Non-metastatic HER2-positive Breast Cancer Research Articles

Safety evaluation of the trastuzumab biosimilar in Iranian women with HER2-positive breast cancer undergoing adjuvant chemotherapy: a post-marketing surveillance

ABSTRACT Background Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). This post-marketing surveillance evaluates the safety of a trastuzumab biosimilar (AryoTrust), produced by AryoGen Co. Iran in Iranian women with HER2-positive non-metastatic breast cancer (BC). Research Design and Methods The patients who had undergone adjuvant chemotherapy regimens received trastuzumab every 3 weeks for nine cycles. The study started in February 2017 and finished in August 2022. Data regarding safety were collected using booklets and then analyzed. Results A total of 597 women with a mean ±SD age of 48.13 ± 10.18 years underwent 5,313 injection cycles. They received pre-study chemotherapies consisting of anthracyclines, taxanes, both, or other medications in 6.70, 7.20, 82.41, and 2.01% of the cases, respectively. One hundred and thirty-nine patients experienced at least one adverse event (AE). The most common AEs were decreased ejection fraction (EF, 5.7%), peripheral neuropathy (5.36%), and nausea (5.19%). Meningioma was the only life-threatening serious AE. Furthermore, bone pain and infusion-related reactions were the two most common grade three AEs. Nevertheless, the mean EF of patients did not change notably during the study. Conclusions The results demonstrate that this trastuzumab biosimilar is a generally well tolerated and safe treatment for HER2-positive BC. Clinical Trial Registration www.clinicaltrials.gov identifier is NCT06021379.

Role of NEDD9 expression in non-metastatic HER2-positive breast cancer.

e12645 Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Short-term efficacy and safety of neoadjuvant pyrotinib plus taxanes for early HER2-positive breast cancer: a single-arm exploratory phase II trial.

The effectiveness and safety of pyrotinib have been substantiated in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC). However, the role of pyrotinib as a single HER2 blockade in neoadjuvant setting among BC patients has not been studied. The objective of this study was to evaluate the efficacy and tolerability of pyrotinib plus taxanes as a novel neoadjuvant regimen in patients with HER2-positive early or locally advanced BC. In this single-arm exploratory phase II trial, patients with treatment-naïve HER2-positive BC (stage IIA-IIIC) received pyrotinib 400 mg once daily and taxanes [docetaxel 75 mg/m2 or nanoparticle albumin-bound (nab)-paclitaxel 260 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly] for a total of four 21-day cycles before surgery. Efficacy assessment was based on pathological and clinical measurements. The primary endpoint of this study was the total pathological complete response (tpCR) rate. The secondary endpoints included breast pCR (bpCR) rate, investigator-assessed objective response rate (ORR) and adverse events (AEs) profiles. From 1 September 2021 to 30 December 2022, a total of 31 patients were enrolled. One patient was withdrawn due to unbearable skin rash after the second cycle of neoadjuvant therapy. The majority of the intention-to-treat (ITT) population was premenopausal (54.8%), had large tumors (90.3%) and metastatic nodes (58.1%) at diagnosis and hormone-receptor positive tumors (64.5%). Most participants used nab-paclitaxel (74.2%) and received mastectomy (67.7%) after neoadjuvant treatment. The tpCR and bpCR rates were 48.4% [95% confidence interval (CI): 30.8-66%] and 51.6% (95% CI: 34-69.2%), respectively. Grade ≥3 treatment-related AEs were observed in 16.1% (5/31) of the ITT population, including diarrhea (n=2, 6.5%), hand and foot numbness (n=1, 3.2%), loss of appetite (n=1, 3.2%), and skin rash (n=1, 3.2%). AE related dose reduction or pyrotinib interruption was not required. In female patients with HER2-positive non-metastatic BC, neoadjuvant pyrotinib monotherapy plus taxanes appears to show promising clinical benefit and controllable AEs [Chinese Clinical Trial Registry (ChiCTR2100050870)]. The long-term efficacy and safety of this regime warrant further verification.

Complete pathological response in patients with HER2 positive breast cancer treated with neoadjuvant therapy in Colombia

Breast cancer is the most common type of cancer and the leading cause of death by cancer in women in Colombia. Approximately 15 to 20% of breast cancers overexpress HER2. To analyze the relationship between multiple clinical and histological variables and pathological complete response in patients with HER2-positive breast cancer undergoing neoadjuvant therapy in a specialized cancer center in Colombia. We performed a retrospective analysis of non-metastatic HER2-positive breast cancer patients who received neoadjuvant therapy between 2007 and 2020 at the Instituto de Cancerología Las Americas Auna (Medellín, Colombia). Assessed parameters were tumor grade, proliferation index, estrogen receptor, progesterone receptor, HER2 status, type of neoadjuvant therapy, pathologic complete response rates, and overall survival. Variables associated with low pathologic complete response rates were tumor grades 1-2 (OR = 0.55; 95% CI = 0.37-0.81; p = 0.03), estrogen receptor positivity (OR =0.65; 95%; CI = 0.43-0.97; p=0.04), and progesterone receptor positivity (OR = 0.44; 95% CI = 0.29-0.65; p = 0.0001). HER2 strong positivity (score 3+) was associated with high pathological complete response rates (OR = 3.3; 95% CI = 1.3-8.35; p=0.013). Five-year overall survival was 91.5% (95% CI = 82.6-95.9) in patients with pathological complete response and 73.6% (95% CI = 66.4-79.6) in patients who did not achieve pathological complete response (p = 0.001). Additionally, the pathological complete response rate was three times higher in patients receiving combined neoadjuvant chemotherapy with anti-HER2 therapy than in those with chemotherapy alone (48% versus 16%). In patients with HER2-positive breast cancer, tumor grade 3, estrogen receptor negativity, progesterone receptor negativity, strong HER2 positivity (score 3+), and the use of the neoadjuvant trastuzumab are associated with higher pathological complete response rates.

Impact of Pertuzumab and Ado-Trastuzumab Emtansine on Cumulative Avoidance of Recurrence Among Women Treated for Locally Advanced, Inflammatory, or Early-Stage Nonmetastatic HER2-Positive Breast Cancer in the United States.

We assessed the impact of HER2-positive early breast cancer (EBC) treatment landscape changes following the introduction of pertuzumab and ado-trastuzumab emtansine (T-DM1) on cumulative population-level recurrences avoided since 2013 (first pertuzumab approval for EBC in the United States; US). We constructed a multi-year epidemiologic population treatment-impact model to estimate annual recurrences between 2013 and 2031. Parameters were: BC incidence; stage I-III proportion; HER2-positive disease proportion; treatment proportions for neoadjuvant-only, adjuvant-only, and neoadjuvant-adjuvant continuation; and therapeutic agent proportions within each of those settings (chemotherapy only, trastuzumab±chemotherapy, pertuzumab with trastuzumab±chemotherapy, or T-DM1). The primary endpoint was cumulative recurrences, estimated by incorporating extrapolated clinical trial data for each regimen of interest into the model under four scenarios. Approximately 889,057 women were predicted to be diagnosed with stage I-III HER2-positive BC from 2006 to 2031 in the US and potentially indicated for HER2-targeted treatment. In steady-state equilibrium, the model estimated that real-world utilization of pertuzumab and T-DM1 will reduce the population-level number of recurrences by approximately 32%, with 7226 recurrences predicted in 2031 based on current utilization rates. In different modeled scenarios, use of neoadjuvant pertuzumab, continuation of pertuzumab in the adjuvant setting, and T-DM1 in the adjuvant setting in women with residual disease after neoadjuvant treatment were all predicted to reduce the number of recurrences. Given the improvement of HER2-targeted treatments, alongside increases in BC disease burden, we expect that the population-level impact of HER2-targeted treatments will accelerate over the next decade. Our results suggest that utilization of HER2-targeted treatments in the US has the potential to change the epidemiology of HER2-positive EBC by preventing a substantial number of women from experiencing disease recurrence. These improvements may help to inform our understanding of the future disease and economic burden of HER2-positive BC in the US.

P056 Factors associated with long-term prognosis in the nonmetastatic HER2-positive breast cancer. A nationwide study from Korean Breast Cancer Society

P056 Factors associated with long-term prognosis in the nonmetastatic HER2-positive breast cancer. A nationwide study from Korean Breast Cancer Society

STARD3: A New Biomarker in HER2-Positive Breast Cancer.

We conducted a retrospective study between 2007 and 2020 on 112 patients with non-metastatic HER2-positive breast cancer treated by NST and then by surgery. We developed an immunohistochemistry assay for STARD3 expression and subcellular localization and determined a score for STARD3-positivity. As STARD3 is an endosomal protein, its expression was considered positive if the intracellular signal pattern was granular. In this series, pCR was achieved in half of the patients. STARD3 was positive in 86.6% of cases and was significantly associated with pCR in univariate analysis (p = 0.013) and after adjustment on other known pathological parameters (p = 0.044). Performances on pCR prediction showed high sensitivity (96%) and negative predictive value (87%), while specificity was 23% and positive predictive value was 56%. Overall, specific, relapse-free, and distant metastasis-free survivals were similar among STARD3 positive and negative groups, independently of other prognosis factors. NST is an opportunity for HER2-positive cancers. In this series of over a hundred HER2-positive and non-metastatic patients, a STARD3-negative score was associated with the absence of pathological complete response. This study suggests that determining STARD3 overexpression status on initial biopsies of HER2-positive tumors is an added value for the management of a subset of patients with high probability of no pathological response.

Dual neoadjuvant blockade plus chemotherapy versus monotherapy for the treatment of women with non-metastatic HER2-positive breast cancer: a systematic review and meta-analysis.

We aimed to determine the effect of dual anti-HER2 blockade compared to monotherapy on clinically important outcomes. We carried out a systematic review updated until July 2022. The outcomes included pathological complete response (pCR), clinical response, event-free survival, and overall survival. We identified eleven randomized clinical trials (2836 patients). When comparing paclitaxel plus dual treatment versus paclitaxel plus trastuzumab or lapatinib, dual treatment was associated with a higher probability of achieving a pathological complete response (OR 2.88, 95% CI 2.02-4.10). Addition of a taxane to an anthracycline plus cyclophosphamide and fluorouracil, plus lapatinib or trastuzumab, showed that the dual treatment was better than lapatinib alone (OR 2.47, 95% CI 1.41-4.34), or trastuzumab alone (OR 1.89, 95% CI 1.13-3.16). Dual treatment may result in an increase in survival outcomes and tumour clinical response, although such benefits are not consistent for all the combinations studied. The use of dual blockade with combinations of trastuzumab and pertuzumab can be recommended for the neoadjuvant treatment of women with HER2-positive breast cancer. PROSPERO Registration number: CRD42018110273.

Prognostic nomogram for female patients suffering from non-metastatic Her2 positive breast cancer: A SEER-based study.

This paper aimed at constructing and validating a novel prognostic nomogram, so that physicians forecast the overall survival (OS) rates of female patients suffering from non-metastatic human epidermal growth element receptor-2 (HER2) positive breast.Information of primary female her2 positive breast cancer patients without metastasis was obtained from the Surveillance, Epidemiology, and End Results (SEER) database with given inclusion and exclusion standards. Independent variables were obtained greatly by performing univariable and multivariate analyses. Based on those independent predictors, a novel prognostic nomogram was constructed for predicting the survival of those with 3- and 5-year OS. Then, concordance index (C-index), receiver operating characteristic curve (ROC), and calibration plot were adopted for the assessment of the predictive power of the nomogram.A total of 36,083 eligible patients were classified into a training cohort (n = 25,259) and a verification cohort (n = 10,824) randomly. According to the identification of multivariate analysis, survival was predicted by age at diagnosis, marital status, race, site, T stage, N stage, progesterone receptor (PR) status, estrogen receptor (ER) status, surgery, radiation, and chemotherapy independently. A nomogram was established by applying the training cohort. The nomogram displayed excellent discrimination and performance as indicated by the C-index (0.764, 95% confidence interval: 0.756–0.772), and the 3- and 5-year area under the curve of ROC (AUC) values (0.760 and 0.692 respectively). The calibration plots for forecasting the 3- and 5-year OS were in great agreement.The OS for female her2 positive breast cancer patients without metastasis was predicted by constructing a nomogram on basis of the SEER database. A precise survival prediction could be offered for each patient.

Pertuzumab study in the neoadjuvant setting for HER2-positive nonmetastatic breast cancer in Australia (PeRSIA).

The pertuzumab study in the neoadjuvant setting for HER2+ nonmetastatic breast cancer in Australia (PeRSIA-ML39622) is an analysis of safety and effectiveness data from the pertuzumab patient registry. Although the prognosis of patients with early stage HER2+ breast cancer has been greatly improved by advances in chemotherapy approximately 25% to 30% of patients develop recurrent disease. Our study aimed to examine the effectiveness of neoadjuvant pertuzumab on surgical outcomes, describe the medium-term effectiveness outcomes of patients treated with pertuzumab, and describe the planned and actual anticancer treatment regimens that patients received. Deidentified data were collected from the patients' medical records and entered into REDCap, between March 2018 and July 2019 (n=95). The adverse events (AEs) reported most frequently were diarrhea (20; 21.1%), rash (4; 4.2%), and LVSD (4; 4.2%; two patients during neoadjuvant treatment and two patients during adjuvant treatment). AEs, ≥Grade 3 were diarrhea (2; 2.1%) and LVSD (1; 1.1%). Following surgery, a breast pathological complete response (bpCR) was achieved in 65 patients (70.7%; 95% CI: 60.2%-79.7%) and total pathological complete response (tpCR) in 59 patients (64.1%; 95% CI: 53.4%-73.9%). All patients who did not achieve a tpCR obtained a partial response (33/92, 35.9%). Our study is the first to capture real-world data on the use of pertuzumab in the neoadjuvant setting in Australia. The effectiveness and safety data are consistent with those reported in clinical trials of pertuzumab in patients with HER2+ breast cancer, with no new safety concerns.

Dynamic changes in intrinsic subtype, immunity status, and risk score before and after neoadjuvant chemo- and HER2-targeted therapy without pCR in HER2-positive breast cancers: A cross-sectional analysis.

Very few studies have been done in HER2 positive patients without complete pathological response (pCR) after combined neoadjuvant chemo- and HER2-target therapy to investigate changes in intrinsic subtype, risk of recurrence (ROR) score, and immunity status before and after treatment.Patients with nonmetastatic HER2-positive breast cancer failed to achieve pCR after neoadjuvant chemotherapy plus trastuzumab were included in current study. We examined the distribution of PAM50 subtypes, ROR score and immunity score in 25 paired baseline and surgical samples. The Miller–Payne grading system was used to evaluate the efficacy of the neoadjuvant therapy. It was observed that the distribution of intrinsic subtype, ROR category and immunity subgroup varied according to hormone receptor (HR) status. HER2-enriched and basal-like subtypes, median-high ROR categories and immunity-weak subgroup were dominant in baseline tumors. Compared to baseline samples, conversion of intrinsic subtype, ROR categories and immunity subgroups were found in 15 (60.0%), 13(52.0%), and 11(44.0%) surgical samples, respectively. The PAM50 subtype, ROR category, and immunity subgroup were concordant between baseline and surgical samples where nonluminal subtypes, median-high ROR categories and i-weak subgroup were still common.In conclusion, the HER2-positive breast cancer is highly heterogeneous with a distribution of 72-gene expression varying according to HR co-expression. The dynamics of the 72-gene expression pre- and posttreatment may become novel biomarker for guiding adjuvant therapy and hence warrant further investigation.

Abstract P2-13-38: Pertuzumab study for HER2-positive non-metastatic breast cancer in the neoadjuvant setting in Australia

Abstract BACKGROUND Adding pertuzumab to trastuzumab in patients (pts) with HER2+ breast cancer improves pathological complete response (pCR) rates. Pertuzumab + trastuzumab + chemotherapy is approved in Australia as neoadjuvant therapy in early stage (>2 cm or node positive), locally advanced and inflammatory HER2+ breast cancer. This study captured real-world data on the safety and effectiveness of pertuzumab in the neoadjuvant setting. METHODS PeRSIA (ML39622) is a secondary data use non-interventional study of pts initiating neoadjuvant pertuzumab treatment for non-metastatic HER2+ breast cancer. The primary objective is to assess the effectiveness and safety of neoadjuvant pertuzumab when added to trastuzumab in the real-world setting. Deidentified data obtained from the pts’ medical notes were captured using REDCaP, hosted at the Walter and Eliza Hall Institute of Medical Research. This analysis reports the co-primary endpoints of breast pCR (bpCR) with or without in situ disease (ypT0/is or ypT0), total pCR (tpCR) with or without in situ disease (ypT0/is ypN0 or ypT0 ypN0), and the incidence of adverse events (AEs) related to pertuzumab. Secondary objectives include describing rates of breast and nodal surgery, relapse free survival (RFS) and overall survival (OS). RESULTS Ninety five pts receiving neoadjuvant pertuzumab were enrolled between March 2018 and July 2019, with data available for all pts. HER2-targeted neoadjuvant treatment was completed in 91 pts (95.8%) with a median number of 4 cycles [range 1-6] of pertuzumab and 5 cycles [range 1-6] of trastuzumab. Four pts did not complete the planned neoadjuvant therapy due to early CR (n=1), and pertuzumab-related AEs (n=3). The most common neoadjuvant chemotherapy regimens were sequential anthracyclines + taxanes (n=59, 62.1%) and single agent taxane (n=29, 30.5%). Surgery was performed in 92 pts (96.8%). Three pts did not proceed to surgery due to patient decision (n=1), physician decision (n=1), and development of a new non-breast cancer which resulted in death (n=1). Of those pts that underwent surgery, 65/92 (70.7%) had a bpCR and 59/92 (64.1%) had a tpCR. All pts who did not achieve a pCR obtained a partial response (33/92, 35.9%). Total pCR was seen in 27/34 (79.4%) pts with hormone receptor-negative and 32/58 (55.2%) pts with hormone receptor-positive cancers. 27/95 (28.4%) pts experienced an AE related to pertuzumab; diarrhea (21.1%) and rash (4.2%) were the most common AEs. Three pts (3.2%) discontinued pertuzumab due to an AE: cardiac toxicity, diarrhea and rash (n=1), cardiac toxicity (n=1), and diarrhea and sepsis (n=1). Following surgery, 93/95 (97.9%) patients received adjuvant HER2-directed therapy, and 4/95 (4.2%) received adjuvant chemotherapy. After a median follow-up from diagnosis of 21.2 [14.0-83.9] months, the RFS and OS were 92.6% and 99.0% respectively. Disease recurrence occurred in 6 pts (distant n=4, contralateral n=2). CONCLUSIONS This is the first multicenter, observational study of neoadjuvant therapy based on dual blockade with pertuzumab and trastuzumab for HER2+ non-metastatic breast cancer in Australia. The pCR rates achieved were numerically higher than previously reported in clinical trials. There were no significant safety findings outside of the expected safety profile for pertuzumab. Acknowledgments: Study sponsored by Roche Products, Pty. Limited. Theresa Wade (WriteSource Medical) provided medical writing. Table: Baseline Characteristics (n=95)CharacteristicNumber (%)Age, median (range)50.3 (24.4 -82.1)Charlson Comorbidity Index- 077 (81.1)- 19 (9.5)- 2 +9 (9.5)Tumour Size12 (12.6)- T156 (59.0)- T225 (26.3)- T3- Unreported2 (2.1)Tumour Grade- 10 (0)- 231 (32.6)- 362 (65.3)- Unreported2 (2.1)Nodal status- Positive63 (66.3)- Negative32 (33.7)Hormone Receptor Status- HR+60 (63.2)- HR-35 (36.8)Median baseline left ventricular ejection fraction (range)65.0% (35-79)Cardiac risk factors- 053 (55.8)- 122 (23.2)- 2+20 (21.1) Citation Format: Sheau Wen Lok, Richard De Boer, Sallt Baron-Hay, Peter Button, Bianca Devitt, Benjamin Forster, Peter Fox, Michael Harold, Sahisha Ketheeswaran, Ganessan Kichenadasse, Belinda E Kiely, Gavin Marx, Louise Nott, Laura Pellegrini, Ali Tafreshi, Peter GIbbs. Pertuzumab study for HER2-positive non-metastatic breast cancer in the neoadjuvant setting in Australia [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-38.

Neoadjuvant pertuzumab in non‑metastatic HER2‑positive breast tumors: Multicentric study in Peru (NeoHer)

Several clinical trials have demonstrated the benefit of adding pertuzumab to trastuzumab plus neoadjuvant chemotherapy in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The comparison of outcomes between nonrandomized groups of patients who received similar treatments in routine practice remains difficult. The present study aimed to evaluate the pathological complete response (pCR) rates achieved with pertuzumab among patients in routine clinical care in Peru using real-world data. The definition of pCR used was the absence of residual invasive cancer from the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy. A total of 44 patients with non-metastatic HER2-positive breast cancer (stages II and III) treated with pertuzumab in the neoadjuvant setting and who underwent surgery at three private clinics in Lima (Peru) were retrospectively evaluated. The pCR was the efficacy endpoint and it was determined and compared with the results from other clinical trials. Furthermore, safety data were described. The median age was 44 years (interquartile range, 39.5-50.5 years) and 65.9% of patients were premenopausal. Regarding the clinical stage, 56.8% were IIA/IIB and 36.4% were IIIA/IIIB/IIIC. All treatment schemes included concurrent trastuzumab. The patients' treatment comprised neoadjuvant therapy of docetaxel/trastuzumab/pertuzumab (THP) with a median of 4 cycles in 30 patients (68.2%) or docetaxel/trastuzumab/pertuzumab/carboplatin (THPCarb) with a median of 6 cycles in 14 patients (31.8%). In total, 70.5% of patients experienced pCR; among hormone receptor-negative cases, 75.0% achieved pCR and in tumors expressing hormone receptors, the rate of pCR was 66.7%. Of those patients subjected to neoadjuvant treatment with THP, 66.7% (20/30) achieved pCR, whereas 78.6% (11/14) of patients who received THPCarb had a pCR. The incidence of drug-related adverse events was 59.1% and in none of the patients, administration was discontinued due to toxicity. The present results of Peruvian patients with HER2 breast cancer treated according to clinical routine demonstrated that dual blockade of HER2 with trastuzumab and pertuzumab in the neoadjuvant setting achieved high rates of pCR even in hormone receptor-positive patients. These results are consistent with those of randomized controlled trials, with a good safety profile.

277 Temporal trends of advanced 2D-speckle tracking echocardiography in trastuzumab treated patients

Abstract Aims Trastuzumab (TZ) is widely used for his key role in HER2 positive breast cancer. However, it may have different side effects on the cardiovascular system. One of the most concerning complication is cardiotoxicity. Many studies have highlighted the importance of the screening for subclinical myocardial dysfunction using left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). However, there are few studies investigating the left atrial function in relation to the development of early cardiac damage. Aim of this study is to analyse the modification of GLS and PALS in patients undergoing therapy with TZ in a follow-up period of 12 months. The eventual fluctuation of left atrial function under chemotherapy was evaluated and the correlation between subclinical atrial disfunction and early left ventricular impairment was searched. Methods One hundred and five women affected by non-metastatic HER-2 positive breast cancer treated with TZ were enrolled. Each patient underwent a complete echocardiography every 3 months, for a total of five exams pro patient. Thirty-seven patients (35%) were excluded from the left atrial function analysis while LV function evaluation was performed in 83 patients (21%). Exclusion criteria were poor quality imaging and lack of a complete Follow-up with consequent missing data. 2D-Speckle tracking analysis was performed at baseline and at each examination using Tomtec software in order to analyse both atrial and left ventricular function. Subclinical LV disfunction was defined as a GLS reduction of ≥ 15% compared to the baseline value. Left atrial impairment was arbitrary defined as a PALS reduction of ≥ 25% compared to the initial value. Finally, trends of GLS and PALS during 12 months-Follow-up periods were analysed. Results A total of 48.9% patients developed subclinical LV dysfunction. Similarly, 48.3% patients showed a left atrial impairment. Interestingly a significant (P = 0.0001) reduction in GLS was observed during the follow-up, particularly in the first 6 months of treatment. PALS showed a similar trend with a significant decrease during the whole 12 months-follow-up (P = 0.0001) and mostly in the first 6 months. Only 11% patients showed a significant reduction of LVEF defined as an absolute reduction of LVEF >10% from baseline. Conclusions In HER 2 positive breast cancer patients treated with Trastuzumab development of left atrial impairment in not uncommon and PALS modifications follow a similar pattern to GLS variations during the treatment course, suggesting a possible cardiotoxic effect of such therapy on both atrial and left ventricular myocardium and physiology. However, the potential role of an early atrial impairment detection in predicting subsequent cardiotoxicity in terms of significant LVEF reduction still needs to be tested with further studies.

Neoadjuvant chemotherapy with biosimilar trastuzumab in human epidermal growth factor receptor 2 overexpressed non-metastatic breast cancer: patterns of use and clinical outcomes in India.

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with poor prognosis and access to anti-HER2 treatment is still a challenge in lower-middle income countries. The availability of the biosimilar trastuzumab has improved access by lowering the costs. We report the pattern of use of neoadjuvant ± adjuvant trastuzumab and outcomes in patients with HER2-positive non-metastatic breast cancer treated with regimens incorporating shorter durations of therapy and the use of the biosimilar trastuzumab compared to the innovator.MethodsWe conducted a retrospective analysis of patients with non-metastatic HER2-positive breast cancer treated with neoadjuvant ± adjuvant trastuzumab (innovator (n = 34 (33%)) and biosimilar (n = 70 (67%)) manufactured by Biocon Biologics) with chemotherapy. Information regarding chemotherapy regimens, duration of trastuzumab use (≤12 weeks and >12 weeks), pathological response (Miller Payne grade), disease free survival (DFS), overall survival (OS) and safety data were collected from electronic medical records.ResultsA total of 135 patients were analysed with a median age of 51 years (range: 23–82); of these, 57% were postmenopausal, 31.8% were hormone receptor positive and 62.9% had stage III disease. The overall pathological complete response (p-CR) in both breast and axilla increased to 37.6% in patients treated with trastuzumab preoperatively as compared to 22.2% in patients who did not receive any trastuzumab. Patients receiving innovator trastuzumab and biosimilar trastuzumab showed a p-CR of 28.5% and 41.7%, respectively. At a median follow-up of 42 months (range: 3–114), there were 18 relapses and 11 deaths. The 3-year DFS was 87.1% and OS was 92.2%. Cardiac dysfunction developed in 4 of 78 (5.1%) evaluable patients.ConclusionAccess to anti-HER2 therapy in the treatment of non-metastatic HER2-positive breast cancer in resource-constrained settings has improved significantly with the availability of the biosimilar trastuzumab. Imbalances in patient profiles at baseline in routine clinical practice led to inconclusive outcomes of ≤12 weeks versus >12 weeks trastuzumab treatment. However, on the basis of historical data, patients could be offered shorter duration of trastuzumab when a standard 1-year treatment of adjuvant trastuzumab is not feasible in resource-constrained settings. The p-CR using the biosimilar trastuzumab in neoadjuvant treatment has been observed to be comparable to the innovator trastuzumab.

Pathological Response and Survival after Neoadjuvant Therapy for Her-2 Positive Breast Cancer

Background: Pathological complete response (pCR) after neoadjuvant systemic treatment represents a good surrogate marker for the prognosis of Her-2 positive Breast Cancer (BCs). The results improved after adding anti-Her-2 therapy to chemotherapy in neoadjuvant setting. Methods: Our retrospective study enrolled a cohort of 56 invasive Her-2 positive non-metastatic BCs treated with neoadjuvant systemic therapy between 2001 and 2018. The patients received neoadjuvant chemotherapy with or without anti-Her-2 therapies before surgery and adjuvant endocrine and anti-Her-2 treatment together with adjuvant radiotherapy, based on clinical, pathological and hormonal receptor expression characteristics. The primary end point was pCR rate and disease-free-survival (DFS), defined as the interval between surgery and documented disease recurrence, progression, or death from any cause. Results: The rate of pCR for our patients was 41% independent of type of chemotherapy regimen and the anti-Her-2 therapy used. The results were improved by adding Trastuzumab in the neoadjuvant setting with statistical significance (p = 0.038). Median DFS was 68 months for the entire cohort. The risk of recurrence was higher in the group without pCR after neoadjuvant treatment (52% vs 17%; p = 0.003). 10 patients died (18%), all of them from group without pCR. The prognosis at 36-months was good, with 84% survival chance at 3 years follow-up. Conclusion: Our retrospective study underlines the positive impact of neoadjuvant systemic treatment on pCR rate and on disease-free survival in real-life Her-2 positive breast cancer patients.

Outcomes of HER2-positive non-metastatic breast cancer patients treated with anti-HER2 therapy without chemotherapy.

Anti-HER2 therapy delivered in the adjuvant setting for breast cancer is given in conjunction with cytotoxic chemotherapy. For HER2-positive (HER2+) patients who cannot tolerate chemotherapy, there is no randomized data regarding the role of anti-HER2 therapy without chemotherapy. The National Cancer Database (NCDB) was queried for non-metastatic breast cancer patients with estrogen receptor-positive (ER+) and HER2+ breast cancer who received surgery and endocrine therapy, without chemotherapy from 2013 to 2016. Outcomes were compared between endocrine therapy alone (ET) or endocrine therapy with anti-HER2 therapy (ET + aHER2). Univariate and multivariate Cox-proportional hazards models were used to analyze the association between clinical characteristics and survival outcomes between groups. Propensity score matching (PSM) was performed to account for differences between the two groups. Of all patients with non-metastatic ER+/HER2+ breast cancer, we identified 9458 (20.5%) who did not receive chemotherapy. Of the 6741 patients who received ET, 17.2% also received aHER2 therapy. Median follow-up was 31.7months (IQR 21.1-42.1). In the aHER2 group (vs. ET), there were more patients with older age, higher stage, node positivity, poorly or undifferentiated disease, lymphovascular invasion, lobular cancer, and Medicare insurance. Compared to the ET cohort, ET + aHER2 was not significantly associated with improved OS on multivariate analysis (HR 0.88 95% CI 0.68-1.15) or after propensity score matching (HR 0.80 95% CI 0.57-1.11). There is no significant difference in survival with the addition of HER2 therapy to endocrine therapy in ER+/HER2+ non-metastatic breast cancer patients who do not receive chemotherapy. To our knowledge, this is the largest series investigating this question.

Pathological Response and Survival after Neoadjuvant Therapy for Her-2 Positive Breast Cancer.

Background: Pathological complete response (pCR) after neoadjuvant systemic treatment represents a good surrogate marker for the prognosis of Her-2 positive Breast Cancer (BCs). The results improved after adding anti-Her-2 therapy to chemotherapy in neoadjuvant setting. Methods: Our retrospective study enrolled a cohort of 56 invasive Her-2 positive non-metastatic BCs treated with neoadjuvant systemic therapy between 2001 and 2018. The patients received neoadjuvant chemotherapy with or without anti-Her-2 therapies before surgery and adjuvant endocrine and anti-Her-2 treatment together with adjuvant radiotherapy, based on clinical, pathological and hormonal receptor expression characteristics. The primary end point was pCR rate and disease-free-survival (DFS), defined as the interval between surgery and documented disease recurrence, progression, or death from any cause. Results: The rate of pCR for our patients was 41% independent of type of chemotherapy regimen and the anti-Her-2 therapy used. The results were improved by adding Trastuzumab in the neoadjuvant setting with statistical significance (p = 0.038). Median DFS was 68 months for the entire cohort. The risk of recurrence was higher in the group without pCR after neoadjuvant treatment (52% vs 17%; p = 0.003). 10 patients died (18%), all of them from group without pCR. The prognosis at 36-months was good, with 84% survival chance at 3 years follow-up. Conclusion: Our retrospective study underlines the positive impact of neoadjuvant systemic treatment on pCR rate and on disease-free survival in real-life Her-2 positive breast cancer patients.

Adjuvant Trastuzumab Emtansine (T-DM1) and Concurrent Radiotherapy for Residual Invasive HER2-positive Breast Cancer: Single-center Preliminary Results.

The treatment of nonmetastatic HER2-positive breast cancer with residual invasive disease using concurrent Trastuzumab emtansine (T-DM1) and radiotherapy appears to be an effective option. Our aim was to evaluate the acute side effects of this treatment regime. Fourteen patients were treated between March 2019 and April 2020 concurrent T-DM1 and radiotherapy. Left ventricular ejection fraction was assessed at baseline, before and after radiotherapy. All toxicities were evaluated using Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. The median age was 55 years (range 36 to 72). All patients received total dose of 50 Gy for the breast/ chest wall, 10 patients got lymph node irradiation, 4 patients received an additional tumor bed boost. The most common side effect was grade 1 radiodermatitis. A reversible grade 2 left ventricular ejection fraction decrease occurred in 2 patients. During our examination 3 patients showed alanine aminotransferases increase after the cycle 4 of T-DM1, 1 patient had grade 1, 1 patient grade 2, and 1 patient grade 3 alanine aminotransferase increases. The acute toxicity rate especially focusing on skin and cardiac toxicity were assumed acceptable in our cohort. To safely administer this concomitant treatment, further examination and prospective data are needed.