experience on the Outcomes of Neoadjuvant Chemotherapy and Trastuzumab alone or in Combination with Pertuzumab in Human Epidermal Growth Factor Receptor 2 Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-62.

Real-life analysis of neoadjuvant-therapy-associated benefits for pathological complete response and survival in early breast cancer patients - role of trastuzumab in HER2+ BC and platinum in TNBC.

Neoadjuvant therapy, which aims to achieve a pathological complete response (pCR) for better overall survival (OS) has several advantages for patients with early breast cancer (eBC) and subtypes of HER2-positive (HER2+) and triple-negative breast cancer (TNBC). However, there has been no large-scale real-world investigation on the clinical outcomes associated with trastuzumab-based and platinum-based neoadjuvant treatments for patients with HER2+ and TNBC, respectively. Taiwan Cancer Registry and National Health Insurance Research Database were utilized in this study. Patients diagnosed with clinically lymph-node-positive (LN+) HER2+ or TNBC were identified for analysis. Logistic regression and Cox proportional hazard models were employed to estimate the adjusted odds ratios (aOR) of achieving pCR and adjusted hazard ratios (aHR) of overall survival associated with treatment agents, respectively. A total of 1,178 HER2+ eBC and 354 early TNBC patients were identified, respectively. Neoadjuvant trastuzumab significantly increased the pCR rates by 3.87-fold among HER2+ patients. Trastuzumab-associated survival benefit was found in HER2+ patients who achieved pCR (aHR [95% CI]: 0.30 [0.11-0.84]) but not in those without pCR (1.13 [0.77-1.67]). Among the TNBC patients, platinum was associated with a 1.6-fold increased pCR rate; however, it did not improve OS regardless of pCR status. Trastuzumab improved pCR and OS for patients with HER2+ subtype. Using platinum agents for TNBC patients increased pCR rates but was not linked to better survival. Optimal neoadjuvant anti-HER2 therapy for patients with HER2+ eBC and the introduction of novel therapy for patients with TNBC should be considered.

Using the HER2/CEP17 FISH Ratio to Predict Pathologic Complete Response Following Neoadjuvant Anti-HER2 Doublet Therapy in HER2+ Breast Cancer.

Clinical trials of HER2-directed therapy that omit neoadjuvant conventional chemotherapy for HER+ breast cancer demonstrate that a subset of patients still obtains a pCR. Identifying tumor characteristics which predict pCR may help select patients for de-escalated neoadjuvant dual HER2-targeted treatment without chemotherapy. This is the first study evaluating the HER2/CEP17 ratio by FISH as a biomarker to predict pCR among patients who received neoadjuvant anti-HER2 regimens without chemotherapy. Data from patients with locally advanced HER2+ breast cancer who received neoadjuvant dual HER2-targeted therapy without conventional chemotherapy from a single center was retrospectively reviewed. All patients were enrolled in one of 3 clinical trials evaluating chemotherapy de-escalation. Logistic regression modeling assessed for a relationship between the HER2/CEP17 FISH ratio obtained from baseline tissue biopsy and pCR based on pathology at the time of definitive breast surgery following neoadjuvant treatment. Following neoadjuvant treatment with dual HER2-targeted therapies in 56 patients, the probability of pCR was 73% among patients with a HER2 ratio of 13.1 compared to a probability of 38% among patients with HER2 ratio of 5.5 (OR 4.14, 95% CI 1.44-11.89; P = .012). This positive association persisted after controlling for different treatment regimens administered (OR 2.87, 95% CI 0.9-9.18, P = .020). These data found a positive association between the HER2/CEP17 FISH ratio and pCR following neoadjuvant dual HER2-targeted therapy without chemotherapy. Larger prospective studies are needed to validate the HER2 ratio as a biomarker to select patients for neoadjuvant dual anti-HER2 therapy without chemotherapy.

Predictive Role of CD36 Expression in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Trastuzumab.

Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere. In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib-based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568). High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy.

Abstract CT232: A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient received the 6 primary intradermal GLSI-100 injections (p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed considered related to the immunotherapy. Trial Design: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status, prior pertuzumab therapy and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: 1. HER2/neu positive and HLA-A*02 2. Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy 3. Exclude Stage IV 4. Completed at least 90% of planned trastuzumab-based therapy Trial Objectives: 1. To determine if GP2 therapy increases IBCFS 2. To assess the safety profile of GP2 3. To monitor immunologic responses to treatment and assess relationship to efficacy and safety Accrual: Site selection and study start-up is in progress at multiple sites. Target enrollment is 598 subjects. Contact information: Snehal Patel Greenwich LifeSciences, Inc. Stafford, TX Email: snehal.patel@greenwichlifesciences.com Website: greenwichlifesciences.com Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal S. Patel, Jaye Thompson, Mira S. Patel, F. Joseph Daugherty, C. Kent Osborne, Mothaffar F. Rimawi. A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT232.

Abstract 1776: Loss of estrogen receptor alters drug responsiveness and supports a basal-like phenotype in endocrine-resistant HER2+/ER+ breast cancer

Abstract At least 50% of human epidermal growth factor 2 (HER2) enriched breast cancer (BC) is estrogen receptor positive (ER+). In clinical trials, patients with HER2+ BC expressing ER respond poorly to neoadjuvant anti-HER2 therapy versus those lacking ER expression. Additionally, combining anti-HER2 with endocrine therapy (ET), like aromatase inhibitor (AI), does not significantly improve pathological complete response in HER2+/ER+ patients. In advanced or de novo HER2+/ER+ metastatic BC (MBC), treatment with ET plus anti-HER2 yields the highest 5-year overall survival. Unfortunately, in the real-world setting outside of clinical trials, just 23% of patients receive this combination, and nearly 40% receive ET alone. The clinical challenge associated with treating advanced HER2+/ER+ BC demands a better understanding of ER signaling and downstream pathways in HER2-driven BC. Our goal is to identify alternative targeted therapies and/or tailor therapeutic combinatorial strategies to treat and/or delay progression of HER2+/ER+ BC. In this study, we established two long-term estrogen (E2) deprived (LTED) HER2+/ER+ cell line models from BT-474 (BT) and MDA-MB-361 (MM) to mimic endocrine therapy resistance (ETR) to AI, and characterized the response of these cell lines to anti-HER2 and other ETs. We also performed whole-genome sequencing (WGS) and single-cell RNA sequencing (scRNAseq) to identify differences between parental and derived ETR-LTEDs. The ER expression was retained in BT-LTEDs but lost in MM-LTEDs as compared to parental cells. Additionally, ER transcriptional activity was confirmed by increased expression of ER-target genes upon E2 stimulation only in BT-LTEDs. However, both LTED variants were less responsive to fulvestrant and showed upregulation of pro-survival AKT signaling. Focusing on the now ER- MM-LTED model, WGS and targeted duplex sequencing identified a significant increase in exonic missense mutations, notably C>T and C>A. Several of the mutated genes encode for transcription and chromatin regulatory factors. scRNAseq analysis showed that MM-LTEDs shift from a luminal- to more basal-like phenotype, with enrichment of genes that regulate immune response and cell motility. Thus, loss of ER expression in MM-LTEDs on the mRNA and protein levels may explain observed intrinsic resistance to fulvestrant and gain of the basal-like phenotype. In summary, we report that our ETR BT- and MM-LTED models capture distinct ER-associated phenotypes of HER2+/ER+ BC. Additional studies are necessary to understand the functional significance of these missense mutations on the development of drug resistance in HER2+/ER+ BC. Ongoing studies are testing pharmacological inhibition of key upregulated genes associated with the basal phenotype to potentially delay disease progression and provide better treatments for ETR HER2+/ER+ BC. Citation Format: Shaymaa Bahnassy, Hillary Stires, Lu Jin, Stanley Tam, Yasmin J. Dunn, Brendan F. Kohrn, Lawrence A. Loeb, Manasi Balachandran, Mircea Podar, Matthew D. McCoy, Robert A. Beckman, Rebecca B. Riggins. Loss of estrogen receptor alters drug responsiveness and supports a basal-like phenotype in endocrine-resistant HER2+/ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1776.

A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01.

TPS1110 Background: GP2 is a biologic nine amino acid peptide of the HER2/ neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived and was followed from more than 6 months ( p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed considered related to the immunotherapy. Methods: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: HER2/neu positive and HLA-A*02; Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy; Exclude Stage IV; Completed at least 90% of planned trastuzumab-based therapy. Trial Objectives: To determine if GP2 therapy increases IBCFS; To assess the safety profile of GP2; To monitor immunologic responses to treatment and assess relationship to efficacy and safety. Accrual: Site selection and study start-up is in progress at multiple sites. Target enrollment is 598 subjects. Clinical trial information: 05232916.

Influencing factors of the recurrence after neoadjuvant therapy in HER2-positive breast cancer.

e12608 Background: HER2-positive breast cancer is the more suitable subtype to perform a neoadjuvant therapy with chemotherapy and antiHER2 therapy because a high pathologic response and significance survival. However, despite this high percentage of pathological responses, there are still recurrences that can affect survival. Methods: We analyze a cohort of 287 HER-2 positive breast cancer treated with neoadjuvant chemotherapy and antiHER2 therapy according to current guidelines, to find the factors that could induce a recurrence. Results: Median age was of 56 (28-89), median tumor size of 37 mm (12-140), 145 (50%) had nodal involvement, estrogen receptor positive in 152 patients (53%) and median ki67 expression of 41% (3-95). HER2 expression by inmunohistochemistry was 2+ in 83 patients (29%) and 3+ in 204 (71%). A total of 50% complete pathological response (pCR) rate was detected and 54 (18,8%) relapsed. 17 patients with pCR (12%) and 37 patients without pCR (25%) had a recurrence (OR 4,31, p: 0,003). The factors that most influenced the relapse in the group of patients with pCR were: the initial size (greater than 5 cm) 30% of relapses, the initial axillary involvement (19%) and the cases with HER2 +3 expression and estrogen receptor negative (17%). In the group without pCR, the relapse was more frequent in patients with HER2 +2 expression and estrogen receptor negative (40%), HER2 +3 expression and estrogen receptor negative (43%), initial tumor size greater than 5 cm (38%) and axillary involvement (38%). Conclusions: Although pCR continues to be the most important factor to avoid relapse, there are other factors that must be considered as determinants of relapse despite achieving a pCR. Initial size greater than 5 cm is a poor prognostic factor despite reaching a pCR with up to 30% relapses, so other adjuvant interventions should be considered after initial neoadjuvant treatment.

Clinical Outcomes of Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2 Breast Cancer Patients: A Single-Center Retrospective Study.

(1) Background: Neoadjuvant therapy is widely used to treat locally advanced breast cancer. It has been recently shown that it can also improve the prognosis of patients during the early stages of breast cancer. In the past, advanced breast cancer with positive Human Epidermal growth factor Receptor 2 (HER2+) resulted in poor prognoses; however, outcomes have since changed after the introduction of HER2-targeting therapy. Achieving pathological Complete Response (pCR) is the most important aim, as it is a predictor of long-term outcomes in high-risk breast cancer subtypes. (2) Methods: We performed a retrospective review of all breast cancer patients who were treated with neoadjuvant therapy at Taichung Veterans General Hospital (VGHTC) between 2010 and 2018. A total of 147 HER2+ breast cancer patients who underwent neoadjuvant chemotherapy involving anthracycline and taxane-based regimens were enrolled. Within that population, 95 and 52 cases received single-blockade (Trastuzumab) and dual-blockade (Trastuzumab and Pertuzumab) neoadjuvant anti-HER2 therapy, respectively. (3) Results: The dual-blockade therapy group displayed a significantly higher pCR rate after surgery as compared to the single-blockade group (63.5% vs. 43.2%, p = 0.019). Advanced stage, larger tumor size, lymph node involvement and HER2 expression status were associated with the pCR rate. The 4-year OS was 85.2% and 100% in the single-blockage and dual-blockade therapy groups, respectively (p = 0.041). (4) Conclusion: Anthracycline, followed by taxane-based neoadjuvant chemotherapy combined with the dual HER2-blockade, had a higher pCR rate and better outcome when compared with the single HER2-blockade strategy in locally advanced HER2 breast cancer.

Abstract P1-02-14: A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases

Abstract A comparative analysis of clinical and pathologic characteristics of HER2 positive breast cancer patients treated with adjuvant versus neoadjuvant antiHer2 therapy: an analysis of 397 cases. Introduction: Currently there are several anti-HER2 therapy options for patients with HER2 positive breast cancer. Surgery as an initial treatment is usually performed in patients with smaller, node negative tumors. Neoadjuvant therapy (NAT) is the treatment of choice for patients with higher stage disease. Detailed analysis of clinical and pathologic characteristics of patients who received adjuvant versus NAT anti-HER2 therapy has not been well elucidated. Objectives: A comparative analysis of clinical and pathologic findings including biomarker expression (ER, PR, HER2 and Ki67) was performed to determine if there were differences in tumor characteristics and clinical outcome in the two groups.Methods:We retrospectively analyzed data on HER2+ breast cancer patients treated with adjuvant and NAT anti-HER2 therapy from 2011 to 2017. Clinical and pathologic parameters including biomarker expression prior to the start of therapy were obtained from the electronic database after IRB approval. In the adjuvant group, patients were treated with initial surgery followed by anti-HER2 therapy plus chemotherapy. In the NAT group, anti-HER2 therapy plus chemotherapy was administered prior to definitive surgery. Types of anti-HER2 therapies and follow-up information were obtained from the electronic medical record. Results:We identified 258 (64.9%) patients who received NAT and 139 (35.0%) received adjuvant anti-HER2 therapy. Table 1.VariablesNeoadjuvant groupAdjuvant groupp-valueAgeBelow 40 years42 (16.2%)11(7.9%)0.02940 years and above Total216 (83.7%) 258128 (92.0%) 139Menopausal statusPremenopausalPostmenopausal Total113 (45.3%)136 (54.6%) 24935 (25.1%)104 (74.8%) 139<0.001Nodal status on biopsyNegativePositive Total31 (18.1%)140 (81.8%) 17117 (53.1%)15 (46.8%) 32<0.001Tumor size by imaging (cm)Mean + SD3.87+2.832.24+1.76<0.001Tumor grade123 Total5 (2%)78 (31.3%167 (66.8%) 2507 (5.3%)49 (37.6%)74 (56.9%) 1300.068HER2 by IHC0 and 1+ (FISH +)2+ (FISH+)3+ Total11 (4.2%)61 (23.8%)184 (71.8%) 2564 (3.5%)41 (36.6%)67 (59.8%) 1120.042HER2 FISH copy no.Mean +SD15.44 ± 8.2512.64 ± 6.470.007HER2 ratioMean SD6.35 ± 3.445.57 ± 3.560.046ER statusNegativePositive Total113 (43.9%)144 (56.0%) 25745 (35.1%)83 (64.8%) 1280.122Percent positive71.38 ± 33.3778.74 ± 29.040.042ER intensity1+2+3+ Total24 (16.9%)38 (26.7%)80 (56.3%) 1422 (2.6%)26 (34.2%)48 (63.1%) 760.001PR statusNegative Positive Total147 (57.1%)110 (42.8%) 25766 (51.9%)61 (48.0%) 1270.389Percent positive42.33 ± 34.5444.72 ± 32.890.645PR intensity1+2+3+ Total20 (18.5%)41 (37.9%)47 (43.5%) 10810 (17.5%)30 (52.6%)17 (29.8%) 570.012KI67 indexPercent positive49.44 ± 22.6638.56 ± 22.36<0.001Anti-HER2 therapyHerceptinHerceptin+ Perjeta Total72 (31.0)160 (68.9%) 23291 (89.2%)11 (10.7%) 102<0.001SurgeryTotal Partial BilateralModified radicalOther Total SurvivalAlive. Dead116 (44.95)75 (29.0%)25 (9.6%)38 (14.7%)04 (1.5%) 258 239 (92.6%) 19 (7.3%)55 (40.4%)56 (41.1%)18 (13.2%)5 (3.6%)02 (1.4%) 136 125 (89.9%) 14 (10.0%)0.002 0.458Conclusions:Patients who received NAT were significantly younger, premenopausal with more aggressive tumor biology (higher Ki67, HER2 expression). Recent advances in anti-HER2 therapy has improved the outcome of these patients despite having higher stage disease. Breast conserving surgery was higher in the adjuvant group since the tumors were smaller in size. There was no significant difference in overall survival when compared to the adjuvant group (p=0.458) Citation Format: Venetia Sarode, Tricia Rood, Yulun Liu, Yisheng Fang, Sunati Sahoo, Yan Peng, Helena Hwang, Marilyn Leitch, Barbara Haley. A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases [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 P1-02-14.

Abstract OT1-18-07: A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with an FDA-approved immunoadjuvant Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF, Sargramostim, Leukine) that stimulates an immune response targeting HER2/neu expressing cancers. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb clinical trial, no recurrences were observed in the HER2/neu positive adjuvant setting after median 5 years of follow-up, if the HLA-A*02 patient received the 6 primary intradermal GLSI-100 injections over the first 6 months (p = 0.0338) in a pre-specified subgroup analysis. Furthermore, the immunotherapy elicited a potent immune response measured by local skin tests and immunological assays. Of the 138 patients that have been treated with GLSI-100 to date over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed related to the immunotherapy. This Phase III trial aims to reproduce the Phase IIb trial and will explore the use of GLSI-100 as adjuvant therapy to increase invasive disease-free survival in HER2/neu positive and HLA-A*02 patients, post-surgery and following the first year of treatment with any trastuzumab-based therapy. Method: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy or an approved biosimilar, 6 intradermal injections of GLSI-100 or placebo (Bacteriostatic Saline/WFI) will be administered for the primary immunization series over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years of treatment. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. An interim analysis is planned, and patients will be stratified based on prior and current treatments. Study Size - Interim Analysis: Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in IDFS, 28 events will be required. An interim analysis for superiority and futility will be conducted when at least half of those events, 14, have occurred. This sample size provides 80% power if the annual rate of events in placebo-treated patients is 2.4% or greater. Eligibility Criteria: The patient population is defined by these key eligibility criteria: Trial Objectives: Contact information: Website: greenwichlifesciences.com. Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal S Patel, David B McWilliams, Christine T Fischette, Jaye Thompson, F. Joseph Daugherty, C. Kent Osborne, Mothaffar F Rimawi. A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy [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 OT1-18-07.

Abstract P4-06-02: Clinically feasible pharmacokinetic model of dynamic contrast-enhanced MRI is prognostic of recurrence free survival in breast cancer patients treated with neoadjuvant therapy

Abstract Background Dynamic contrast-enhanced (DCE) MRI is commonly used for diagnosis and treatment planning of cancers. Its main use is the identification of tumors in soft tissues, where the tumor progression-induced angiogenic changes result in leaky vasculature which is readily highlighted by contrast enhancement. While allowing tumor morphology assessment, DCE MRI also contains rich information on perfusion and permeability which can be modeled as a pharmacokinetic (PK) process, a subject of extensive investigation in the clinical research setting. Several breast DCE MRI studies have suggested that PK parameters might be indicative of response to therapy and recurrence. However, these studies rely on high temporal resolution DCE MRI for accurate PK modeling, which presents a hurdle to adoption in clinical settings where DCE MRI is acquired with low temporal resolution. Methods We present a novel two-parameter modeling framework which circumvents this temporal limitation, allowing kinetic parameters to be extracted from clinical DCE MRI containing 3-6 timepoints spaced 60-90 seconds apart. We sought to examine whether these kinetic parameters (hereafter KP1 and KP2) binned into "high" and "low" values had prognostic value in determining disease recurrence. KP1 reflects the rate of leakiness from vessels into extravascular space, while KP2 reflects the rate of the reverse process. A study was conducted with a cohort of 458 breast cancer patients treated with neoadjuvant therapy (NAT) in which 117 recurrences occurred. Model parameters were extracted from pre-treatment clinical DCE MRI with low temporal resolution. Univariate and multivariate (Cox Proportional Hazard; CPH) analyses were performed to test the prognostic value of covariates in predicting recurrence free survival (RFS). Results A CPH model was constructed that included age, receptor status, cancer stage, kinetic parameters, and pathologic complete response (pCR) as covariates (Table 1). KP2 and pCR were statistically significantly prognostic markers of RFS (p<0.05). KP1 was not a significant prognostic marker of RFS (p=0.055). Interestingly, KP2 had a hazard ratio (HR) similar to pCR (HR: -1.04 [-1.75, -0.33]; p<0.0039 vs. HR: -0.97 [-1.5, -0.44], p<0.00034). Using univariate analysis, we investigated whether KP2 was prognostic of recurrence. Patients were stratified by therapy type, whether they achieved pCR or had residual disease (RD), and by disease subtype. KP2 was found to be predictive of RFS for patients with RD after treatment with NAT chemotherapy (p<0.0004, n=241, log-rank test), but not for patients treated with anti-HER2 NAT (p=0.84, n=124) or patients that achieved pCR (p=0.68, n=139). KP2 was also found to be prognostic in Hormone Receptor+/HER2- patients with RD (p<0.012, n=151) and Hormone Receptor-/HER2+ patients treated with NAT chemotherapy (p<0.001, n=64). The parameter was not found to be prognostic in patients with triple-negative disease. Conclusions We developed a new prognostic imaging marker for disease recurrence in breast cancer patients treated with NAT that relies on only pre-treatment standard-of-care, low temporal resolution DCE MRI. Since the marker was found to have similar prognostic value in terms of hazard ratio as pCR, but in patients with RD, it could prove to be a powerful tool in patient management after surgery. Table 1.Results of Cox Proportional Hazard model.FactorHazard Ratio95% CIp-valueAge-0.01[-0.02, 0.01]0.51ER+-0.35[-0.85, 0.15]0.17HER2+0.02[-0.38, 0.41]0.93PR+0.05[-0.46, 0.56]0.85Stage II0.54[-0.62, 1.7]0.36Stage III1.08[-0.1, 2.27]0.074KP1-0.68[-1.38, 0.01]0.055KP2-1.04[-1.75, -0.33]0.0039pCR-0.97[-1.5, -0.44]0.00034 Citation Format: Joseph R Peterson, Tyler M. Earnest, Wei Huang, Hiroyuki Abe, John A Cole, Jr. Clinically feasible pharmacokinetic model of dynamic contrast-enhanced MRI is prognostic of recurrence free survival in breast cancer patients treated with neoadjuvant therapy [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 P4-06-02.

Abstract PD10-11: Keyriched-1- A prospective, multicenter, open label, neoadjuvant phase ii single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype

Abstract Background: De-escalating strategies seem promising in HER2-positive early breast cancer (EBC) and chemo-free regimens are thus of key interest. Recent data have underlined the role of tumor immunogenicity in response to de-escalated neoadjuvant anti-HER2 therapy. Therefore, the prospective single arm hypothesis-generating phase II KEYRICHED-1 trial (NCT03988036) investigates the pCR-rate in patients with HER2-enriched EBC receiving four cycles of the dual anti-HER2 blockade in combination with the checkpoint inhibitor pembrolizumab. Initial studies with dual antibody-based HER2 blockade alone were able to achieve pCR-rates of 20-40%, which did not quite match the pCR-rates obtained with concurrent chemotherapy. KEYRICHED-1 aims at achieving pCR-rates comparable to standard chemotherapy-containing regimens by incorporating appropriate molecular selection and immune oncology.. Methods: A total of 48 pre- and postmenopausal patients with newly diagnosed HER2 2+ or 3+ EBC (stage I-III) and HER2-enriched (HER2-E) subtype by PAM50 were enrolled in this single-arm study. All patients received four cycles of study treatment with pembrolizumab (200mg), trastuzumab biosimilar (Trazimera®, loading dose 8mg/kg bodyweight (BW), maintenance dose 6mg/kg BW), and pertuzumab (loading dose 840mg/kg BW, maintenance dose 420mg/kg BW) q21d. Primary endpoint was centrally confirmed pCR (ypT0/is, ypN0). The trial was planned as a Simon's two-stage design (null and alternative pCR were 40% and 60%); interim analysis after 16 patients had to show a pCR rate of at least 50% to continue recruitment.. Results: Between 05/2020 and 03/2021, 98 patients were screened. N=52 (55%) had HER2-E subtype, of whom 48 patients entered the treatment phase. Median patient age was 57 years (28-83). 65% had tumors > 2 cm and 30% positive lymph node status. Centrally confirmed pCR-rate in surgical specimens was 46% (95% CI 0.31-0.62) in the 43 patients of the per-protocol-population, and 52% (95%CI 0.37-0.67) in all 46 evaluable patients (local assessment; two pCRs verified only by core biopsy) (p=0.22 and p=0.06 for null hypothesis, respectively). Despite HER2-E subtype, no pCR was observed in the four patients with immunohistochemical (IHC) HER2 2+/ISH-positive status in contrast to 20/39 (51.2%) pCR in IHC HER2 3+ tumors. Centrally confirmed pCR-rate in HR+/HER2+ tumors was 38.5% compared to 58.5% in HR-/HER2+ tumors. No new safety signals were observed.. Conclusions: These are the first results of a neoadjuvant chemotherapy-free 12-week de-escalation anti-HER2-regimen with trastuzumab and pertuzumab in combination with the PD-1 inhibitor pembrolizumab in patients with a HER2-E EBC. In the context of the WSG ADAPT HER2+ de-escalation trials the observed pCR-rates compare favorably in HR+ as well as HR- HER2+ EBC. Moreover, KEYRICHED-1 demonstrates that with appropriate molecular patient selection clinically meaningful pCR-rates in the range of those obtained with longer, more toxic chemotherapy-containing regimens can be achieved. Citation Format: Sherko Kuemmel, Oleg Gluz, Mattea Reinisch, Athina Kostara, Iris Scheffen, Monika Graeser, Rachel Wuerstlein, Ulrike Nitz, Kerstin Luedtke-Heckenkamp, Andreas Hartkopf, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens Blohmer, Christine zu Eulenburg, Matthias Christgen, Stephan Bartels, Hans Kreipe, Enrico Pelz, Peter Schmid, Nadia Harbeck. Keyriched-1- A prospective, multicenter, open label, neoadjuvant phase ii single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype [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 PD10-11.

Abstract P2-13-03: KEYRICHED-1 - A prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype

Abstract Background: De-escalating strategies seem promising inHER2-positive early breast cancer (EBC) and chemo-free regimens are thus of keyinterest. Recent data have underlined the role of tumor immunogenicity inresponse to de-escalated neoadjuvant anti-HER2 therapy. Therefore, theprospective single arm hypothesis-generating phase II KEYRICHED-1 trial (NCT03988036)investigates the pCR rate in patients with HER2-enriched EBC receiving fourcycles of the dual anti-HER2 blockade in combination with the checkpointinhibitor pembrolizumab. Initial studies with dual antibody-based HER2 blockadealone were able to achieve pCR-rates of 20-40%, which did not quite match the pCRrates obtained with concurrent chemotherapy. KEYRICHED-1 aims at achieving pCR-ratescomparable to standard chemotherapy-containing regimens by incorporating appropriatemolecular selection and immune oncology. Methods: A total of 48 pre- and postmenopausal patients with newly diagnosed HER22+ or 3+ EBC (stage I-III) and HER2-enriched (HER2-E) subtype by PAM50 wereenrolled in this single-arm study. All patients received four cycles of studytreatment with pembrolizumab (200mg), trastuzumab biosimilar (Trazimera®,loading dose 8mg/kg bodyweight (BW), maintenance dose 6mg/kg BW), and pertuzumab(loading dose 840mg/kg BW, maintenance dose 420mg/kg BW) q21d . Primaryendpoint was centrally confirmed pCR (ypT0/is, ypN0). The trial was planned asa Simon's two-Stage design (null and alternative pCR were 40% and 60%); interimanalysis after 16 patients had to show a pCR rate of at least 50% to continuerecruitment. Results: Between 05/2020 and 03/2021, 98 patients werescreened. N=52 (55%) had HER2-E subtype,of whom 48 patients entered thetreatment phase. Median patient age was 57 years (28-83). 65% had tumors > 2cm and 30% positive lymph node status. Centrally confirmed pCR rate in surgicalspecimens was 46% (95% CI 0.31-0.62) in the 43 patients of the per protocolpopulation, and 52% (95%CI 0.37-0.67) in all 46 evaluable patients (localassessment; two pCRs verified only by core biopsy) (p=0.22 and p=0.06 for nullhypothesis, respectively). Despite HER2-E subtype, no pCR was observed in the 4patients with immunohistochemical (IHC) HER2 2+/ISH-positive status in contrastto 20/39 (51.2%) pCRs in IHC HER2 3+ tumors. Centrally confirmed pCR rate in HR+/HER2+tumors was38.5% compared to 58.5% in HR-/HER2+ tumors. No new safety signals wereobserved. Conclusions: These are the first results of a neoadjuvant chemotherapy-free12-week de-escalation anti-HER2-regimen with trastuzumab and pertuzumab incombination with the PD-1 inhibitor pembrolizumab in patients with a HER2-E EBC.In the context of the WSG ADAPT HER2+ de-escalation trials the observed pCRrates compare favourably in HR+ as well as HR- HER2 EBC. Moreover, KEYRICHED-1demonstrates that with appropriate molecular patient selection clinicallymeaningful pCR rates in the range of those obtained with longer, more toxicchemotherapy-containing regimens can be achieved. Citation Format: Sherko Kuemmel, Oleg Gluz, Mattea Reinisch, Athina Kostara, Iris Scheffen, Monika Graeser, Kerstin Luedtke-Heckenkamp, Andreas Hartkopf, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens Blohmer, Christine zu Eulenburg, Matthias Christgen, Stephan Bartels, Hans Kreipe, Enrico Pelz, Peter Schmid, Nadia Harbeck. KEYRICHED-1 - A prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype [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 P2-13-03.

Neoadjuvant Treatment with HER2-Targeted Therapies in HER2-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis.

Simple SummaryHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer causes more aggressive progression of disease and poorer outcomes for patients. HER2-targeted medicines used as neoadjuvant systemic therapy could improve clinical outcomes in early-stage or locally advanced breast cancer patients. The purpose of this systematic review and network meta-analysis was to identify the neoadjuvant anti-HER2 therapy with the best balance between efficacy and safety. We found that trastuzumab emtansine + pertuzumab + chemotherapy had a high pathologic complete response with a low risk of adverse events compared to other neoadjuvant anti-HER2 regimens, while the pertuzumab + trastuzumab + chemotherapy regimen showed the highest disease-free survival. However, further trial data on neoadjuvant regimens with trastuzumab emtansine are needed to confirm these findings.This systematic review aimed to identify neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapies with the best balance between efficacy and safety. Methods: A network meta-analysis was applied to estimate the risk ratios along with 95% confidence intervals (CIs) for pathological complete response (pCR) and serious adverse events (SAE). A mixed-effect parametric survival analysis was conducted to assess the disease-free survival (DFS) between treatments. Results: Twenty-one RCTs with eleven regimens of neoadjuvant anti-HER2 therapy (i.e., trastuzumab + chemotherapy (TC), lapatinib + chemotherapy (LC), pertuzumab + chemotherapy (PC), pertuzumab + trastuzumab (PT), trastuzumab emtansine + pertuzumab (T-DM1P), pertuzumab + trastuzumab + chemotherapy (PTC), lapatinib + trastuzumab + chemotherapy (LTC), trastuzumab emtansine + lapatinib + chemotherapy (T-DM1LC), trastuzumab emtansine + pertuzumab + chemotherapy(T-DM1PC), PTC followed by T-DM1P (PTC_T-DM1P), and trastuzumab emtansine (T-DM1)) and chemotherapy alone were included. When compared to TC, only PTC had a significantly higher DFS with a hazard ratio (95% CI) of 0.54 (0.32–0.91). The surface under the cumulative ranking curve (SUCRA) suggested that T-DM1LC (91.9%) was ranked first in achieving pCR, followed by the PTC_T-DM1P (90.5%), PTC (74.8%), and T-DM1PC (73.5%) regimens. For SAEs, LTC, LC, and T-DM1LC presented with the highest risks (SUCRA = 10.7%, 16.8%, and 20.8%), while PT (99.2%), T-DM1P (88%), and T-DM1 (83.9%) were the safest regimens. The T-DM1PC (73.5% vs. 71.6%), T-DM1 (70.5% vs. 83.9%), and PTC_T-DM1P (90.5% vs. 47.3%) regimens offered the optimal balance between pCR and SAE. Conclusions: The T-DM1PC, T-DM1, and PTC_T-DM1P regimens had the optimal balance between efficacy and safety, while DFS was highest for the PTC regimen. However, these results were based on a small number of studies, and additional RCTs assessing the efficacy of regimens with T-DM1 are still needed to confirm these findings.

Pathologic complete response to neoadjuvant anti-HER2 therapy is associated with HER2 immunohistochemistry score in HER2-positive early breast cancer.

To evaluate whether pathologic complete response (pCR) to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapy is dependent on the HER2 immunohistochemistry (IHC) score.A total of 181 HER2-positive early breast cancer patients who had received neoadjuvant anti-HER2 therapy were included in this study. Associations were examined between IHC score and tumor pCR status (commonly defined by ypT0+ypN0, ypT0/is+ypN0, or ypT0/is).In trastuzumab-based neoadjuvant-treated patients, ypT0+ypN0 was achieved in 46.0% of patients with HER2 IHC 3+ tumors but only 25.0% of patients with HER2 IHC 2+/fluorescence in situ hybridization (FISH)-positive tumors (P = .016). When pCR was defined as ypT0/is+ypN0 or ypT0/is, 54.7% and 61.3% of patients with HER2 IHC 3+ tumors had a pCR, whereas only 29.5% and 38.6% with HER2 IHC 2+/FISH-positive tumors achieved pCR (P = .004 and P = .008, respectively). The association between dual HER2 blockade and pCR was almost exclusively confined to HER2 IHC 3+ tumors (ypT0+ypN0: 61.9% vs 38.9%, P = .013; ypT0/is+ypN0: 71.4% vs 47.4%, P = .009; and ypT0/is: 81.0% vs 52.6%, P = .002) and was absent in HER2 IHC 2+/FISH-positive tumors. Multivariate logistic regression revealed that HER2 IHC 3+ tumors had a significantly higher probability of achieving ypT0+ypN0 (odds ratio [OR], 0.265; 95% confidence interval [CI], 0.109–0.645; P = .003), ypT0/is+ypN0 (OR, 0.221; 95% CI, 0.094–0.521; P = .001), and ypT0/is (OR, 0.254; 95% CI, 0.111–0.583; P = .001) than HER2 IHC 2+/FISH-positive tumors. A significantly better pCR rate was also found in patients with T1 tumors and patients with dual HER2 blockade.The pCR rate was highly correlated with the HER2 IHC score in neoadjuvant anti-HER2 treatment. The addition of pertuzumab to a neoadjuvant trastuzumab-based regimen improved pCR rates, but there was no significant difference in pCR rates in the IHC 2+/FISH-positive group. This suggests that HER2 IHC scores can predict the effectiveness of treatment.

142P Long-term follow-up of neoadjuvant dual anti-HER2 therapy with trastuzumab and lapatinib plus paclitaxel, with or without endocrine therapy for HER2-positive primary breast cancer: Neo-LaTH (JBCRG-16) study

Dual blockade of HER2 promises increased pathological complete response (pCR) rates compared with single blockade in the presence of chemotherapy for HER2-positive (+) primary breast cancer. We have reported that CpCRypN0 was confirmed in 46% (98/212); in 62% and 34% of ER-negative and ER-positive patients, respectively, from the neoadjuvant JBCRG-16 study (Breast Cancer 25:407-15, 2018). Long-term 5-year follow-up after surgery has been successful.