Chemotherapy In HER2-positive Breast Cancer Research Articles

Neoadjuvant pyrotinib plus trastuzumab and chemotherapy for HER2-positive breast cancer: a prospective cohort study

BackgroundThis prospective study aims to investigate the efficacy and safety of pyrotinib (P) combined with 4 cycles of epirubicin and cyclophosphamide followed by 4 cycles of taxane and trastuzumab (P + EC-TH) regimen as neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2) positive breast cancer and to investigate the predictive value of p53, p63, and epidermal growth factor receptor (EGFR) status for neoadjuvant efficacy.MethodsA total of 138 HER2-positive breast cancer patients who received neoadjuvant therapy and underwent surgery were included. Case group: 55 patients received P + EC-TH regimen. Control group: 83 patients received EC-TH regimen. The chi-square test, Fisher’s exact test, and logistic regression analysis were applied. The primary endpoint was total pathologic complete response (tpCR), and the secondary endpoints were breast pathologic complete response (bpCR), overall response rate (ORR), and adverse events (AEs).ResultsIn the case group, the tpCR rate was 63.64% (35/55), the bpCR rate was 69.09% (38/55), and the ORR was 100.00% (55/55). In the control group, the tpCR rate was 39.76% (33/83), the bpCR rate was 44.58% (37/83), and the ORR was 95.18% (79/83). The case group had significantly higher tpCR and bpCR rates than those of the control group (P < 0.05), but there was no significant difference in ORR (P > 0.05). The tpCR was associated with the status of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR), and the patients with any negative ER, PR, AR, or combined, were more likely to achieve tpCR than those with positive results (P < 0.05). The p53-positive patients were more likely to achieve tpCR and bpCR than p53-negative patients (P < 0.05). The incidence of hypokalemia and diarrhea in the case group was higher than that in the control group (P < 0.05). The AEs developed were all manageable, and no treatment-related death occurred.ConclusionThe efficacy and safety of the P + EC-TH regimen were verified by this study. The HER2-positive breast cancer patients treated with the EC-TH neoadjuvant regimen were more likely to achieve tpCR or bpCR if pyrotinib was administered simultaneously.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Ultrasound and clinicopathological characteristics-based model for prediction of pathologic response to neoadjuvant chemotherapy in HER2-positive breast cancer: a case–control study

BackgroundThe objective of this study was to develop a model combining ultrasound (US) and clinicopathological characteristics to predict the pathologic response to neoadjuvant chemotherapy (NACT) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer.Materials and methodsThis is a retrospective study that included 248 patients with HER2-positive breast cancer who underwent NACT from March 2018 to March 2022. US and clinicopathological characteristics were collected from all patients in this study, and characteristics obtained using univariate analysis at p < 0.1 were subjected to multivariate analysis and then the conventional US and clinicopathological characteristics independently associated with pathologic complete response (pCR) from the analysis were used to develop US models, clinicopathological models, and their combined models by the area under the receiver operating characteristic (ROC) curve (AUC), accuracy, sensitivity, and specificity to assess their predictive efficacy.ResultsThe combined model had an AUC of 0.808, a sensitivity of 88.72%, a specificity of 60.87%, and an accuracy of 75.81% in predicting pCR of HER2-positive breast cancer after NACT, which was significantly better than the clinicopathological model (AUC = 0.656) and the US model (AUC = 0.769). In addition, six characteristics were screened as independent predictors, namely the Clinical T stage, Clinical N stage, PR status, posterior acoustic, margin, and calcification.ConclusionThe conventional US combined with clinicopathological characteristics to construct a combined model has a good diagnostic effect in predicting pCR in HER2-positive breast cancer and is expected to be a useful tool to assist clinicians in effectively determining the efficacy of NACT in HER2-positive breast cancer patients.

Pathological complete response and survival of HER2-positive invasive breast cancer following docetaxel, carboplatin, and trastuzumab neoadjuvant therapy: a Vietnamese experience

Introduction. Neoadjuvant chemotherapy for HER2-positive breast cancer consists of a chemotherapy regimen plus trastuzumab with or without pertuzumab. The use of trastuzumab has been shown to improve pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Purposes: To evaluate the efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in the treatment of HER2-positive breast cancer in Vietnamese patients. Material and methods. This retrospective study reviewed stage II–III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) at the Vietnamese National Cancer Hospital. The primary endpoint was the pCR rate which was defined as the absence of invasive tumor in the breast and axillary nodes (ypT0/is, ypN0). The secondary endpoints were DFS, OS, and toxicities. Results. The complete and partial clinical response of 51 patients were 33.3% and 58.8%, respectively. The pCR rate was 41.2%; there was a significantly higher response in cT1-2 patients compared to cT3-4 ones (61.1% vs. 39.3%, p = 0.033). Three-year estimated DFS and OS rates were 81.3% and 93.0%, respectively. Treatment was generally well tolerated. Grade 3/4 neutropenia and anemia were uncommon (21.6% and 7.8%). No symptomatic cardiac dysfunction occurred. Conclusions. Neoadjuvant TCH, non-anthracycline chemotherapy with single anti-HER2 regimen achieved high efficacy, with a good pCR rate and favorable tolerability in stage II or III HER2-positive breast cancer patients.

Abstract 5436: Developing artificial intelligence algorithms to predict response to neoadjuvant chemotherapy in HER2-positive breast cancer

Abstract Increasing implementation of whole slide image (WSI) and advances in computing capacity enable the use of artificial intelligence (AI) in pathology, such as quantification of biomarkers, aids in diagnosis and detection of lymph node metastasis. However, predicting therapy response in cancer patients from pre-treatment histopathologic images remains a challenging task, limited by poor understanding of tumor immune microenvironment. In this study, we aimed to develop AI models using multi-source histopathologic images to predict neoadjuvant chemotherapy (NAC) response in HER2-positive (HER2+) breast cancers. First, pretreatment tumor tissues were stained with Hematoxylin and Eosin (H&amp;E) and multiplex immunohistochemistry (IHC) including tumor immune microenvironment markers (PD-L1: immune checkpoint protein; CD8: marker for cytotoxic T-cells; and CD163: marker for type 2 macrophages). Next, we developed an AI-based pipeline to automatically extract histopathologic features from H&amp;E and multiplex IHC WSIs. The pipeline included: A) H&amp;E tissue segmentation based on DeepLabV3 model to generate stroma, tumor, and lymphocyte-rich regions. B) IHC marker segmentation to segment CD8, CD163, and PD-L1 stained cells. C) H&amp;E and IHC non-rigid registration to match H&amp;E and IHC images since they were stained from different levels of tissue. D) Image-based registration and segmentation histopathologic feature construction. A total of 36 histopathological features were constructed to represent tumor immune microenvironment characteristics such as ratios of PD-L1, CD8 and CD163 in tumoral, stromal or lymphocyte-rich regions. They were used to train machine learning (ML) models to predict NAC response in a training dataset with 62 HER2+ breast cancers (38 with complete and 24 with incomplete response). The ML model using logistic regression demonstrated the best performance with an area under curve (AUC) of 0.8975. We also tested ML models using pathologists-derived histopathologic features, but the best performed model showed an AUC of 0.7880. Finally, the developed logistic regression ML model was tested on an external validation dataset with 20 HER2+ breast cancers (10 with complete and 10 with incomplete response) and yielded an AUC of 0.9005. In summary, we described an automatic, accurate and interpretable AI-based pipeline to extract histopathologic features from H&amp;E and IHC WSIs and then used these features to develop machine learning model to accurately predict NAC response in HER2+ breast cancers. The ML model using AI-based extracted features outperformed the model using features manually generated by pathologists. Citation Format: Zhi Huang, Anil V. Parwani, Kun Huang, Zaibo Li. Developing artificial intelligence algorithms to predict response to neoadjuvant chemotherapy in HER2-positive breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5436.

PIK3CA mutations are associated with pathologic complete response rate to neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer

BackgroundNeoadjuvant treatment with a dual anti-human epidermal growth factor receptor 2 (HER2) blockade with pyrotinib and trastuzumab has been shown to be effective for HER2-positive breast cancer.MethodsThe genomic characteristics of 425 cancer-related genes from the archived tumour blocks of 50 patients enrolled in a prospective neoadjuvant pyrotinib and trastuzumab plus chemotherapy clinical trial (ChiCTR1900022293) were assessed by next-generation sequencing (NGS). The relationship between tumour biomarkers and the postoperative pathological complete response (pCR) were explored.ResultsForty-five patients completed neoadjuvant chemotherapy and final surgery, of which 26 (58%) achieved a pCR. Among all driver gene mutations, PIK3CA mutation was screened out for having a significant relationship with the treatment response. The pCR rate of patients with wild-type PIK3CA was significantly higher than patients with mutated PIK3CA (80.8% vs. 26.3%; P = 0.00057), and remained significant after a multiple comparison adjustment (Padjusted = 0.024). We further evaluated the predictive value with logistic regression model of clinical features, genetic biomarkers or both, an AUC of 0.912 (95% CI: 0.827−0.997) was achieved in the integrated model.ConclusionsOur data suggest that HER2-positive breast cancers with activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy.

Neoadjuvant Trastuzumab and Pertuzumab for Early HER2-Positive Breast Cancer: A Real World Experience.

Background Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3–57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3–4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8–46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75–99%). Conclusion This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.

Circulating Proteins Associated with Response and Resistance to Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

Simple SummaryThe goal of this study was to find circulating proteins that can be easily sampled and incorporated into a clinical setting to improve predictive treatment response in HER2-positive breast cancer patients receiving neoadjuvant chemotherapy. We looked for potential biomarkers in serum, which we identified using two proteomics techniques: qualitative LC-MS/MS and a quantitative assay that assessed protein expression between responders and non-responders HER2-positive breast cancer patients to neoadjuvant chemotherapy.Despite the increasing use of neoadjuvant chemotherapy (NAC) in HER2-positive breast cancer (BC) patients, the clinical problem of predicting individual treatment response remains unanswered. Furthermore, the use of ineffective chemotherapeutic regimens should be avoided. Serum biomarker levels are being studied more and more for their ability to predict therapy response and aid in the development of personalized treatment regimens. This study aims to identify effective protein networks and biomarkers to predict response to NAC in HER2-positive BC patients through an exhaustive large-scale LC-MS/MS-based qualitative and quantitative proteomic profiling of serum samples from responders and non-responders. Serum samples from HER2-positive BC patients were collected before NAC and were processed by three methods (with and without nanoparticles). The qualitative analysis revealed differences in the proteomic profiles between responders and non-responders, mainly in proteins implicated in the complement and coagulation cascades and apolipoproteins. Qualitative analysis confirmed that three proteins (AFM, SERPINA1, APOD) were correlated with NAC resistance. In this study, we show that serum biomarker profiles can predict treatment response and outcome in the neoadjuvant setting. If these findings are further developed, they will be of significant clinical utility in the design of treatment regimens for individual BC patients.

The Therapeutic Effectiveness of Neoadjuvant Trastuzumab Plus Chemotherapy for HER2-Positive Breast Cancer Can Be Predicted by Tumor-Infiltrating Lymphocytes and PD-L1 Expression.

IntroductionNeoadjuvant trastuzumab plus chemotherapy may affect programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in HER2-positive breast cancer. Discordant results were shown on the correlation between PD-L1 expression or TILs and the effectiveness of neoadjuvant therapy in HER2-positive breast cancer patients. This study aimed to clarify the predictive value of PD-L1 expression and TILs in neoadjuvant therapy in patients with HER2-positive breast cancer.MethodsHER2-positive breast cancer cases receiving neoadjuvant treatment (NAT; n = 155) were retrospectively collected from July 2013 to November 2018. Histopathologic analysis of TILs was performed on hematoxylin and eosin (H&E)-stained sections from pre- and post-NAT specimens. The TIL score as a categorical variable can be divided into high (≥30%) and low (<30%) categories. The expression of PD-L1 was detected by immunohistochemistry, and the percentage of positive membranous staining (at least 1%) in tumor cells (PD-L1+TC) and TILs (PD-L1+TILs) was scored.ResultsIn our study, 87 patients received neoadjuvant chemotherapy alone and 68 received neoadjuvant trastuzumab plus chemotherapy. Multivariate logistic regression analysis confirmed that lymph node metastasis, high TILs, and PD-L1+TILs in pre-neoadjuvant therapy specimens were independent predictors of pathological complete response (pCR) in neoadjuvant therapy (p < 0.05, for all). Among all patients, TILs were increased in breast cancer tissues post-neoadjuvant therapy (p < 0.001). Consistent results were found in the subgroup analysis of the trastuzumab plus chemotherapy group and the chemotherapy alone group (p < 0.05, for both). In 116 non-pCR patients, PD-L1+TC was decreased in breast cancer tissues post-neoadjuvant therapy (p = 0.0219). Consistent results were found in 43 non-pCR patients who received neoadjuvant trastuzumab plus chemotherapy (p = 0.0437). However, in 73 non-pCR patients who received neoadjuvant chemotherapy, there was no significant difference in PD-L1+TC expression in pre- and post-neoadjuvant therapy specimens (p = 0.1465). On the other hand, in the general population, the neoadjuvant trastuzumab plus chemotherapy group, and the neoadjuvant chemotherapy group, PD-L1+TILs decreased after treatment (p < 0.05, for both).ConclusionHigher TIL counts and PD-L1+TILs in pre-neoadjuvant therapy specimens and lymph node metastasis are independent predictors of pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapy. TIL counts, PD-L1+TC, and PD-L1+TILs changed before and after neoadjuvant trastuzumab plus chemotherapy for HER2-positive breast cancer, which may suggest that, in HER2-positive breast cancer, neoadjuvant trastuzumab plus chemotherapy may stimulate the antitumor immune effect of the host, thereby preventing tumor immune escape.

Neoadjuvant chemotherapy for HER2-positive breast cancer using dose-consolidated regimens and dual anti-HER2 blockade with pertuzumab and trastuzumab (preliminary results)

The main goal of neoadjuvant chemotherapy (NACT) in aggressive breast cancer (BC) subtypes (triple-negative, HER2-positive) is to achieve complete pathological response (pCR), since it is associated with a significant decrease in the likelihood of recurrence and death. Currently, the standard approach for HER2+ BC stage II–III is NACT with the inclusion of a double anti-HER2 blockade, since this significantly increases the frequency of pCR. To date, it remains unclear whether the intensification of modern anthracycline-taxane-containing regimens of NACT affects the incidence of pCR in different BC subtypes, including HER2-positive, provided that a double anti-HER2 blockade is used.The aim of our prospective observational study from daily clinical practice was to assess the efficacy (according to the RCB system and the frequency of pCR) and tolerability of dose-dense NACT in stage II–III HER2-positive BC.Materials and methods. The study included 86 patients, mean age 45 years (26–74 years), in 96.5% of cases, the tumor was represented morphologically by invasive cancer of a nonspecific type, in 53.5% of the tumors had a positive luminal B HER2 phenotype, in 46.5% – non-luminal HER2+. The majority of patients (67.4%) had locally advanced inoperable breast cancer; in 80.2% of cases, metastatic lesions of regional lymph nodes were determined. NACT included anthracyclines and taxanes: four cycles of AC in a dose-dense regimen (once every 2 weeks), then four cycles of docetaxel 75 mg/m2 once every 3 weeks + trastuzumab + pertuzumab.Results. The frequency of pCR = RCB0 in the entire group was 54.7% (47/86), in locally advanced breast cancer – 55.9%, in operable breast cancer – 51.9%. In the luminal HER2+ subtype, the frequency of pCR was lower than in the non-luminal HER2+ subtype – 43.5% vs 67.5%, however, the differences were statistically insignificant (p = 0.09). The frequency of RCB0–I in ER+ HER2+ subtype was 60.9%, as in ER-HER2+ – 80%. Conclusions. In our study, for the first time, the efficacy of dose-dense NACT in HER2+ breast cancer was assessed; it was shown that the frequency of pCR and RCB0–I correspond to those in standard anthracycline-taxane-containing regimens. In the context of the use of double anti-HER2 blockade, the anthracycline stage, most likely, does not need to be escalated, since this does not lead to an increase in the frequency of complete pathomorphological regressions.

HER2 Testing Characteristics Can Predict Residual Cancer Burden following Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

Objectives The response to HER2-targeted neoadjuvant chemotherapy (NAC) in HER2-positive (+) breast cancer can be quantified using residual cancer burden (RCB) pathologic evaluation to predict relapse free/overall survival. However, more information is needed to characterize the relationship between patterns of HER2 testing results and response to NAC. We evaluated clinicopathologic characteristics associated with RCB categories in HER2+ patients who underwent HER2-directed NAC. Methods A retrospective chart review was conducted with Stage I–III HER2+ breast cancer cases following NAC and surgical resection. HER2 immunohistochemistry (IHC) staining and fluorescence in situ hybridization (FISH), histologic/clinical characteristics, hormone receptor status, and RCB scores (RCB-0, RCB-I, RCB-II, and RCB-III) were evaluated. Results 64/151 (42.4%) patients with HER2+ disease had pathologic complete response (pCR). Tumors with suboptimal response (RCB-II and RCB-III) were more likely to demonstrate less than 100% HER2 IHC 3+ staining (p < 0.0001), lower HER2 FISH copies (p < 0.0001), and lower HER2/CEP17 ratios (p = 0.0015) compared to RCB-I and RCB-II responses. Estrogen receptor classification using ≥10% versus ≥1% staining showed greater association with higher RCB categories. Conclusions HER2+ characteristics show differing response to therapy despite all being categorized as positive; tumors with less than 100% IHC 3+ staining, lower HER2 FISH copies, and lower HER2/CEP17 ratios resulted in higher RCB scores.

Is there a correlation between HER2 gene amplification level and response to neoadjuvant treatment with trastuzumab and chemotherapy in HER2-positive breast cancer?

There are contradictory data regarding the correlation between HER2 amplification level determined by in situ hybridization and evolution after treatment with anti-HER2 therapies. The aim of this study was to correlate quantitative results of FISH (ratio HER2/CEP17 and number of HER2 signals/nucleus) with pathological response achieved after neoadjuvant treatment with trastuzumab and chemotherapy. For this purpose, we analysed 100 consecutive HER2-positive cases of breast carcinoma treated with neoadjuvant therapy. HER2 amplification determined by FISH was found in 92 of the 100 cases studied. pCR was obtained in 58% of the patients whose tumours presented amplification. In contrast, no pCR was obtained in the 8 patients with non-amplified tumours. A significant direct correlation between HER2 high amplification (HER2/CEP17 ratio > 5 or HER2 signals/nucleus > 10) and pCR was found. In conclusion, HER2 amplification levels are clinically relevant because they provide oncologists with valuable information on the possibilities of achieving pCR after neoadjuvant treatment.

Adjuvant concomitant treatment with traditional Chinese medicines in patients receiving chemotherapy for HER2-Positive breast cancer: A pilot randomized controlled trial

This study aimed to evaluate the impact of Chinese medicine on controlling cancer and easing adverse events in patients with HER2-positive breast cancer. We recruited consecutive HER2-positive breast cancer patients who underwent radical mastectomy from January 2015 to January 2019. Patients were randomly assigned to receive chemotherapy plus Chinese medicine or chemotherapy alone. The left ventricular global longitudinal strain was better in the experimental group (P < 0.01). The reduction in white blood cells was more significant in the control group (P < 0.01). Hepatic function in the experimental group was better than that in control group after chemotherapy (P < 0.01). In addition, the scores of symptom dimensions for pain, diarrhea, and hair loss were better in the experimental group than in the control group after chemotherapy (P < 0.01). For patients with HER2-positive breast cancer, personalization of traditional Chinese medicine can not only enhance the anti-cancer function of chemotherapy but also ease serious adverse effects.

Abstract PS5-27: The predictive value of tumor-infiltrating lymphocytes and PD-L1 expression on the efficacy of neoadjuvant trastuzumab plus chemotherapy in HER2-positive breast cancer

Abstract Background:Many studies have explored the predictive factors for the efficacy of neoadjuvant therapy in HER2 + breast cancer. However, no reliable and widely used biomarker was found till now except several clinicalpathologic factors including HER2. HER2 oncogene can regulate the recruitment and activation of tumor-infiltrating immune cells (TILs) and trastuzumab therapeutic effects by inducing programmed death ligand 1 (PD-L1), suggesting that TILs and the expression of PD-L1 may be associated with the efficacy of trastuzumab. Several studies have verified certain predictive value of TILs and PD-L1 in HER2 + breast cancer patients, but controversy remains. Besides, most of them focus on the expression of PD-L1 or TILs before neoadjuvant therapy, but not the change in the paired tissues before and after neoadjuvant therapy. This study aimed to investigate the change of TILs and the expression of PD-L1 in the paired tissues before and after neoadjuvant therapy and the correlation to the efficacy of neoadjuvant trastuzumab plus chemotherapy and disease-free survival (DFS) in HER2+ breast cancer patients.Methods:HER2+ breast cancer cases receiving neoadjuvant therapy (n=115) were retrospectively collected between July 2013 and November 2018. The expression of PD-L1 was detected by immunohistochemistry using SP142 antibody and the percentage of positive membranous staining in tumor cells (TC-PD-L1) and TILs (TILs-PD-L1) was scored respectively. TIL percentile score for full sections were assessed by two pathologists independently. Results:In our study, 87 patients receiving neoadjuvant chemotherapy alone, and 68 patients receiving neoadjuvant trastuzumab plus chemotherapy. Among them, 39 patients achieved pCR and 116 patients were non-pCR. Univariate analysis confirmed that the pCR was positively correlated with high TILs and TILs-PD-L1 expression before neoadjuvant therapy (P&amp;lt; 0.05). Multivariate logistic regression analysis confirmed that pre-treatment TILs-PD-L1 expression but no other clinicalpathologic factors,was independent predictor of pCR in neoadjuvant therapy (P&amp;lt;0.05).Among all patients, TILs increased in breast cancer tissues after neoadjuvant therapy (P&amp;lt;0.001). Consistent results were found in subgroup analysis of trastuzumab plus chemotherapy group and chemotherapy alone group (P&amp;lt;0.05). In 116 non-pCR patients, TC-PD-L1 was down-regulated in breast cancer tissues after neoadjuvant therapy (P=0.0219). Consistent results were found in 43 non-pCR patients receiving neoadjuvant trastuzumab plus chemotherapy(P=0.0437). While in 73 non-pCR patients receiving neoadjuvant chemotherapy, there was no significant difference in TC-PD-L1 expression before and after neoadjuvant therapy (P=0.1465). On the other hand, in the general population, neoadjuvant trastuzumab plus chemotherapy group and neoadjuvant chemotherapy group, TILs-PD-L1 were all down-regulated after treatment(P&amp;lt;0.05).Kaplan-Meier analysis showed that the changes of TILs, TC-PD-L1, TILs-PD-L1 between pre and post neoadjuvant therapy have no correlations with DFS. In multivariate Cox regression analysis, lymph node status and distant metastasis were independent prognostic factors for DFS.Conclusions:1. Pre-treatment high TILs-PD-L1 was an independent predictor of PCR in patients with HER2+ breast cancer treated with neoadjuvant therapy.2. Trastuzumab maybe relate to the down-regulation of TC-PD-L1 and TILs-PD-L1 expression. 3. Lymph node status and distant metastasis were independent prognostic factors.4. Both TILs-PD-L1 and TILs change before and after neoadjuvant therapy for HER2-positive breast cancer, which may suggest that the immune microenvironment plays a role in neoadjuvant therapy. Citation Format: Huihui Li, Mao Shang, Yajing Chi, Sha Yin. The predictive value of tumor-infiltrating lymphocytes and PD-L1 expression on the efficacy of neoadjuvant trastuzumab plus chemotherapy in HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-27.

Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial.

Background:Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade.Methods:Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0).Results:From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8–50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3–67.9) in the TCH group (p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group (p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group (p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group (p = 0.006).Conclusion:For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy.Trial registration:This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

Association Between the HER2 Protein Expression Level and the Efficacy of Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

ObjectiveThis study aimed to assess the relationship between human epidermal growth factor receptor-2 (HER2) protein expression level and clinicopathological features of HER2-positive breast cancer, and to analyze whether the expression level of HER2 protein could predict the response to anti-HER2 therapy.MethodsThe present study included 296 patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy (NAC) containing trastuzumab between January 2014 and November 2019. The univariate comparisons of the differences in clinicopathological parameters between different HER2 protein expression groups, and the association between HER2 protein expression level and efficacy of NAC, were made using a X2 test or Mann–Whitney U-test. Multivariate analyses of the differences in clinicopathological parameters between different HER2 protein expression groups, and the association between HER2 protein expression level and efficacy of NAC, were performed using logistic regression analysis.ResultsA total of 110 patients achieved a pathological complete response (pCR) after NAC. The pCR rate was 37.2%. The study showed that patients who were HR-negative, AR-positive, and CK5/6-negative had significantly higher expression level of HER2 protein [odds ratio (OR) = 0.183, P < 0.001; OR = 6.414, P = 0.004; OR = 0.261, P = 0.004, respectively]. Patients with HER2 3+ detected by immunohistochemistry (IHC) had significantly higher pCR rates compared with patients with HER2 2+. The HER2 protein expression level might effectively predict the efficacy of NAC in patients with HER2-positive breast cancer (OR = 3.520, P = 0.003).ConclusionThe HER2 protein expression level was related to multiple clinical features in patients with HER2-positive breast cancer. For example, hormone receptor, androgen receptor, cytokeratin5/6, and HER2 protein expression level may be used to predict the response to NAC in patients with HER2-positive breast cancer and may serve as a predictive factor for NAC efficacy.

50P Cardiosafe nano-formulation of doxorubicin allows coadministration with trastuzumab in neoadjuvant setting improving antitumor efficacy and preventing trastuzumab-mediated cardiotoxicity in HER2 + murine model of breast cancer

The mainstay of neoadjuvant chemotherapy for HER2-positive breast cancer (BC) is the combination of highly cytotoxic drugs such as doxorubicin (DOX) and the anti-HER2 therapy with Trastuzumab (TZ), which allows a pathological complete response in up to 50% of patients. Unfortunally, their co-administration is strongly limited by intrinsic cardiotoxicity, therefore only a sequential administration of DOX and TZ is allowed in clinical practice. However, the concurrent use of DOX and TZ has been demonstrated to be more useful both for responder and non-responder patients representing an unmet clinical need in BC oncology.

Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer: results of a randomised Phase 2 study

BackgroundThe effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated.MethodsPatients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate.ResultsA total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4–56.7; P = 0.025).ConclusionsThe standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer.Clinical trial registrationClinical Trial Registration: UMIN-CTR as UMIN000007074.

1O - Trastuzumab emtansine (T-DM1) vs trastuzumab (H) in Chinese patients (pts) with residual invasive disease after neoadjuvant chemotherapy for HER2-positive breast cancer (BC) in the phase III KATHERINE study

BackgroundPts with HER2+ early BC and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a higher risk of recurrence and death than those with a pCR. The KATHERINE (NCT01772472) study showed significantly improved invasive disease-free survival (IDFS) with adjuvant T-DM1 vs H in this population. Here, we compare Chinese pts in KATHERINE to the overall population. MethodsPts with HER2+ BC and residual invasive disease after taxane- and H-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w). IDFS and the secondary endpoints of disease-free survival including non-invasive breast cancers, overall survival, distant recurrence-free interval, and safety were compared between Chinese pts (mainland China, Taiwan, Hong Kong) and the overall population. ResultsThere were 101 (6.8%) Chinese pts in KATHERINE. IDFS was greater in the T-DM1 vs the H group (HR = 0.57; 95% CI: 0.25–1.31), with similar results for secondary endpoints (Table). As in the overall population, Chinese pts receiving T-DM1 vs H had more grade ≥3 adverse events (AEs; 39% vs 4%), serious AEs (SAEs; 20% vs 2%); and AEs leading to treatment discontinuation (28% vs 0). The most common grade ≥3 AE in the T-DM1 arm was thrombocytopenia (22%), a frequency higher than in the overall population (6%). Grade ≥3 hemorrhage was reported in 1 pt (T-DM1 arm). All grade ≥3 thrombocytopenia was resolved or resolving at data cutoff.Table1OTableChineseOverallHT-DM1HT-DM1(N = 50)(N = 51)(N = 743)(N = 743)IDFSPts with event, n (%)14 (28.0)9 (17.6)165 (22.2)91 (12.2)3-yr EF rate, %70.483.877.088.3HRa (95% CI)0.57 (0.25–1.31)0.50 (0.39–0.64); P < 0.001DFSPts with event, n (%)14 (28.0)9 (17.6)167 (22.5)98 (13.2)3-yr EF rate, %70.483.876.987.4HRa (95% CI)0.57 (0.25–1.31)0.53 (0.41–0.68)OSPts with event, n (%)4 (8.0)3 (5.9)56 (7.5)42 (5.7)5-yr EF rate, %90.293.686.892.1HRa (95% CI)0.68 (0.15–3.04)0.70 (0.47–1.05)DRFIPts with event, n (%)8 (16.0)6 (11.8)121 (16.3)78 (10.5)3-yr EF rate, %82.389.583.089.7HRa (95% CI)0.68 (0.24–1.97)0.60 (0.45–0.79)aunstratified hazard ratio Abbreviations: EF, event-free; IDFS, invasive disease-free survival; DFS, disease-free survival (including noninvasive breast cancers); OS, overall survival; DRFI, distant recurrence-free interval. ConclusionsConsistent with the overall study population, T-DM1 was associated with increased efficacy compared to H in Chinese pts. Compared to all pts, increases in SAEs, grade ≥3 AEs, and AEs leading to discontinuation were observed in Chinese pts and were driven by an increase in thrombocytopenia, consistent with previous data in Asian pts. Clinical trial identificationNCT01772472. Editorial acknowledgementMedical writing assistance was provided by Twist Medical and was funded by F. Hoffmann–La Roche. Legal entity responsible for the studyF. Hoffmann-La Roche. FundingF. Hoffmann-La Roche. DisclosureC. Huang: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): EirGenix; Research grant / Funding (institution): MSD; Research grant / Funding (institution): OBI Pharma. Y. Yang: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Mundipharma; Research grant / Funding (institution): Orient Europharma; Full / Part-time employment: Taichung Veterans General Hospital. A. Kwong: Honoraria (self), ICG Fluorescence in Breast Surgery speaker: Stryker; Honoraria (self), Chairing Meeting: AstraZeneca; Honoraria (self), Chairing Meeting: Pfizer; Honoraria (self), Honoraria (institution), Chairing Meeting, Support on trial to HKU: Roche; Honoraria (institution), Suppprt on trial to HKU: Merck; Honoraria (institution), Support on trial to HKU: Novartis; Honoraria (institution), Supporting device & consumables for Prospective Study on Cryosurgery for treatment of Early Breast Cancer.: WKK Medical Equipment company limited; Leadership role, Chairman: Hong Kong Hereditary Breast Cancer Family Registry; Leadership role, Founding member: Asian BRCA (ABRCA); Leadership role, Council Member: Hong Kong Society of Breast Surgeons. L-M. Tseng: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: AstraZeneca. M-C. Liu: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. Y. Feng: Full / Part-time employment: Roche (China) Holding Ltd. G. Sun: Full / Part-time employment: Roche (China) Holding Ltd. I.R. Yan: Full / Part-time employment: Roche (China) Holding Ltd. All other authors have declared no conflicts of interest.

Clinicopathologic Factors Associated With Response to Neoadjuvant Anti-HER2–Directed Chemotherapy in HER2-Positive Breast Cancer

BackgroundHER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2+ breast cancer. Patients and MethodsPatients with HER2+ breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio. ResultsSmall tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P < .05). TIL hot spot was associated with RCB in univariate (P < .05) but not multivariate analyses. ConclusionClinicopathologic features may help predict HER2+ breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.