HER2-positive Operable Breast Cancer Research Articles

Abstract PO1-27-01: Comparing the Efficacy and Safety of TQB2440 versus the Reference Pertuzumab for the Treatment of HER2-Positive Early or Locally Advanced Breast Cancer: A Multicenter, Randomized, Double-Blind, Parallel-Controlled Phase 3 Trial

Abstract Background: Pertuzumab is a recombinant humanized monoclonal antibody targeting the extracellular dimerization domain II of HER2. On September 30, 2013, the FDA have granted accelerated approval of a pertuzumab regimen for neoadjuvant treatment of patients (pts) with high-risk, HER2-positive early stage breast cancer. TQB2440 is a pertuzumab (Perjeta®, Roche) biosimilar. This study aimed to compare the efficacy and safety of TQB2440 and the reference pertuzumab combined with trastuzumab and docetaxel in pts with HER2-positive early or locally advanced breast cancer. Methods: In this multicenter, randomized, double-blind phase 3 study, eligible pts were aged 18-75 with operable HER2-positive (IHC 3+ or ISH+) clinical stage II-IIIC breast cancer negative for ER/PR and had an ECOG PS of 0-1. The pts were randomly assigned to receive either TQB2440 or the reference pertuzumab (Perjeta®) (840 mg on day 1, cycle 1, followed by 420 mg on cycle 2-4, q3w) added to trastuzumab (8 mg/kg on day 1, cycle 1, followed by 6 mg/kg for cycles 2-4, q3w) + docetaxel (75 mg/m2, cycle 1-4, q3w). The pts then underwent surgery followed by adjuvant treatment with FEC regimens (fluorouracil 600 mg/m², epirubicin 90 mg/m², cyclophosphamide 600 mg/m², cycle 5-7, q3w), then TQB2440 (840 mg on day 1, cycle 8, followed by 420 mg on cycle 9-20, q3w) + trastuzumab (8 mg/kg on day 1, cycle 8, followed by 6 mg/kg for cycles 9-20, q3w) or until disease progression or intolerable toxicity. The primary endpoint was total pathologic complete response (tpCR) by independent review committee (IRC). Equivalence was established if the 90% confdence intervals (CIs) of the relative ratio [RR] within the interval of 0.76 to 1.32. Secondary endpoints included breast pathologic complete response (bpCR) by IRC, tpCR & bpCR by investigator, breast conserving surgery (BCS) rates, objective response rate (ORR), event-free survival (EFS), disease-free survival (DFS), OS and safety. Results: Between October 21, 2020, and November 21, 2022, 412 pts were enrolled (TQB2440 group, n=207; the reference pertuzumab group, n=205). Data cutoff was November 30, 2022. In the intention-to-treat (ITT) population, the tpCR by IRC of the TQB2440 group and the reference drug group were 58.94% and 58.05%, respectively. The RR was 1.02 (90% CI, 0.89, 1.16), which was within the predefined equivalence interval of 0.76 to 1.32. There was no statistically significant difference in the bpCR by IRC between the TQB2440 group and the reference pertuzumab group (67.63% [95% CI, 60.80%, 73.95%] vs. 63.90% [95% CI, 56.92%, 70.48%], P=0.4249). The BCS rate also comparable between the two groups with 13.04% (95% CI, 8.77%, 18.41%) vs. 13.17% (95% CI, 8.86%, 18.58%) (P=0.9695). Additionally, the results of the PP (per-protocol) population were similar to those of the ITT population. The incidence of treatment-related adverse events (TRAEs) and grade ≥3 TRAEs were similar between the TQB2440 group and the reference pertuzumab group with 79.71% vs. 75.98% and 49.28% vs. 41.67%, respectively. Conclusion: In patients with HER2-positive early or locally advanced breast cancer, TQB2440 demonstrated equivalent efficacy and similar safety to the reference pertuzumab. Clinical trial information: NCT05985187. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd Citation Format: Qingyuan Zhang, Shusen Wang, Nanlin Li, Qiao Cheng, Yu ren, Xuchen Cao, Jianjun Huang, Caigang Liu, Hongwei Yang, Limin Wei, Zhangjun Song, Huadong Zhao, Fangling Ning, Xiaojia Wang, Dehong Zou, Xiaohua Zeng, Jie Hao, Yunjiang Liu, Huijuan Wang, Nie Jianyun, Liang Li, Lina Liu, Tao Sun, Xiaobo Hu, Zhenhua Zhai, Huihua Xiong, Yuanqi Zhang, Enxiang Zhou, Jing Sun, Zhenhai Cai, Antai Zhang, Shui Wang, Junyang Mo, Qun Su, Xiuheng Qi, Guoren Zhou, Shuqun Zhang, Guozhong Cui, Wei Wang, Mingjiang Fan, Xinyu Qian, Xinhong Wu, Zhihong Wang, Jiuda Zhao, Yonghui Luo, Yanming Zhang, Fuguo Tian, Jiye Zhang, Dongning Chai, Qingshan Li. Comparing the Efficacy and Safety of TQB2440 versus the Reference Pertuzumab for the Treatment of HER2-Positive Early or Locally Advanced Breast Cancer: A Multicenter, Randomized, Double-Blind, Parallel-Controlled Phase 3 Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-01.

Abstract PO3-01-04: Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study

Abstract Introduction Neoadjuvant therapy (NAT) is considered the standard of care in patients with HER2-positive breast cancer mainly due to the possibility to adjust the post-neoadjuvant treatment based on the tumor response to NAT. However, there is no convincing evidence on a survival benefit with NAT compared to adjuvant therapy (AT) for HER2-positive breast cancer. The aim of the present study was to compare the two therapeutic strategies in a register-based cohort of Swedish patients with primary operable HER2-positive breast cancer. Method The research database BCBaSe 3.0, which is based on the Swedish National Quality breast cancer register, was used to identify patients with primary operable HER2-positive breast cancer that diagnosed between 2008 and 2020 and received either NAT or AT including chemotherapy and trastuzumab. To mitigate confounding by indication bias, propensity score matching (PSM) with 1:1 matching was applied. The effectiveness of the two therapeutic strategies was investigated through analyzing distant disease-free survival (DDFS), breast-cancer specific survival (BCSS), and overall survival (OS). Multivariate Cox regression analyses were performed for the outcomes of interest to provide Hazard Ratios (HR) and corresponding 95% Confidence Intervals (CI). Results In total, 7258 patients with primary operable HER2-positive breast cancer treated with either NAT or AT were identified, 1789 (24.6%) received NAT and 5469 (75.4%) AT. After 1:1 PSM, 1258 patients in each therapeutic strategy were available for comparisons. After a median follow-up of 63 months, no statistically significant differences between NAT and AT were observed in either outcome (HR for DDFS: 0.97; 95% CI: 0.72 – 1.30; HR for BCSS: 0.69; 95% CI: 0.45 – 1.07; HR for OS: 0.72; 95% CI: 0.50 – 1.05). In subgroup analyses, estrogen-receptor status did not impact the results that remained statistically non-significant between NAT and AT whereas in patients with clinically positive lymph node status, NAT resulted in better BCSS (HR: 0.44; 95% CI: 0.22 – 0.89) and OS (HR: 0.49; 95% CI: 0.29 – 0.90). The latter trend was not evident in patients with clinically negative lymph node status. Conclusion Our study results confirm the equivalence of NAT and AT in terms of prognosis for patients with operable HER2-positive disease and imply a potential benefit of NAT compared to AT in patients with clinically positive lymph node status. Considering the emerging treatment strategies in HER2-positive breast cancer patients treated with NAT (pertuzumab as a part of NAT, T-DM1 as post-neoadjuvant therapy) that have been shown to improve survival but are not reflected in the study cohort, NAT should be considered as the strategy with the higher possibility to improve long-term prognosis for patients with HER2-positive disease. Citation Format: Servah Hosseini-Mellner, Åsa Wickberg, Antonis Valachis, Andreas Karakatsanis. Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-04.

Correlation of SUV on Early Interim PET with Recurrence-Free Survival and Overall Survival in Primary Operable HER2-Positive Breast Cancer (the TBCRC026 Trial).

Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SULmax) on 18F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that 18F-FDG PET/CT SULmax parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP (n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. 18F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between 18F-FDG PET/CT (≥40% decline in SULmax between baseline and C1D15, or C1D15 SULmax ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SULmax of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SULmax decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SULmax of 3 or less on 18F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy.

Phase II neoadjuvant trial of albumin-bound paclitaxel, trastuzumab and pertuzumab followed by anthracycline based regimens in patients with operable HER2 positive breast cancer (OMC-BC05).

e12594 Background: Anthracycline and Taxane have been widely used and studied in neoadjuvant setting for treatment of locally advanced breast cancer. Various regimens have explored the addition of newer agents to determine safety and efficacy, and pathological complete response(pCR) has been demonstrated to be associated with favorable overall survival in primary breast cancer. Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to Trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (Her2)-positive breast cancer. In addition, APHINITY trial showed that Pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to Tastuzumab and chemotherapy. We conducted a clinical phase II neoadjuvant trial of nab-Paclitaxel, Trastuzumab and Pertuzumab followed by Anthracycline Based Regimens in Patients with Operable Her2 Positive Breast Cancer. Methods: The study is designed to evaluate nab-paclitaxel, Trastuzumab and Pertuzumab followed by EC or AC or FEC as neoadjuvant therapy in patients with Her2 positive operable breast cancer. Patients are treated with neoadjuvant nab-paclitaxel(260 mg/m2 ), Trastuzumab and Pertuzumab followed by EC(Epirubicin 90 mg/m2 , Cyclophosphamide 600 mg/m2) or AC(Doxorubicin 60 mg/m2 , Cyclophosphamide 600 mg/m2) or FEC(Fluorouracil 500mg/m2, Epirubicin 100 mg/m2 , Cyclophosphamide 500 mg/m2 ) q21d x 4. Patients undergo surgery 4-6 weeks later from completing chemotherapy. The primary endpoint, pCR is defined as no evidence of invasive tumors in the final surgical sample both in the breast and axillary lymph nodes. Secondary endpoints include overall response rate, disease-free survival, rate of breast conserving surgery, histological response rate, rate of sensory neuropathy ant the safety of the treatment. Results: In 30 evaluable patients, the pCR rate was 50%; 6/19 (31.6%) in ER-positive and 9/11 (81.8%) in ER-negative, 1/7 (14.3%) in IHC 2+, FISH positive and 14/23 (60.9%) in IHC 3+ . Of the study treatments, the most frequent reason for delay or dose reduction was hematologic toxicity; no patient required a dose reduction for nab-PTX because of peripheral neuropathy. Conclusions: Neoadjuvant treatment using albumin-bound Paclitaxel, Trastuzumab and Pertuzumab followed by Anthracycline based regimens appears to be effective especially in pure HER2 type or IHC 3+ cases.

Abstract P4-07-28: Prognostic Impact of Delaying Multimodality Treatment in HER2 Positive Breast Cancer

Abstract Objective: Multimodality treatment in breast cancer is a key to the improved survival outcomes. The effects of delays in multimodality treatment in HER2 amplified breast cancer were studied. Patients and Methods: Of the patients with primary HER2 amplified breast cancer who were treated between 2009 and 2018 in a single institution, 1,075 patients met the inclusion criteria. The patterns of the multimodality treatments and the prognostic effects of treatment delays were studied. Kaplan-Meier method was used to estimate the relapse free survival (RFS) and overall survival (OS). Hazard ratio (HR), their 95% confidence interval (CI) and p value were computed using the Cox proportional-hazards model adjusting for 11 covariates including age, ethnicity, clinical T stage, clinical N stage, ER, PR, Ki67, LVI, histologic grade, surgery type (mastectomy versus lumpectomy), neoadjuvant versus adjuvant chemotherapy. The Harrell’s C statistics were used to determine the Cox model accuracy. Adjusted multivariate analyses of recurrence/death and death were computed using Cox proportional-hazards model. Delays in treatment were defined as starting treatment beyond 60 days after diagnosis or after the completion of the leading treatment. Results: Of the patients included, 49% received neoadjuvant chemotherapy/HER2 target treatment and surgery, 43% had adjuvant treatments and surgery and 8% had surgery only without chemotherapy. Timely commencement of treatment in the 3 groups were 85.7%, 72.1% and 78.4% respectively. The 5-year RFS was 88.7% and OS was 98.2%. Patients who received neoadjuvant and adjuvant chemotherapy were combined, and six treatment groups with delays in various treatments were compared: no delay in chemotherapy/target treatment and surgery (1); surgery delay (2); chemotherapy delay (3); delays in both treatments (4) and surgery only groups with (5) or without delays (6). Concordance statistics showed that the covariate adjusted Cox proportional-hazards model had a better accuracy than the unadjusted. Compared to those without delays, patients with both chemotherapy and surgery delayed had worse recurrence/death (adjusted HR = 4.11, 95% CI: 1.39-12.5, p= 0.0161). Delays in either surgery or chemotherapy also increased recurrence/death, although to a lesser magnitude. The adjusted death in surgery delay, chemotherapy delay and delays in both had HR 2.91; 2.22; and 2.29 respectively when compared to the group without delays in either treatment although not significant at p < 0.05. Adjusted recurrence/death and death were similar between neoadjuvant and adjuvant groups (HR 0.99 & HR 0.85 respectively). The group that received surgery only without chemotherapy was associated with worse recurrence/death (adjusted HR=1.78, 95% CI: 0.19 – 16.9) Conclusion: Delays in any treatment adversely impacted recurrence and death and chemotherapy/target treatment is a critical component in treating patients with operable HER2 positive breast cancer. Citation Format: Helena Chang, Jeffrey Gornbein, Sin Yee Lim. Prognostic Impact of Delaying Multimodality Treatment in HER2 Positive Breast Cancer [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 P4-07-28.

PS-R06-8: AMLODIPINE WELL RESPONDED TO HYPERTENSION ALONG WITH HEADACHE IN PATIENT UNDERGOING WHOLE BRAIN RADIATION THERAPY (CASE REPORT)

Objective: According to the current treatment guideline for breast cancer issued by Japanese Breast Cancer Society, surgery or stereotactic radiotherapy is recommended for patients with solitary brain metastasis (BM), while whole brain radiotherapy (WBRT) is recommended for patients with multiple BMs. Common treatment-related toxicities during radiotherapy include fatigue, drowsiness, alopecia, headache, nausea, or vomiting, however, elevation of blood pressure has not been reported. We report a case of headache due to high blood pressure during WBRT. Case: A 5X-year female was diagnosed as HER2-positive operable left breast cancer underwent radical mastectomy followed by adjuvant chemotherapy including one-year trastuzumab. Three years after surgery she was diagnosed as having cancerous pleurisy, cancerous pericarditis, and multiple bone metastases. The patient received 6 cycles of trastuzumab, pertuzumab and docetaxel and 5 cycles of trastuzumab and pertuzumab. She noticed chronic headache and magnetic resonance imaging of the brain showed metastases to the right frontal lobe and left cerebellum. She was hospitalized and underwent WBRT. She received corticosteroid and glycerin-fructose injection to reduce the intracranial pressure (ICP) along with WBRT. On the 10th day of hospitalization, she complained severe headache with numerical rating scale (NRS) of 6. While an analgesic was not effective, elevated blood pressure (160/80 mmHg) since admission was suspected as a cause of headache. High-dose amlodipine at the dose of 10 mg was prescribed and the patient well responded to amlodipine as blood pressure of 130/70 mmHg and headache was relieved. Discussion: In patients with BMs, headache is common symptom due to elevate ICP or leptomeningeal dissemination. However, analgesic and ICP relief therapy did not work in this case. Guidelines for the management of hypertension 2019 (JSH 2019) define hypertension as 140/90 mmHg or higher, and in low-risk cases without underlying disease, non-pharmacologic therapy is recommended. Ultimately, the use of a calcium channel blockers resulted in a decrease in blood pressure and improvement in headache. It is possible that the headache was caused by increased sympathetic nerve activity via ischemia in the brainstem due to increased ICP, such as in brain tumors, which can lead to hypertension. Amlodipine is recommended for patients with chronic cerebrovascular disease because of its long acting and slow onset of effect, as well as its ability to protect organ blood flow. Conclusion: This case revealed hypertension may be the cause of headaches during WBRT, in which case amlodipine was effective.

Trastuzumab and pertuzumab without chemotherapy in early-stage HER2+ breast cancer: aplain language summary of the PHERGain study.

This is a summary of a publication about the PHERGain study, which was published in The Lancet Oncology in May 2021. The study includes 376 women with a type of breast cancer called HER2-positive breast cancer that can be removed by surgery. In the study, researchers wanted to learn if participants could be treated with two medicines called trastuzumab and pertuzumab without the need for chemotherapy. To identify HER2-positive tumors with more sensitivity to anti-HER2 therapies, the researchers used a type of imaging called a FDG-PET scan to check how well the treatments were working. Participants took a treatment before surgery, consisting of either chemotherapy (docetaxel and carboplatin) plus trastuzumab and pertuzumab (group A) or trastuzumab and pertuzumab alone (plus hormone therapy if the tumor was hormone receptor-positive; group B). After two cycles of treatment, participants underwent a FDG-PET scan. Participants assigned to group A completed 6 cycles of treatment regardless of 18F-FDG-PET results. Participants in group B continued the same treatment until surgery if their FDG-PET scan showed the treatment was working. While participants who did not show a response started treatment with chemotherapy in addition to trastuzumab and pertuzumab. All participants then had surgery. The results revealed that, of the participants in group B who showed a response using FDG-PET scan, 37.9% achieved a disappearance of all invasive cancer in the breast and axillary lymph nodes. This rate appears to be higher than those reported in previous studies evaluating the same treatment. These participants also had less side effects and improved overall quality of life compared with participants taking chemotherapy plus trastuzumab and pertuzumab. Early monitoring of how well participants respond to treatment by FDG-PET scan seems to identify participants with operable HER2-positive breast cancer who were more likely to benefit from trastuzumab and pertuzumab without the need to have chemotherapy. The PHERGain study is still ongoing and results on long-term survival are expected to be released in 2023. Clinical Trial Registration: NCT03161353 (ClinicalTrials.gov).

191P Correlation of early change in standardized uptake value (SUV) on positron emission tomography (PET/CT) with recurrence-free survival (RFS) and overall survival (OS) in patients with primary operable HER2-positive breast cancer (TBCRC026)

Predictive biomarkers of response to HER2-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early changes in tumor standardized uptake values corrected for lean body mass (SULmax) on FDG-PET/CT predicted pathologic complete response (pCR) to neoadjuvant trastuzumab and pertuzumab (HP) in HER2-positive breast cancer (PMID:33999652). We hypothesized that early changes on FDG-PET/CT will predict RFS/OS.

28-gene classifier model for prediction of local recurrence and distant metastasis risk in HER-2 positive operable breast cancer.

e13018 Background: Accurate prediction of postoperative recurrence risk is very important for the formulation of appropriate treatment for breast cancer patients. However, traditional clinicopathological indicators cannot accurately assess the recurrence risk of patients. We aimed to build a novel gene-clinical variable model, which included 28 genetic profiles and clinical variable information, to assess the risk of recurrence in a more individualized and accurate manner. Methods: We retrospectively included a cohort of operable HER-2 positive breast cancer patients treated in Cancer Hospital of the Chinese Academy of Medical Sciences from 2010 to 2016. The genetic and clinical data were used to train and validate the 28-gene classifier model in predicting local recurrence and distant metastasis risk. Results: A total of 260 HER-2 positive breast cancer patients were Included in the study. All patients received standard adjuvant chemotherapy and routine targeted therapy after mastectomy. All patients were followed up for a median of 60.4 months for disease recurrence. Among them, 21 patients had distant metastasis events and 18 patients had local recurrence events. We used the 28 gene-clinical variable model to classify 260 patients into high- and low-risk groups. Kaplan-Meyer survival curves were used to compare the prognostic difference of DFS into high- and low- risk groups. Conclusions: 28 gene-clinical variable model may be a reliable toll to predict local recurrence and distant metastasis risk in HER-2 positive operable breast cancer.

79P The impact of trastuzumab administration patterns on the clinical outcomes of patients with early breast cancer in resource-limited settings

Administration of trastuzumab (TRA) in resource-limited settings (RLS) is associated with significant deviations from per-label recommendations such as underdosing, interruptions, and a reduced number of doses. The impact of these deviations on the clinical outcomes of patients (pts) with HER2-positive early breast cancer is unclear. Patients with operable HER2-positive breast cancer who received at least one fixed dose of intravenous TRA as (neo)adjuvant treatment from 2013 to 2018 were retrospectively included in our cohort. Low relative dose intensity (RDI) was defined as drug dose delivered per time unit ≤ 65% of the intended dose intensity. Underdosed patient defined as having >100 mg reduction from the ideal weight-based maintenance dose. We used Cox regression analysis to identify predictors of survival. A total of 208 pts with a median age of 45 (22-70 years) were included. 64% were node-positive. A total of 175 (84%) pts showed at least one per label deviation, including 54 pts (26%) who were underdosed with a mean maintenance dose reduction of 54 ±107 mg, 64 (31%) received a reduced number of doses (≤ 9), and 103 pts (49.5%) received TRA at low RDI. Reduced number of doses was the only factor associated with worse hazard of recurrence-free survival (RFS) and overall survival (OS) (HR: 2.25, 95% CI: 1.35-3.75, adjusted p =0.002) and (HR: 2.48, 95%CI: 1.36-4.52, adjusted p =0.003) respectively. Conversely, low RDI and underdosing were not significant predictors to worse RFS or OS (p > 0.5). A propensity score matching with 164 TRA-naïve pts from the METABRIC project confirmed that TRA-treated pts with deviations still draw clinical benefit with a 39% reduction in risk of disease recurrence and 52% reduction in risk of death compared to TRA-naïve, consistent with relative benefit observed in TRA adjuvant trials. The majority of patients in RLS suffered from at least one per label deviation of TRA administration. However, apart from the reduced number of doses, these deviations did not impact the survival outcomes adversely. The Cost-effectiveness of protracted fixed-dose administration should be investigated in this setting.

A phase II randomised study of preoperative trastuzumab alone or combined with everolimus in patients with early HER2-positive breast cancer and predictive biomarkers (RADHER trial)

IntroductionResistance to trastuzumab in breast cancer is an ongoing challenge. Clinical and biological effects of co-targeting HER2 and mammalian target of rapamycin (mTOR) in patients with HER2-positive early operable breast cancer via the addition of everolimus to preoperative trastuzumab were evaluated in a phase II randomised study. MethodsPatients were randomised 1:1 to receive trastuzumab (4 mg/kg initial dose then 2 mg/kg weekly for 5 weeks) alone or combined with everolimus (10 mg/day for 6 weeks) and then underwent surgery. Tumours were assessed by clinical examination and echography at the baseline and on treatment. The primary end-point was the clinical response rate at 6 weeks. Pathological response and safety were also evaluated. Baseline and surgery tumour samples were assessed by immunohistochemistry and multiplex immunoanalysis for predictive downstream effectors of the PI3K/AKT/mTOR and MAP kinase (MAPK) pathways. ResultsEighty-two patients were enrolled, 41 per arm. The clinical response rates were 34.1% and 43.9% with trastuzumab alone and combined with everolimus, respectively. Pathological response rates were 43.6% and 47.5%, respectively. Addition of everolimus increased toxicity, notably mucositis (82.5% versus 5.0%) and rash (57.5% versus 10.0%), but grade III/IV events were rare. No correlation between response to treatments and baseline candidate biomarkers was identified, except for PIK3CA mutations which were found to predict trastuzumab resistance. Significant changes were seen in several MAPK pathway effectors after combination therapy. ConclusionsThe addition of everolimus did not improve the efficacy, but induced MAPK signalling. Combination therapy to overcome pathway cross-talk should be considered to maximise the effectiveness of trastuzumab in this setting.ClinicalTrial.gov Identifier NCT00674414.

P086 - Phase II neoadjuvant trial of Albumin-Bound Paclitaxel, Trastuzumab and Pertuzumab followed by anthracycline based regimens in patients with operable Her2 positive breast cancer (OMC-BC05)

P086 - Phase II neoadjuvant trial of Albumin-Bound Paclitaxel, Trastuzumab and Pertuzumab followed by anthracycline based regimens in patients with operable Her2 positive breast cancer (OMC-BC05)

The role of the neoadjuvant approach in the treatment of primary operable HER2 positive breast cancer

Neoadjuvant systemic therapy is an essential component of the comprehensive treatment of primary operable HER2‑positive breast cancer. Therefore, it is extremely important to search for treatment efficacy predictors and optimal system for assessing tumor response to treatment. The study analyzed factors predicting pathological complete response (pCR) in patients with luminal and non‑luminal HER2‑positive tumor subtypes. The morphological assessment of the tumor response to treatment was carried out using the RCB system; additional characteristics of the residual tumor were studied as well. It was shown that a comprehensive assessment involving the use of the RCB system and determination of the Ki ‑ 67 level helps to divide patients into prognostic groups and individualize the adjuvant therapy plan.

Clinical impact of interruption in adjuvant Trastuzumab therapy in patients with operable HER-2 positive breast cancer

BackgroundTrastuzumab-induced cardiotoxicity (TIC) can lead to early discontinuation of adjuvant therapy, however there is limited evidence on long-term survival outcomes in patients with operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) experiencing treatment interruption or discontinuation.MethodsThe primary objective of the study was to evaluate disease-free survival (DFS) in non-metastatic, HER2-positive, female BC patients who experienced treatment interruption or early discontinuation of trastuzumab therapy. Clinical and histopathological data were collected on 400 patients at The Ohio State University, an NCI-designated comprehensive cancer center between January 2005 and December 2015. Treatment interruption was defined as any delay of ≥2 weeks during trastuzumab therapy, including permanent cessation prior to completing planned therapy. TIC was defined as LVEF < 50% or > 15 points decline from baseline as evaluated by 2D echocardiogram after initiation of (neo) adjuvant therapy. DFS was defined as the time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary BC or death. Overall survival (OS) was defined as the time from diagnosis to death or last known follow up. OS/DFS estimates were generated using Kaplan-Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHR) for OS/DFS.ResultsA total of 369 patients received trastuzumab therapy; 106 (29%) patients experienced treatment interruption at least once and 42 (11%) permanently discontinued trastuzumab prior to completing planned therapy. TIC was the most common reason for interruption (66 patients, 62%). The median duration of trastuzumab in patients with treatment interruption was 11.3 months (range: 0.5–16.9) with 24 (23%) patients receiving ≤6 months of therapy. This duration includes the time delay related to treatment interruption. Patients with any treatment interruption had worse DFS (aHR: 4.4, p = 0.001) and OS (aHR: 4.8, p < 0.001) after adjusting for age, stage, grade, ER, node status and TIC.ConclusionsTreatment interruption or early discontinuation of trastuzumab therapy in early HER2-positive BC, most often from TIC, is an independent prognostic marker for worse DFS and OS in operable HER2-positive BC. Future prospective studies should consider targeting at-risk populations and optimizing cardiac function to avoid interruption in trastuzumab therapy.

NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response.

In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41. Eligible patients had a baseline preadjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter Breast Cancer 360 gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base 2. To screen for candidate genes and metagene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization. Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early-stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens. The identified genes are involved in important pathways such as epithelial-mesenchymal transition, adhesion and migration, estrogen receptor signaling, DNA damage and repair, apoptosis, and proliferation. The AUC from a 10-fold cross-validation on predicting pCR, with these 20 genomic markers in a logistic regression model, was 0.73. The expression level of ERBB2, ESR1, and a few other genomic markers was highly predictive of pCR after trastuzumab-containing regimens. These findings need to be validated and calibrated in future studies.

Markers to Evaluate the Efficacy of PH-based Regimen as a Neoadjuvant Therapy for Operable HER2 Positive Breast Cancer

Markers to Evaluate the Efficacy of PH-based Regimen as a Neoadjuvant Therapy for Operable HER2 Positive Breast Cancer

Abstract P1-18-19: Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

Abstract Background: Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with increased therapeutic efficacy of trastuzumab/pertuzumab-based neoadjuvant therapy (NT) in patients (pts) with HER2-positive breast cancer (BC). Subcutaneous (SC) trastuzumab has non-inferior efficacy to intravenous (IV) administration, with a similar safety profile. Interestingly, SC trastuzumab has been observed to be more immunogenic than IV trastuzumab and act at different immunologic levels. Therefore, by modifying the modality of administration of trastuzumab, it could be possible to interfere with different immune pathways and exert a favorable immunomodulation in HER2-positive BC. Methods: In this non-comparative, phase II, neoadjuvant, randomized study, pts were eligible if they had previously untreated, histologically confirmed, locally advanced, inflammatory, or early-stage HER2-positive BC. Pts were treated with FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; cyclophosphamide 500 mg/m2) q21 × 3 cycles. Then, they were randomly assigned (1:1) to receive: docetaxel (75 mg/m2) plus pertuzumab (840 mg loading dose (LD), then 420 mg) plus IV trastuzumab (8 mg/kg LD, then 6 mg/kg) q21 × 4 cycles (arm A) or, docetaxel plus pertuzumab plus SC trastuzumab (fixed dose of 600 mg) q21 × 4 cycles (arm B). After surgery, pts received trastuzumab q21 × 14 cycles using the same formulation (SC or IV) of the preoperative phase. The primary endpoint was the rate of stromal TILs (sTILs) on residual disease after surgery. Tumor biopsy and posttreatment surgical samples were centrally analyzed for TILs. Blood samples were also collected during NT for tumor-specific lymphocyte cell activity analysis. Feasibility, efficacy and safety were also evaluated. ClinicalTrials.gov: NCT03144947. Results: Between November 2016 and September 2017, according to an adaptive Simon's two-stage optimal design, we enrolled 65 pts, of whom two were deemed ineligible for the study. Thus, 63 pts (31 in arm A and 32 in arm B) were assessed for the primary and secondary endpoints. The pathologic complete response (pCR; no invasive tumor in breast and axilla) rates were 64.5% (95% CI, 47-81) in arm A, and 59.4% (95% CI, 42-76) in arm B. The most common adverse events of grade 3 or higher were neutropenia (15 [48.4%] pts in arm A, and 11 [34.4%] in arm B), neurotoxicity (1 [3.2%], and 2 [6.2%], respectively), and diarrhea (1 [3.2%], and 1 [3.1%], respectively). There were no events of congestive heart failure. At surgery, 11 pts in arm A and 13 pts in arm B were evaluable for TIL analysis. The median value of sTILs (7.5%) on pre-treatment tumor biopsies was used as the cut-off value, and high sTIL levels were observed in 27.3% and in 46.1% of residual tumors after treatment arm A and B, respectively. There was a positive correlation between pretreatment sTILs and PD-L1 expression on stromal immune cells (Kendall’s τ =0.80). Interestingly, a significant inverse correlation was observed between PD-L1 expression on pretreatment sTILs and the T cell co-receptor CD3 expressed on posttreatment sTILs (Pearson’s ρ = -0.70). This finding was particularly evident in the arm B group (ρ = -0.85). Conclusions: NT with either SC or IV trastuzumab in combination with pertuzumab and chemotherapy had a significant effect on sTIL expression at surgery. In particular, the SC trastuzumab-based arm exerted the most relevant enrichment of sTILS in posttreatment residual tumors. These findings suggest a role for the SC administration of trastuzumab in determining favorable variations of host immune response parameters among pts with HER2-positive early BC who had residual disease after NT. Citation Format: Antonino Musolino, Stefania Gori, Elisabetta Cretella, Alessandra Marabese, Luigi Cavanna, Antonio Frassoldati, Giancarlo Bisagni, Chiara Casarini, Emilio Bria, Luisa Carbognin, Elena Fiorio, Alba A Brandes, Claudio Zamagni, Lorenzo Gianni, Alberto Zambelli, Filippo Montemurro, Michele Tognetto, Renata Todeschini, Giuseppe Maglietta, Gabriele Missale, Enrico M Silini. Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [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 P1-18-19.

Abstract GS1-04: Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer

Abstract Background: The APHINITY trial demonstrated that pertuzumab, when added to adjuvant trastuzumab and chemotherapy, modestly but statistically significantly improved invasive disease-free survival (IDFS) among patients with HER2-positive, operable breast cancer. From November 2011 until August 2013, 2400 patients were randomly assigned to receive pertuzumab and 2405 to receive placebo. The clinical cut off-date for the primary analysis was 19 Dec 2016 after a median follow-up of 45.4 months. In the intent-to-treat (ITT) population, the estimates of the 3-year rates of IDFS were 94.1% in the pertuzumab group and 93.2% in the placebo group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The benefit appeared more pronounced in patients with node-positive disease, with a HR of 0.77 (95% CI 0.62-0.96), and in those with hormone receptor-negative disease, where the HR was 0.76 (95% CI 0.56-1.04). Based on these results, pertuzumab in combination with trastuzumab was approved for high risk early HER2-positive breast cancer patients. The first interim analysis of OS took place at that same time. A total of 169 patients had died, with no significant treatment effect with regards to mortality found at that time. Diarrhea, grade 3 or higher, was more frequent within the pertuzumab group (9.8%) compared with the placebo group (3.7%). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Results: At 74.1 months of median follow-up (clinical cut-off date June 19, 2019), we now report results of the pre-planned, calendar-driven second interim OS analysis which requires a p-value of 0.0012 to reach statistical significance. Updated descriptive analyses of IDFS and cardiac safety were also performed. Fewer deaths were observed in the pertuzumab (P) arm [125 (5.2%) vs 147 (6.1%)], however statistical significance was not reached at this interim analysis. The hazard ratio for OS is 0.85 [95% CI 0.67-1.07 (p=0.17)]; 6-year OS percents are 94.8% vs 93.9% (0.9% difference).Updated IDFS results based on 508 events in the ITT population are: hazard ratio 0.76 [95% CI 0.64-0.91]; 6-year IDFS percents are 90.6% vs 87.8% (2.8% difference). Of note, the difference was due mainly to the reduction in distant (5.9% vs 7.7%) and loco-regional (1.2% vs 2.0%) BC relapses. The node-positive cohort continues to derive clear benefit from the addition of P: hazard ratio 0.72 (95% CI 0.59-0.87). The benefit in terms of 6-year IDFS percent is 4.5% [87.9% vs 83.4%].In the node-negative cohort, the IDFS hazard ratio is 1.02 (95% CI; 0.69-1.53) with 95% of patients being event-free in both arms at 6 years.With longer follow up, a treatment benefit of P is also seen in the hormone receptor (HR) positive cohort: IDFS hazard ratio for HR positive is 0.73 (95% CI 0.59 -0.92). IDFS hazard ratio for HR negative is 0.83 (95% CI 0.63 -1.10). No new cardiac safety concerns emerged. One additional primary cardiac event (heart failure) was reported in the P arm and 1 additional patient in each arm had a secondary cardiac event resulting to 18 and 8 for primary cardiac events and 65 and 68 for secondary cardiac events in the P and placebo arms, respectively. The benefit of P in HER2+ early BC is maintained, with the greatest benefit continuing to be observed in the node positive population. With longer follow-up, the benefit of P no longer appears to depend on HR status. Continued follow up of patients is very important to determine possible benefit for OS. A calendar-driven third interim OS analysis is planned in 2.5 years, and the event-driven final OS analysis is planned when 640 deaths have occurred. Citation Format: Martine Piccart, Marion Procter, Debora Fumagalli, Evandro de Azambuja, Emma Clark, Michael S. Ewer, Eleonora Restuccia, Guy Jerusalem, Susan Dent, Linda Reaby, Hervé Bonnefoi, Ian Krop, Tsang-Wu Liu, Tadeusz Pieńkowski, Masakazu Toi, Nicolas Wilcken, Michael Andersson, Young-Hyuck Im, Ling-Ming Tseng, Hans-Joachim Lueck, Marco Colleoni, Estefania Monturus, Mihaela Sicoe, Sébastien Guillaume, José Bines, Richard Gelber, Giuseppe Viale, Christoph Thomssen. Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer [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 GS1-04.

Abstract P1-18-28: Myocet or carboplatin as part of chemotherapy in HER2-positive operable breast cancer treated with trastuzumab and pertuzumab in the neoadjuvant setting: Efficacy data and cardiotoxicity in 60 patients diagnosed from 2016-2019 at a single institution

Abstract Objectives: To evaluate the efficacy and cardiotoxicity profile of liposomal anthracycline or Carboplatin as part of neoadjuvant therapy added to taxanes and dual blockade in HER2-positive operable breast cancer patients. Methods: A total of 60 patients diagnosed from August 2016 to May 2019 were included in the study. The treatment consisted of a sequential regimen of taxanes and non- pegilated liposomal anthracycline (Myocet) plus trastuzumab and pertuzumab, or taxanes in combination with carboplatin plus trastuzumab and pertuzumab. The clinical and pathologic responses were evaluated and correlated with clinical and biological factors. Pathologic complete response was defined as the total absence of invasive tumor in both breast and axillary nodes (ypT0/is ypN0).The cardiotoxicity profile was also analyzed. Results: The median age was 52(26-77) years and 5%, 62% and 33% of patients had stage I, II and III breast cancer, respectively, while 7% had inflammatory breast cancer at diagnosis. Hormone receptor (HR) status was negative in 48%, and 65% and 50% had grade III and ki-67 value up to 35%, respectively breast cancer. 65% of patients received weekly paclitaxelx12-trastuzumab-pertuzumab followed by Myocet-cyclophosphamide with -trastuzumab x 4 cycles or this sequence but beginning with the anthracycline, 23% of patients the same regimen but with pertuzumab concurrently with all chemotherapy treatment. The remaining 12% received docetaxel-carboplatin x6 cycles plus trastuzumab and pertuzumab. All treatment was administered previous surgery. The clinical complete response rate, was 57% and 63%, as assessed using ultrasound and MRI, respectively, and this allowed a high rate of conservative surgery (60%). The pathologic complete response (pCR) rate was 52%, and it was higher in HR-negative (61%) than in HR-positive (39%), in grade 3 (71%) than in grade 2(29%) tumors. There were not statistical significant differences in pCR between different chemotherapy treatments. Five patients showed a 10% decrease in left ventricular ejection fraction (LVEF) to below 50% at the end of neoadjuvant treatment. Asymptomatic drops in 2 patients and with heart failure symptoms in 3 of them. Myocet was part of chemotherapy in all of them. All patients recovered after discontinuation of adjuvant trastuzumab and heart medication. Two of these patients did not complete all preplanned adjuvant trastuzumab doses. Conclusion: A sequential regimen of taxanes and non-pegilated liposomal anthracycline or carboplatin plus trastuzumab and pertuzumab was effective, with high pCR rates and a good cardiotoxicity profile. Citation Format: Silvia Antolin, Cristina Reboredo, Rocío Lesta, Aurea Molina, Joaquin Mosquera, Patricia Cordeiro, Eva Pérez, Lourdes Calvo. Myocet or carboplatin as part of chemotherapy in HER2-positive operable breast cancer treated with trastuzumab and pertuzumab in the neoadjuvant setting: Efficacy data and cardiotoxicity in 60 patients diagnosed from 2016-2019 at a single institution [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 P1-18-28.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients: extended follow-up of JBCRG-cohort study 01

BackgroundPrevious large trials of trastuzumab (TZM) demonstrated improved outcomes in patients with HER2-positive early breast cancer. However, its effectiveness and safety in Japanese patients is not yet clear. Recently, new anti-HER2 agents were developed to improve treatment outcomes, but the patient selection criteria remain controversial.PurposeThe aim of this study was to evaluate the long-term effectiveness of TZM therapy as perioperative therapy for HER2-positive operable breast cancer in daily clinical practice and to create a recurrence prediction model for therapeutic selection.MethodsAn observational study was conducted in Japan (UMIN000002737) to observe the prognosis of women (n = 2024) with HER2-positive invasive breast cancer who received TZM for stage I–III C disease between July 2009 and June 2011. Moreover, a recurrence-predicting model was designed to evaluate the risk factors for recurrence.ResultsThe 5- and 10-year disease-free survival (DFS) rates were 88.9 (95% CI 87.5–90.3%) and 82.4% (95% CI 79.2–85.6%), respectively. The 5- and 10-year overall survival (OS) rates were 96% (95% CI 95.1–96.9%) and 92.7% (95% CI 91.1–94.3%), respectively. Multivariate analysis revealed that the risk factors for recurrence were an age of ≥ 70 years, T2 or larger tumors, clinically detected lymph node metastasis, histological tumor diameter of > 1 cm, histologically detected lymph node metastasis (≥ n2), and the implementation of preoperative treatment. The 5-year recurrence rate under the standard treatment was estimated to be > 10% in patients with a score of 3 or greater on the recurrence-predicting model.ConclusionThe recurrence-predicting model designed in this study may improve treatment selection of patients with stage I–III C disease. However, further studies are needed to validate the scores generated by this model.