Early Human Epidermal Growth Factor Research Articles

Abstract PO3-14-05: Integration of metabolomics and transcriptomics to Reveal Potential Biomarkers Associated with Treatment Response of Neoadjuvant Therapy in HER2+ Breast Cancer

Abstract Background: Neoadjuvant therapy (NAT) has become the standard treatment for early human epidermal growth factor receptor 2 positive (HER2+) breast cancer. For patients with HER2+ breast cancer, achieving a pathologic complete response (pCR) is highly indicative of their prognosis. However, not all HER2+ breast cancer patients could benefit from the NAT, about 40%-50% patients could not achieve pCR at surgery, even if they used the present standard neoadjuvant regime of TCbHP (taxane, carboplatin, trastuzumab and pertuzumab). This study was conducted to explore potential indicators associated with neoadjuvant efficacy of TCbHP in HER2+ breast cancer. Methods: Consecutive HER2+ breast cancer patients, who received and completed NAT with TCbHP regime and subsequent surgery at Chongqing University Cancer Hospital were prospectively enrolled. LC-MS and GC-MS platform-based untargeted metabolomics were performed to determine the metabolic profiles of plasma samples from these patients at different time points during treatment period. Random forest (RF) was used to establish predictive models based on pre-therapeutic metabolic traits. The potential monitors for the treatment response were obtained by time series analysis. Transcriptome analysis was performed in available samples to identify differentially expressed genes (DEGs) before treatment. qRT-pCR was used to detect DEGs in tastuzumab-sensitive and -resistant cell lines. Metabolic and transcriptomic data were integrated to explore substantially altered pathways that might be responsible for drug resistance. Results: From July 20, 2020 to May 28, 2021, a total of 40 HER2+ breast cancer patients with 120 plasma samples were eligible and recruited for this study. Of whom 21 (52.5%) patients achieved pCR and 19 (47.5%) achieved non-pCR, there are no significant difference in baseline clinicopathological features between pCR and non-pCR patients. There were significant differences in plasma metabolic profiles between non-pCR and pCR groups before and during treatment. A total of 100 differential metabolites were identified between pCR and non-pCR patients at pre-therapeutic period, which were markedly enriched in 40 metabolic pathways. Four key metabolites [sophorose, N-(2-acetamido)iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] were selected by RF analysis. The AUC value to discriminate pCR and non-PCR group to NAT of the single potential metabolite or combined panel of these metabolites were more than 0.910. 18 metabolites exhibit a potential for monitoring efficacy. Among 163 DEGs identified by RNA-seq, some genes might associate with trastuzumab resistance detected by qRT-PCR in cell lines. 39 altered pathways were found abnormally expressed at both the transcriptional and metabolic levels, including ABC transporters, protein digestion and absorption, mineral absorption, et al. Conclusion: By metabolomics analysis, we have both offered a road map of the molecular alterations underlying NAT of TCbHP regime in HER2+ breast cancer and a preliminary analysis of a unique metabolic signature that might be used to distinguish non-pCR from pCR patients. Metabolomics integrated with transcriptomics analysis could assist for gaining new insights into biochemical pathophysiology and might facilitate the development of new treatment targets for insensitive patients. Citation Format: Ningning Zhang, Yuxin Huang, Guanwen Wang, Yimei Xiang, Zhouhong Jing, Junjie Zeng, Feng Yu, Xianjun Pan, Wenqi Zhou, Xiaohua Zeng. Integration of metabolomics and transcriptomics to Reveal Potential Biomarkers Associated with Treatment Response of Neoadjuvant Therapy in HER2+ Breast Cancer [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 PO3-14-05.

Selective Avoidance of Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in Human Epidermal Growth Factor 2-Positive/Triple-Negative Breast Cancer Patients With Excellent Response.

The Avoid Axillary Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy (ASLAN) trial aims to demonstrate the oncologic safety of omitting axillary surgery in patients with excellent response after neoadjuvant chemotherapy (NACT) for early human epidermal growth factor 2 (HER2)-positive (+)/triple-negative breast cancer (TNBC) who have undergone breast-conserving surgery (BCS) and adjuvant radiotherapy. The ASLAN trial will provide crucial information that could change the procedure in highly selected patients undergoing axillary surgery after NACT. ASLAN is a prospective, multicenter, and single-arm surgical trial. The recruitment will be conducted among five tertiary care hospitals in the Republic of Korea. The total number of patients to be recruited will be 178, and we plan to complete patient enrollment by December 2023. The enrollment is considered among patients with HER2+ breast cancer (BC) or TNBC at clinical stage T1-3N0-1M0 who are expected to achieve breast pathological complete response (BpCR) based on a combination of radiologic imaging and physical examination after NACT. BCS was performed on eligible patients. After BCS, patients who showed BpCR were enrolled with the omission of sentinel lymph node biopsy (SLNB). The primary study endpoint upon completion of this trial is 5-year recurrence-free survival, and the secondary endpoints include the 5-year ipsilateral breast tumor recurrence interval, 5-year ipsilateral axillary recurrence interval, 5-year distant metastasis-free survival, 5-year BC-specific survival, 5-year overall survival, 5-year contralateral BC-free survival, re-operation rate according to breast biopsy after NACT, adverse events within 5 years, and quality of life. Several clinical trials are currently underway to determine whether SLNB can be omitted after NACT in patients with HER2+ BC or TNBC that are expected to achieve pathologic complete response. The ASLAN trial is expected to provide valuable clues regarding the feasibility of omitting axillary surgery in highly selected patients. ClinicalTrials.gov Identifier: NCT04993625. Registered on August 6, 2021. Clinical Research Information Service Identifier: KCT0006371. Registered on July 22, 2021.

Anthracyclines versus No Anthracyclines in the Neoadjuvant Strategy for HER2+ Breast Cancer: Real-World Evidence.

Deescalation strategies omitting anthracyclines (AC) have been explored in early human epidermal growth factor receptor 2-positive breast cancer (HER2+ EBC), showing similar efficacy regarding pathological complete response (pCR) and long-term outcomes as AC-containing regimens. The standard treatment for this tumor subtype is based on chemotherapy and dual HER2 blockade with trastuzumab and pertuzumab, with AC-containing regimens remaining a frequent option for these patients, even in non-high-risk cases. The primary aim of this study was to assess and compare the effectiveness of neoadjuvant regimens with and without AC used in the treatment of HER2+ EBC in the clinical practice according to the pCR achieved with each. This retrospective multicentric study included patients with HER2+ EBC from Portuguese, Spanish, and Chilean hospitals (January 2018-December 2021). Patients receiving neoadjuvant therapy (NAT) with dual HER2 blockade (trastuzumab and pertuzumab), followed by surgery, were included. Statistical analysis used chi-squared/Fisher's exact test for associations, multivariate logistic regression for pCR, and Kaplan-Meier method for event-free survival (EFS). IBM SPSS Statistics 29.0 analyzed the data. The study included 371 patients from eight hospitals. Among them, 237 received sequential AC and taxane-based chemotherapy with 4 cycles of trastuzumab and pertuzumab, while 134 received 6 cycles of TCHP (docetaxel, carboplatinum, trastuzumab, and pertuzumab). The average age of the patients was 52.8 years and 52.7 years, respectively. Omitting AC from the neoadjuvant approach did not preclude achieving pCR [p=0.246, 95% confidence interval (CI) 0.235-0.257] and was safe regardless of patient characteristics. Relapse rates were 6.8% (16 patients) in the AC group and 4.5% (6 patients) in the TCHP group. Over a median follow-up of 2.9 years, the estimated 3-year EFS was 92.5% in the AC group and 95.4% in the TCHP group (hazard ratio 0.602, 95% CI 0.234-1.547, p=0.292, favoring TCHP). This study reports real-world evidence showing similar pCR and EFS outcomes with treatment regimens with and without AC and raises awareness of possible overtreatment and long-term toxicity in some patients with HER2+ EBC with the use of AC.

Neoadjuvant Therapy and Axillary Lymph Node Status in HER2-Positive Breast Cancer

Based on an estimating model, the aim of our study was to evaluate the axillary lymph node involvement of patients with primary invasive early human epidermal growth factor receptor 2 (HER2)-positive breast cancer before receiving neoadjuvant therapy (NAT). Patients with primary surgery (n = 63) were compared with patients who had received NAT (combined chemo/HER2-targeted antibody therapy) before surgery (n = 152). In patients receiving NAT, a positive N stage was estimated in 73.2 (49.8%) tumors resulting in a conversion (positive N stage-ypNpositive) of 35.5%. In 126 cases with ypN0 stage, a positive N stage was estimated in 41.4%.

Abstract OT2-14-01: Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial

Abstract Objective: Trastuzumab-based adjuvant therapy was demonstrated to improve the prognosis of early human epidermal growth factor receptor 2 (HER-2) positive breast cancer, while about 10% of patients showed primary resistance. ExteNET study showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in women with HER2-positive breast cancer. Besides, for patients with early hormone receptor positive breast cancer within 1 year of prior trastuzumab with residual disease after neoadjuvant therapy, extended adjuvant neratinib showed prolonged overall survival, which suggested the potential benefit of extended adjuvant therapy for high-risk patients. Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting epidermal growth factor receptor, HER2, and HER4, which showed promising efficacy and manageable safety profiles in the treatment of HER-2 positive advanced breast cancer. In this study, we aimed to evaluate the efficacy and safety of extended adjuvant pyrotinib following trastuzumab-based adjuvant therapy in patients with high-risk early HER-2 positive breast cancer. Methods: In this ongoing multicenter, open-label, phase II trial at 23 centers in China, women with operable high-risk early HER-2 positive breast cancer and known hormone receptor status, who have completed trastuzumab-based adjuvant therapy within 6 months were enrolled. High-risk patients must meet one of the following criteria: N stage ≥1; T stage ≥2; did not achieve pathological complete response (pCR) after neoadjuvant therapy; had pCR after neoadjuvant therapy but with tumor size ≥ 5cm or N stage ≥2; or tumor size less than 2cm but with high Ki67, histologic grade 3 or with lymph node micrometastasis. Eligible patients were assigned to receive 6 month or 1 year of oral pyrotinib 400mg/day. The primary endpoint was the 2-year iDFS rate. Results: Between January, 2019 and February, 2022, a total of 142 eligible women were enrolled and assigned to receive pyrotinib, with a median age of 50 (range: 25-72) years old. Ninety-seven patients had a T stage ≥2. A total of 108 patients (76.1%) had node-positive disease, and 64 (45.1%) were hormone receptor positive. Twenty-five patients used neoadjuvant therapy previously, and all of them did not receive pCR (Table 1). After a median follow-up of 20 (range: 0.25-41) months, the 2-year iDFS rate was not available. Two and four patients reported invasive disease events after 6-month and 1-year of follow-up, with the 6-month and 1-year iDFS rates of 98.6% and 97.2%, respectively. The most common adverse events reported was diarrhea (78.2%), followed by fatigue (36.6%), lymphocyte count decreased (36.6%), nausea (33.1%) and hand-foot syndrome (33.1%). Forty-three patients experienced grade 3 diarrhea, and no grade 4 or higher adverse event was reported (Table 2). Adverse event leading to treatment discontinuation occurred in 12 (8.5%) patients. Conclusion: Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy was well-tolerated and showed potential efficacy in high-risk early HER-2 positive breast cancer. The follow-up is ongoing to determine the long-term benefit of extended adjuvant pyrotinib. Table 1. Baseline characteristics of patients ER: estrogen receptor; PR: progesterone receptor. Table 2. Treatment-emergent adverse event occurring in at least 10% of the patients Citation Format: Feilin Cao, Zhaosheng Ma, Guinv Hu, Xiaotao Zhu, Shuguang Li, Shuzheng Chen, Binglie Chen, Zhanwen Li, Weizhu Wu, Xiaochun Ji, Jingde Shu, Deyou Tao, Xiaoqing Hu, Min Zheng, Ouchen Wang, Qingjing Feng, Jing Hao, Xujun Li. Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-14-01.

Neoadjuvant therapy with vs. without anthracyclines for HER2-positive breast cancer: a systematic review and meta-analysis.

Neoadjuvant therapy has become the standard treatment for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer, with most regimens using a combination of anti-HER2-targeted drugs and chemotherapy. However, the combination of anthracyclines and trastuzumab has high cardiac toxicity, and the efficacy evaluation of targeted therapy with or without anthracyclines is not unified. The purpose of this meta-analysis was to evaluate the relative efficacy and safety of anti-HER2-targeted therapy combined with vs. without anthracyclines neoadjuvant treatment. The following databases: PubMed, Medline, Embase, and Cochrane Library were systematically searched. Study inclusion was determined according to PICOS principles. PICOS: Patients, HER2-positive breast cancer; Intervention, anti-HER2-targeted therapy combined with anthracyclines; Control, without anthracyclines; Outcomes, the percentage of pathologic complete response (pCR), breast-conserving surgery (BCS), and grade 3 or worse adverse events according to CTCAE version 4.03; Studies, randomized controlled trials (RCTs) and retrospective studies. The meta-analysis was performed using RevMan5.3 software, and the odds ratio (OR) with 95% confidence intervals (CIs) was performed. In total, 11 articles involving 1,998 patients were included with 1,155 patients in the anthracycline-containing group and 843 patients in the anthracycline-free group. For efficacy, there was no statistically significant difference in the percentage of pCR (OR 0.95; 95% CI: 0.61-1.48; P=0.83) and BCS (OR 1.18; 95% CI: 0.93-1.49; P=0.17) on anthracycline-free regimens compared with anthracycline-containing regimens. For safety, the combined effect values showed a significantly lower incidence of left ventricular ejection fraction decreases with the anthracycline-free regimen than with the anthracycline-containing regimen (OR 0.50; 95% CI: 0.35-0.71; P=0.0001). Other adverse effects and survival events were generally not statistically different in incidence between the two groups. The subgroup analysis suggested that hormone receptor status might be the source of heterogeneity in this study. Our study demonstrated that the targeted therapy combined with anthracyclines was associated with an increased risk of cardiac adverse events compared with the anthracycline-free group, with no significant difference in the percentage of pCR and BCS. Due to the high heterogeneity of this meta-analysis, more studies with longer follow-up are needed to validate the current findings and to further explore the removal and retention of anthracyclines.

A multicenter study on efficacy of dual-target neoadjuvant therapy for HER2-positive breast cancer and a consistent analysis of efficacy evaluation of neoadjuvant therapy by Miller-Payne and RCB pathological evaluation systems (CSBrS-026).

The aim of this study was to investigate the factors influencing pathological complete response (pCR) rate in early breast cancer patients receiving neoadjuvant dual-target [trastuzumab (H) + pertuzumab (P)] therapy combined with chemotherapy. Additionally, the consistency of the Miller-Payne and residual cancer burden (RCB) systems in evaluating the efficacy of neoadjuvant therapy for early human epidermal growth factor receptor-2 (HER2)+ breast cancer was analyzed. The clinicopathological data of female patients with early-stage HER2+ breast cancer who received dual-target neoadjuvant therapy at 26 hospitals of the Chinese Society of Breast Surgery (CSBrS) from March 2019 to December 2021 were collected. Patients were allocated to four groups: the HER2 immunohistochemistry (IHC) 3+/hormone receptor (HR)-, IHC3+/HR+, IHC2+ in situ hybridization (ISH)+/HR- and IHC2+ ISH+/HR+ groups. The overall pCR rate for patients, the pCR rate in each group and the factors affecting the pCR rate were analyzed. The consistency between the Miller-Payne and RCB systems in assessing the efficacy of neoadjuvant therapy was analyzed. From March 1, 2019, to December 31, 2021, 77,376 female patients with early-stage breast cancer were treated at 26 hospitals; 18,853 (24.4%) of these patients were HER2+. After exclusion of unqualified patients, 2,395 patients who received neoadjuvant dual-target (H+P) therapy combined with chemotherapy were included in this study. The overall pCR rate was 53.0%, and the patients' HR statuses and different HER2+ statuses were significantly correlated with the pCR rate (P<0.05). The consistency of the pathological efficacy assessed by the Miller-Payne and RCB systems was 88.0% (κ=0.717, P<0.001). Different HER2 expression statuses and HR expression statuses are correlated with the pCR rate after dual-target neoadjuvant therapy in HER2+ breast cancer patients. There is a relatively good consistency between Miller-Payne and RCB systems in evaluating the pathologic efficacy of neoadjuvant therapy for HER2+ breast cancer.

Targeted Therapeutic Options and Future Perspectives for HER2-Positive Breast Cancer.

Simple SummaryThe development of several antiHuman Epidermal Growth Factor Receptor 2 (HER2) treatments over the last few years has improved the landscape of HER2-positive breast cancer. Despite this, relapse is still the main issue in HER2-positive breast cancer. The reasons for therapeutic failure lie in the heterogeneity of the disease itself, as well as in the drug resistance mechanisms. In this review, we intended to understand the milestones that have had an impact on this disease up to their implementation in clinical practice. In addition, understanding the underlying molecular biology of HER2-positive disease is essential for the optimization and personalization of the different treatment options. For this reason, we focused on two relevant aspects, which are triple-positive disease and the role that modulation of the immune response might play in treatment and prognosis.Despite the improvement achieved by the introduction of HER2-targeted therapy, up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown a significant improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). In ER+ HER2+ patients, target therapies such as phosphoinositide-3-kinase (PI3K) pathway inhibition or cyclin-dependent kinases 4/6 blocking may be effective in controlling downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies. Multiple trials have explored these strategies with some promising results, and probably, in the next years conclusive results will succeed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents such as HER-2 therapy plus checkpoint inhibitors, or new vaccines approaches have been investigated in this setting, with promising but controversial results obtained to date.

Abstract P3-14-04: Tailored duration of adjuvant trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer

Abstract Background: A number of clinical trials were conducted to assess the efficacy and toxicity of shorter durations of adjuvant trastuzumab compared with 12-month standard duration. However, the results were controversial and the reduced time varied among trials. To assess the effect of treatment time of adjuvant trastuzumab on the clinical outcomes at trial level, we performed a systematic literature search and a trial-level meta-regression analysis to figure out the appropriate time for trastuzumab treatment. Methods: A comprehensive search of (neo)adjuvant trastuzumab in breast cancer in PUBMED and EMBASE databases from Jan 2000 to June 2019 was performed. We treated the “12-month trastuzumab” as the standard. The “shorter duration” is less than 12 months, including extreme value of 0-month for no trastuzumab. The primary clinical outcome is DFS. HR with 95% confidence intervals (CIs) should be reported. Shortened treatment time (months) and DFS outcome (expressed as HRs) were extracted from each trial. Meta-regression was performed using HR of DFS and shortened time of adjuvant trastuzumab in random-effects model. The coefficient of determination (R2) and the regression coefficient (β) were calculated. We also performed sensitivity analysis by omitting each study to find the potential outliers. Results: A final set of 12 trials was included in the analysis. Five studies compared the 12-month trastuzumab with shorter duration in a non-inferiority setting and 7 studies compared with no trastuzumab in a superiority design (Table 1). The between-study variance τ2 is 0.0062 and the adjusted R2 is 63.14%, which means 63% of the variability among the effects on DFS can be explained by the shortened time of adjuvant trastuzumab, and the remaining between-study variance appears small at 0.0062. We estimated the effects of different shortened times of trastuzumab on DFS and the regression coefficients β of shortened treatment time is 0.04 (P=0.038, 95% CI, 0.0029-0.0788), indicating for each month reduced, the ln(HR) of DFS events increased 0.04. If transferred to HR, the values were 1.042 (e0.04), indicating the risk of DFS would increase 4.2% for each month trastuzumab shortened. Similarly, if 3-month reduced, the risk increased 12.7% (e0.12=1.127); 6-month reduction would increase risk of 27.1%, and 9-month, 43.3% (Table 2). Further subgroup analyses according to estrogen receptor status and lymph nodes status yielded qualitatively similar results. Conclusion: We revealed a significant linear association between shortened time of trastuzumab and the risk of DFS events. These findings suggest that a shorter duration of trastuzumab might be appropriate for patients with lower-risk disease but unacceptable for those with high-risk disease. We believe that the duration of adjuvant trastuzumab should be tailored according to the risk, as well as toxicity and cost. Table 1. Summary of included studies.IDITT numberTrial designHazard marginHR with 95% CIShortened time (month)EndpointMedian Follow-up (year)PHARE1691non-inferiority1.151.08 (0.93-1.25)6DFS7.5HORG481non-inferiority1.531.57 (0.86-2.10)6DFS3Short-HER1253non-inferiority1.291.15 (0.87-1.53)9.9DFS5.2SOLD2174non-inferiority1.31.39 (1.08-1.80)9.9DFS5.2PERSEPHONE4088non-inferiority1.291.07 (0.90-1.27)6DFS5.4E2198227superiorityNA1.18 (0.56-2.44)12DFS6.4NCCTG N98311944superiorityNA1.72 (1.52-1.92)12DFS8.4NSABP B-312102superiorityNA1.72 (1.52-1.92)12DFS8.4HERA3401superiorityNA1.45 (1.27-1.69)12DFS8BCRIG-0062147superiorityNA1.39 (1.18-1.64)12DFS10.3PACS04528superiorityNA1.16 (0.82-1.64)12DFS3.9NOAH235superiorityNA1.69 (1.11-2.63)12EFS3.2 Table 2. Shortened time of adjuvant trastuzumab and increased risk of DFSShortened Time (Month)Change in ln(HR)Increased relative risk of DFS eventsPredicted DFS in APT trial (%)Predicted DFS in N9831/B31 trials (%)10.044%937330.1213%927160.2427%916790.3643%9063120.4862%8958 Citation Format: Ke-Da Yu, Zhi-Rui Zhou, Zhi-Ming Shao. Tailored duration of adjuvant trastuzumab for early human epidermal growth factor receptor 2-positive 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 P3-14-04.

Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer.

PurposeCombining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy.MethodsRCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes.ResultsWe demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS.ConclusionWe conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.

Do early HER2-overexpression breast cancer patients benefit from undergoing neoadjuvant trastuzumab and mastectomy? A meta-analysis.

PurposeTo assess the overall survival (OS) of early human epidermal growth factor receptor 2 (HER2)-enriched breast cancer patients after receiving neoadjuvant trastuzumab (NAT) compared to adjuvant trastuzumab (AT) treatment and the difference in local-regional relapse (LRR) rate with this tumor and treatment between women after mastectomy and women after breast-conserving therapy (BCT).MethodsArticles were retrieved from PubMed, Embase, Web of Science, and Cochrane Library. A pooled odds ratio (OR) with a 95% confidential interval (CI) was calculated. The StataSE version 12.0 software was employed for meta-analysis.ResultsTwelve available clinical studies containing 2366 subjects were included. The OS of NAT compared with that of AT was not significantly different (pooled OR=1.04; 95% CI, 0.47–2.33). There was a significantly lower LRR rate for patients with mastectomy compared to those with BCT (pooled OR=0.58; 95% CI, 0.38–0.89); however, subgroup analysis revealed that the significant advantage of LRR for mastectomy compared to BCT was only represented in women without trastuzumab treatment (pooled OR=0.52; 95% CI, 0.31–0.88) compared to those who received trastuzumab treatment (pooled OR=0.71; 95% CI, 0.34–1.49).ConclusionEarly stage HER2-overexpression breast cancer patients benefit with an equivalent OS from NAT treatment compared to AT. Patients who underwent mastectomy and BCT experienced a similar LRR rate if they received anti-HER2 targeted therapy of trastuzumab, but the LRR rate was discernibly reduced in patients who received mastectomy compared to BCT if they did not also receive trastuzumab treatment.

Organising pneumonia during breast cancer treatment with trastuzumab

A 57-year-old female with early human epidermal growth factor receptor 2 (HER2) positive breast cancer on adjuvant trastuzumab and anastrozole treatment presented with difficulty breathing and fever. Chest X-ray revealed left lower zone consolidation. She was treated with several courses of antibiotics, and despite improvement in her inflammatory markers, the clinical and radiological picture did not. Microbiological cultures from bronchoalveolar lavage fluid were negative. Organising pneumonia was suspected and computed tomography (CT) guided lung biopsy confirmed this. Trastuzumab was suspected as the likely culprit and stopped. High dose steroids commenced and the patient recovered, but later as per the patient’s choice trastuzumab treatment was re-started and she re-developed similar symptoms to her previous presentation with chest X-ray showing new right middle zone consolidation, in the absence of infection, and recurrence of organising pneumonia was diagnosed confirming trastuzumab as the cause. She improved clinically on a higher dose of steroids.

Changing pattern of recurrences in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy in the era of dual anti-HER2 therapy

BackgroundOver the last 10 years, there has been a major treatment revolution for early human epidermal growth factor receptor 2 (HER2)–positive breast cancer. We aimed to explore the outcome of...

Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear. To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab. Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries. Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year. The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety. In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group. Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study. ClinicalTrials.gov Identifier: NCT00593697.

Abstract P1-13-13: The treatment patterns and clinical outcomes of trastuzumab in early human epidermal growth factor receptor 2 (HER2) positive breast cancer in the real-world setting in China

Abstract Background:Several prospective interventional studies have proved the efficacy and safety of trastuzumab in adjuvant treatment in HER2positive breast cancer,while limited data existed to address the treatment patterns and real-world performance of trastuzumab in early HER2 positive breast cancer in China. Methods:We retrospectively analyzed all the pts who were diagnosed with HER2-positive breast cancer,underwent surgery and received adjuvant treatment in National Cancer Center from 2000 to 2012.The treatment patterns and disease free survival (DFS),overall survival (OS) were analyzed respectively. Results:A total of 1398 HER2 positive breast cancer pts were identified.The median follow-up time was 79.1 months.68.5% pts received chemotherapy alone,3.4% pts only received mono trastuzumab,28.2% pts received trastuzumab plus chemotherapy.Among 433 trastuzumab treated pts,64.7% received concurrent trastuzumab with chemotherpy,and 35.3% pts received sequential trastuzumab with chemotherapy Baseline characteristics by Chemotherapy alone and Chemotherapy + Trastuzumab.No(%) of patients characteristicTrastuzumab- (N=957)Trastuzumab+ (N=441)Total (N=1398)Age (years) &amp;lt;=3596 ( 10.0)44 ( 10.0)140 ( 10.0)36 - 50434 ( 45.4)244 ( 55.3)678 ( 48.5)&amp;gt;50427 ( 44.6)153 ( 34.7)580 ( 41.5)Histologic grade I15 ( 1.6)7 ( 1.6)22 ( 1.6)I-II,II480 ( 50.2)224 ( 50.8)704 ( 50.4)II-III,III285 ( 29.8)166 ( 37.6)451 ( 32.3)IDC148 ( 15.5)29 ( 6.6)177 ( 12.7)Other29 ( 3.0)15 ( 3.4)44 ( 3.1)Clinical stage 026 ( 2.7)16 ( 3.6)42 ( 3.0)I259 ( 27.1)108 ( 24.5)367 ( 26.3)II434 ( 45.4)196 ( 44.4)630 ( 45.1)III238 ( 24.9)121 ( 27.4)359 ( 25.7)Hormone receptor status Positive635 ( 66.4)256 ( 58.0)891 ( 63.7)Negative322 ( 33.6)185 ( 42.0)507 ( 36.3) .Trastuzumab plus chemo had significantly longer DFS compared with chemo alone.(85.03%vs72.15%,hazard ratios,HR=0.531,95% confidence interval,95%CI:0.406-0.696, p&amp;lt;0.001).In addition,the concurrent trasuzumab showed the trend with longer DFS compared to the sequential regimen(86.07%vs82.35%,HR=0.843,95%CI:0.515-1.378, p=0.495).Age,tumor size, lymph node status,clinical stage were associated with DFS Results of Cox regression hazard model with treatment groups and patient characteristics on DFSGroupHR95% CIP valueTreatment group Concurrent Trastuzumab0.8430.515-1.3780.495Sequential Trastuzumab Chemotherapy+Trastuzumab0.5310.406-0.696&amp;lt;0.001Chemotherapy alone Age group (years) 0.001&amp;lt;=351.6501.198-2.2730.00236 - 500.8880.702-1.1220.319&amp;gt;50 Histologic grade &amp;lt;0.001I0.5200.210-1.2880.158I-II,II0.5040.379-0.671&amp;lt;0.001II-III,III0.5320.390-0.725&amp;lt;0.001Other0.5140.264-0.9970.049IDC Clinical stage &amp;lt;0.00100.2610.107-0.6370.003I0.2860.207-0.395&amp;lt;0.001II0.4800.379-0.607&amp;lt;0.001III Hormone receptor status 0.022Positive0.7730.621-0.9620.021Negative .OS was also prolonged in trastuzumab plus chemotherapy compared with chemotherapy alone.(93.20%vs85.45%,HR=0.561,95%CI:0.377-0.835, p=0.004). Conclusions:Our study revealed that,there were still more than half of HER2-positive breast cancer pts couldn't reach anti-HER2 therapy in China,the early stage HER2-positive breast cancer pts could significantly benefit from trastuzumab adjuvant therapy in real-world setting. Citation Format: Guo J, Xu B, Li Q, Zhang P, Yuan P, Wang J, Ma F, Fan Y, Cai R, Luo Y, Li Q. The treatment patterns and clinical outcomes of trastuzumab in early human epidermal growth factor receptor 2 (HER2) positive breast cancer in the real-world setting in China [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-13.

Major clinical research advances in gynecologic cancer in 2017.

In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer. For ovarian cancer, 5 topics were selected including poly(ADP-ribose) polymerases inhibitors and immunotherapy. The other potential practice changers covered in this review were lymphadenectomy in advanced disease, secondary cytoreductive surgery in recurrent disease, weekly dose-dense regimen for first-line chemotherapy, incorporation of bevacizumab maintenance in platinum-sensitive recurrent disease, and effect of platinum-free interval prolongation. Conflicting opinions of academic societies on periodic pelvic examination were introduced in conjunction with relevant literature review. For the field of radiation oncology, results of 2 big trials, The Postoperative Radiation Therapy in Endometrial Carcinoma-3 and Gynecologic Oncology Group-258, for endometrial cancer and recent advance in high-dose-rate brachytherapy for cervical cancer were reported. Topics for breast cancer covered adjuvant capecitabine after preoperative chemotherapy, adjuvant pertuzumab and trastuzumab in early human epidermal growth factor receptor 2-positive disease, olaparib for metastatic cancer in patients with a germline BRCA mutation, 20-year risks of recurrence after stopping endocrine therapy at 5 years, and contemporary hormonal contraception and the risk of breast cancer.

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort

AimAdjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab. MethodsA population combining patients from Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan–Meier method, and comparisons between groups were based on the log rank test. ResultsThe SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86–1.19) and similar DFS (HR = 1.08; 95% CI: 0.96–1.21). ConclusionThese results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.