Early-stage HER2-positive Breast Research Articles

Abstract PS09-07: SPAG5 as a companion prognostic and predictive test for management of early stage HER2 positive breast cancer (BCs)

Abstract Background: SPAG5 is a novel oncogene that is amplified in 40% of HER2+BC. Herein, we evaluated the prognostic and predictive significance of SPAG5 in HER2+ BC Methods: This retrospective cohort study included 2454 patients with HER2+BC derived from 6 cohorts in adjuvant (Adj) and neoadjuvant (NACT) settings. Adj cohorts: The association between SPAG5 and survivals were evaluated in 1354 HER2+ BC who received Adj therapy: 1) HER2+ Adj transcript cohort (n=448): 31% (137/448) did not receive Anthracycline (AC), Taxane (TX), Trastuzumab (TZ) or Pertuzuman (PZ) whereas 20% (89/448) had received AC alone and 35% (155/448) received TZ + AC +/- TX (Median follow- up (MFU): 60 months (m). 2) HER2+ Adj Molecular Taxonomy of BC International Consortium cohort (n=240): patients with ER- and lymph node (LN) + received Adj chemotherapy but none received TZ (MFU: 109 m). 3) HER2+ Adj Historical cohort (n=206): no TZ, AC or TX was received (MFU: 143 m). 4) HER2+/ER- cohort (n=101): AC alone was received; MFU: 62 m. 5) HER+ Adj TZ cohort (n=359): patients received TZ +TX+/-AC (MFU: 90 m). Neo-Adjuvant cohort: the associations of SPAG5 protein expression with pathological complete response (pCR) was evaluated in 1100 BCs (MFUT: 67 m) including 200 local cases participated in ROSCO trial. In this cohort; 73% (803/1100) received AC+TX. AC alone was given to 187/1100 (17%) whereas 88/1100 (8%) received TX alone. Of HER2+ BC, 14% (54/399) received AC +/- TX and 63% received TZ + TX +/-AC and 23% (92/399) received TZ + PZ + TX +/- AC. Sections were IHC profiled for HER2, ER, PR, Ki67 and SPAG5 and stained for Fluorescent in situ hybridisation (FISH) using a novel triple colour probe (HER2/SPAG5/Ch17). ASCO guidelines recommendations were followed. Results: In univariate survival analysis, High SPAG5 (+) transcript was associated with shorter 5- year distant metastases free survival (5-y DRFS); p< 0.0001, compared to SPAG5 low (-) in HER2+ patients who did not receive TZ or AC whereas in those who received AC alone, SPAG5+ was associated with lower risk of 5-y DRFS than SPAG5- (p < 0.001). Multivariable Cox regression analysis showed that SPAG5+ transcript ; as well as LN status, was independently associated with poor prognosis (HR (95% CI): 4.9 (2.0-12.0), p< 0.001). The interaction term between SPAG5 and AC was significantly associated with lower risk of DR. Multivariable Cox regression analysis for 10-year relapse free survival (10y-RFS) in HER2+ patients who did not receive AC or TZ confirmed that SPAG5+ protein expression ; as well as LN status and tumour size, were independently associated with poor prognosis (HR (95% CI): 2.1 (1.3, 3.5), p=0.002). SPAG5+ predicted response for NACT +/- HER2 targeting agents. For instance; None of HER2 IHC 2+ with SPAG5- expression/(0/191) either with HER2 FISH- (0/121) or HER2 FISH+ (0/70) achieved pCR whereas 51% (48/95) of those of HER2 IHC 2+/SPAG5+ achieved pCR (p < 0.0001). Similarly patients with HER2+ IHC 3+/SPAG5+ achieved higher pCR rate compared to those with SPAG5- expression [73% (107/146) vs., 10% (14/135); respectively]; p< 0.0001. Noteworthy, after receiving TZ+ PZ +Texans +/- AC, patients with SPAG5+ achieved higher pCR rate compared to those with SPAG5- expression [85% (50/59) vs., 0% (0/51); respectively, p< 0.001]. Similarly in HER2 + BC patients who received TZ + TX +/- AC, SPAG5+ expression was associated with higher pCR [67% (67/101)] compared to those with SPAG5- [10% (11/107)]; p< 0.001. In HER2+ who received AC alone, SPAG5+ cases achieved higher pCR compared to those with SPAG5- [56% (20/36) vs., 6% (3/47); p< 0.001; respectively]. Multivariable logistic regression analysis showed that SPAG5+ expression as well as ER, HER2 IHC, grade, clinical TNM and HER2 targeting agents were independent predictors for pCR (OR (95% CI: 13.74 (5.76-32.79; p< 0.001). Conclusions SPAG5 is an independent poor prognostic factor in HER2+ BC and could help in distinguishing those who would and would not benefit from NACT and HER2 targeting agents. Citation Format: TAREK ABDEL-Fatah, Graham Ball, Daniel Yeo, Graham Hickman, Arlene Chan, Ian Ellis, Stephen Chan. SPAG5 as a companion prognostic and predictive test for management of early stage HER2 positive breast cancer (BCs) [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 PS09-07.

Trastuzumab-Related Cardiotoxicity in Adjuvant Setting: A Real-World Scenario.

Rachana Chennamaneni Trastuzumab, a humanized monoclonal antibody, significantly improves outcomes in HER 2-neu positive breast cancer. The incidence of cardiotoxicity with trastuzumab is approximately 8 to 10%. This study was designed to analyze the incidence and risk factors associated with trastuzumab-related cardiotoxicity in real-world settings. This was a single institutional retrospective analysis of the incidence of trastuzumab-related cardiotoxicity in nonmetastatic HER 2-positive, invasive breast cancer from January 2013 to December 2018. Trastuzumab-related cardiotoxicity was defined as symptomatic heart failure or asymptomatic decline in left ventricular ejection fraction (LVEF) by more than or equal to 10% or LVEF less than 50%. Risk factors analyzed were higher body mass index (≥30 kg/m 2 ), history of diabetes, hypertension, cardiac disease, left-sided radiotherapy (RT), and prior exposure to anthracyclines. Out of the 246 patients diagnosed with early stage HER 2-positive breast cancer, 117 (47.5%) received trastuzumab and constituted the study population. Trastuzumab-related cardiotoxicity was seen in a total of 16 (13.6%) patients. Eleven (9.4%) patients had an asymptomatic decline, while symptomatic LV dysfunction was seen in five (4.2%) patients. The median baseline ejection fraction was 65% (range, 56-72). The median time to development of cardiotoxicity was 18.5 weeks (range, 3-52) and the median trastuzumab cycle for cardiotoxicity was 6 (range, 2-16). Ten (62.5%) patients were rechallenged with trastuzumab following which one patient developed an asymptomatic decline in ejection fraction and one patient developed symptomatic heart failure. Cardiac-related mortality was seen in one (0.85%) patient. Left-sided RT to chest ( p = 0.012) and presence of more than or equal to two risk factors ( p = 0.01) had significant impact on incidence of cardiotoxicity. Approximately 14% developed trastuzumab-related cardiotoxicity that was slightly higher compared with that seen in clinical trials. Left-sided RT to chest and presence of two or more risk factors had significant impact on development of cardiotoxicity.

Neoadjuvant therapy of HER2 directed conventional dendritic cell (DC1) intratumoral (IT) therapy plus weekly paclitaxel, trastuzumab, and pertuzumab in patients with HER-2 positive breast cancer: NATASHA trial.

596 Background: Early stage HER2 positive breast cancer (BC) patients (pts) are commonly treated with neoadjuvant HER2-targeted therapy. Optimizing neoadjuvant therapy by improving efficacy while reducing toxicity is a critical unmet need. IT DC 1 therapy combined with an IgG1 antibody mediating ADCC drives strong anti-HER-2 CD4 Th1 responses and complete tumor regression in preclinical models. We initiated a phase I/II neoadjuvant study to explore the efficacy and immune stimulation effects of an initial 6 weeks of immunotherapy phase (IP) using IT DC1 vaccine plus trastuzumab (H) and pertuzumab (P) (as source of IgG1) followed by 12 weeks of paclitaxel (T) and HP. Methods: Early stage HER2+ BC pts with tumor ≥ 1cm were eligible. Treatment included IT DC1 weekly x6 followed by paclitaxel 80 mg/m2 IV weekly x 12. Trastuzumab IV every (q) 3 weeks (8 mg/kg loading dose, then 6 mg/m2) and pertuzumab IV q 3 weeks (840 mg loading dose, then 420 mg) x 6 cycles starting from day 1. Two dose levels (DL) of IT DC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated including 6 pts in each DL. Once the optimal DL is determined based on toxicities, additional 22 patients will be enrolled in expansion phase 2 trial. The primary end point of the phase 1 is the safety, immune responses (measured by ELISPOT). MRI breast was performed at the baseline, post-immunotherapy and post-chemotherapy. Here we are reporting the safety and immune correlates in phase 1 study. Results: Twelve pts were enrolled between 10/2021 and 10/2022. Median age was 57 (range 34-74). Nine pts had hormone receptor positive disease with clinical stage I/II/III (5/5/2) and 4 pts had node positive disease. All pts completed IP and 10 patients completed THP chemotherapy as of 2/1/2023. Radiologic response per MRI breast on pre and post-IP showed 6 partial response, 3 complete response and 3 stable disease. Nine pts underwent surgery and 6 out of 9 pts had pCR (RCB 0). The most frequently observed toxicities were chills (50%), diarrhea (42%), nausea (42%), fatigue (42%), and headache (42%). ELISPOT demonstrated a significant decrease of HER2- specific T cell response following 6 weeks of DC1 IT injections in DL2 compared to DL1. Conclusions: The addition of IT DC1/HP to neoadjuvant chemotherapy was well tolerated with manageable toxicities. The 100 million DC1 led to a significant decrease in peripherally circulating anti-HER2 T cell response at week 6 following IP and improved radiologic tumor responses which correlates with a higher likelihood of pCR. Data from another IT DC1 trial suggests decreased circulating HER2 responsive T cells are due to increased trafficking of reactive T cells out of circulation into the tumor possibly leading to an enhanced anti-tumor effect. Updated results including correlative biomarkers will be presented at the meeting. Clinical trial information: NCT05325632 .

Analysis of pathological complete response (PCR) and impact of modifiable risk factors on the premature discontinuation of pertuzumab use in early stage HER-2 breast cancer: A retrospective single-institutional study.

e12627 Background: In patients with HER-2 positive breast cancer, Pertuzumab in combination with Trastuzumab forms a potent Anti HER-2 regimen. Randomized clinical trials have concluded that addition of Pertuzumab to Trastuzumab and Chemotherapy leads to improved rates of Pathological Complete Response and also improved Invasive-disease-free survival rates in early stage HER-2 positive breast cancer. Pertuzumab is frequently associated with treatment limiting diarrhea and other adverse effects. In this study, we report our experience with the use of Pertuzumab in early stage HER-2 breast cancer. We analyzed the adverse events, PCR rates for those patients who had premature discontinuation of treatment versus those who had successful treatment completion, and modifiable risk factors that may have affected completion of treatment. Methods: We conducted an IRB approved, retrospective study, analyzing the use of Pertuzumab at our institution for early stage (Stage I-III), HER-2 positive female and male breast cancer patients seen from June 2018 to June 2022. Data were obtained from our Institutional Cancer Registry. Results: One hundred and eighteen (118) patient charts were reviewed. Sixty Five (55.08%) patients received Pertuzumab. Of the patients who received Pertuzumab, 61 (93.85%) received it in the Neoadjuvant setting. Thirty Eight (58.46%) patients completed the treatment and 27 (41.5%) patients had premature treatment discontinuation due to adverse effects. The rate of PCR in patient who completed the prescribed treatment course was 55.56%, and 51.85% for those who did not (p value 0.77). Among the patients in whom treatment was discontinued, diarrhea (51%), followed by rash (11.11%) were the main adverse effects. Almost 66% of non-smokers completed treatment as compared to 48% of smokers (p value 0.15). Patients with a normal BMI had a treatment completion rate of 76% compared to obese or overweight patients who had a rate of 52% (p value 0.08). Conclusions: Our retrospective study showed that there was a high premature discontinuation rate of the use of Pertuzumab. This is due to adverse effects, diarrhea being the most notable. However, the PCR rate difference was not statistically significant (55.56 vs 51.85, P value 0.77) in patients who completed treatment versus those who did not. There was a positive trend observed that non-smokers and non-obese patients were more likely to complete treatment with Pertuzumab. Although it was observed that premature discontinuation of Pertuzumab did not significantly impact PCR, further studies are required to validate this observation.

Management of early stage HER2 positive breast cancer and increased implementation of axillary imaging to improve identification of nodal metastasis.

Given the significant benefit of targeted therapies for HER2+ breast cancer patients in both the neoadjuvant and adjuvant settings, it is critical to identify all eligible patients for these treatments. We sought to investigate cT1cN0 HER2+ patients to determine the rate of postsurgical nodal positivity, and to identify presurgical factors associated with nodal positivity. We hypothesize there is a subset of underdiagnosed HER2+ patients who would benefit from preoperative axillary imaging and inclusion in neoadjuvant chemotherapy regimens. We performed a 10-year retrospective analysis of T1 HER2+ breast cancer patients. Clinicopathologic characteristics were evaluated based on surgical nodal data. We identified 38 patients with cT1cN0 HER2+ cancer. Of this cohort, 24% had positive lymph nodes on final pathology. High tumor grade (p = 0.035) on core needle biopsy and the presence of lymphovascular invasion (p = 0.0036) were associated with an increased likelihood of lymph node positivity. The majority (66%) of lymph node positive patients were clinically T1c. We identified a 24% nodal positivity rate in clinically node negative T1 HER2+ breast cancer patients. In particular, HER2+ patients with high-grade T1c cancers should undergo preoperative diagnostic axillary imaging to expand potential benefit from targeted therapies.

Innovative Approach for a Typology of Treatment Sequences in Early Stage HER2 Positive Breast Cancer Patients Treated With Trastuzumab in the French National Hospital Database.

Our objective was to describe the hospital-based systemic treatment sequences in early stage HER2+ breast cancer patients treated with trastuzumab in France in 2016. This retrospective observational study was based on the national hospital discharge database (PMSI). Patients hospitalized for breast cancer in 2016 and administration of trastuzumab between 6 months prior and 1 year after surgery were included. The following treatments were identified: (1) trastuzumab ± chemotherapy; (2) chemotherapy alone; (3) q3w trastuzumab weekly chemotherapy. Hospital admissions for cardiac events before and after the surgery were investigated. An unsupervised machine learning technic called TAK (Time-sequence Analysis through K-clustering) was used to identify and visualize typical systemic treatment sequences. Overall, 3531 patients were included: 2619 adjuvant cohort patients (74.2%) and 912 neoadjuvant cohort patients (25.8%). The mean age was 56.4 years (±12.3), 99.7% patients were female. Treatment initiation occurred within 6 weeks of the surgery in 58% and 92% of patients, and trastuzumab treatment lasted 12 months (±1 month) in 75% and 66% of patients in the adjuvant and neoadjuvant cohorts, respectively. Nevertheless, 12% and 22% of patients were treated with trastuzumab for <11 months in the adjuvant and neoadjuvant cohorts, respectively. There was not one standard sequence of treatments per cohort, but 4 and 3 typical treatment sequences in the adjuvant and the neoadjuvant cohorts, respectively, plus 2 treatment sequences with an early treatment withdrawal. The frequency of patients with ⩾1 hospital stay with a cardiac event was higher among patients with an early treatment withdrawal. The treatment sequences of most patients were in line with the recommendations in force. The machine learning approach provided a telling visual display of the results, thereby allowing healthcare professionals, health authorities, patients, and care givers to see the whole picture of the hospital-administered drug strategies.

Survival Outcomes among Human Epidermal Growth Factor Receptor 2- (HER2-) Positive Breast Cancer Patients at Kenyatta National Hospital.

Introduction HER2-positive breast cancer is associated with poor outcomes and higher mortality rates than other breast cancer subtypes. The advent of trastuzumab has significantly changed the natural history of HER2-positive breast cancer. However, it is not an affordable treatment option in sub-Saharan African countries. Because of the expense, most patients in our setting do not receive trastuzumab for the optimal control of their disease. Additionally, there is a lack of comprehensive data about the survival outcomes of HER2-positive breast cancer patients in our setting. The present study was aimed at determining the survival outcomes among HER2-positive breast cancer patients at the Oncology Department of Kenyatta National Hospital. Methods A hospital-based retrospective cohort design was used to evaluate the survival outcomes among patients with HER2-positive breast cancer treated from 1st January 2015 to 31st December 2019 at Kenyatta National Hospital. A total of 50 eligible HER2-positive breast cancer patients were included in the study. In the predesigned data abstraction tool, data were collected by reviewing the medical records of the patients. The data were entered and analyzed using the Statistical Package for the Social Sciences version 27 software. The mean survival time was estimated using Kaplan-Meier survival analysis. Results The mean age was 45.44 ± 12.218 years, with a majority (80%) of the patients being below 60 years. Most patients (64%) had advanced-stage disease. The median follow-up time for patients with curative stages of breast cancer was 41 months, while the median follow-up time for those with the advanced incurable disease was 8.5 months. The 4-year survival rate was 62.5% for those curable-stage HER2-positive breast cancer compared to 5.6% for those with metastatic disease at presentation. Conclusion The 4-year survival rate for both early-stage and advanced-stage HER2-positive breast cancer in our setting is suboptimal when compared to existing outcome data from health care systems where trastuzumab is more widely available.

Influence of Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in early-stage HER2 positive breast cancer

Trastuzumab has improved the prognosis of HER2 positive breast cancer, but cardiotoxicity remains a concern. We aimed to identify risk factors for trastuzumab-induced cardiotoxicity, with an emphasis on the HER2 Ile655Val single nucleotide polymorphism. This single-center case–control study included 1056 patients with early-stage HER2 positive breast cancer that received adjuvant trastuzumab. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) > 15% in patients without previous cardiomyopathy, or > 10% in patients with baseline LVEF of < 50%. Patient characteristics and cardiac parameters were compared in 78 (7.38%) cases and 99 randomly assigned controls, and the polymorphism was genotyped using real-time polymerase chain reaction. Cardiotoxicity was independently associated with advanced age (P = 0.024), lower body mass index (P = 0.023), left breast involvement (P = 0.001), N3 status (P = 0.004), diabetes (P = 0.016), and a family history of coronary artery disease (P = 0.019). Genotype distribution was as follows: A/A (Ile/Ile) was found in 111 (62.7%) patients, A/G (Ile/Val) in 60 (33.9%) patients, and G/G (Val/Val) in 6 (3.4%) patients. The genotype was not associated with cardiotoxicity or the severity of heart failure, reversibility, and recovery time. We found no association between the HER2 Ile655Val polymorphism and trastuzumab-induced cardiotoxicity; therefore, we do not recommend routine cardiotoxicity-risk stratification using this polymorphism.

Lisinopril or carvedilol in prevention of trastuzumab-induced cardiotoxicity in patients with HER2-positive early stage breast cancer: Longitudinal changes of left ventricular ejection fraction below normal levels (LVEF &lt;50%).

509 Background: Treatment of HER2-positive breast cancer patients with trastuzumab is highly effective. However, a trastuzumab-associated decline in the left ventricular ejection fraction (LVEF) and clinical heart failure often prompt interruption and discontinuation of treatment. We therefore evaluated the preventive impact of an ACE inhibitor or beta blockers on the left ventricular ejection fraction (LVEF) during treatment of trastuzumab and chemotherapy. Methods: In a prospective randomized study, women with early stage HER2 positive breast cancer undergoing (neo)adjuvant chemotherapy with trastuzumab were randomized to receive either once daily lisinopril (10mg), carvedilol (10mg) or placebo during treatment with trastuzumab and further stratified by anthracycline use (AC+T versus nonAC+T). In a follow up to the initially presented primary endpoint of overall cardiotoxicity, we measured the protective effects of lisinopril or carvedilol to prevent a trastuzumab induced LVEF decrease to less than 50% over the course of therapy as well as the impact on LVEF decrease by &gt;10% within normal LVEF levels. Results: A total of 468 women (mean age was 51±10.7 years) with HER2 overexpressing early-stage breast cancer from 127 community-based oncology practices were enrolled, a prespecified minimum target of 189 (40%) patients were treated with AC+T and 279 (60%) with nonAC+T. Baseline cardiac risk factors of this study population included obesity and an elevated blood pressure. Patients in the anthracycline group were younger and without hypertension. A small, not clinically relevant decrease in LVEF was observed during trastuzumab therapy in all patients which was not significantly altered by any of the cardiac interventions. The rate of LVEF decline to &lt;50% was much more frequent in patients treated with an anthracycline than those with a non-anthracycline containing regimen (21% vs 4.1%). Treatment with lisinopril averted the decline in LVEF in the AC+T group compared to placebo (10.8% vs 30.5%, p=0.045). A smaller but not significant effect was seen by carvedilol. The incidence of cardiotoxicity manifesting as LVEF decrease by ≥10% within the normal range was similar in both AC+T and the nonAC+T arms, and not affected by either lisinopril or carvedilol. Conclusions: In patients treated with trastuzumab without anthracyclines, the impact of trastuzumab on LVEF is small and infrequent. In contrast, patients treated with anthracyclines prior to trastuzumab, demonstrated a decrease in LVEF to below normal levels in a larger than previously reported number of women in this community based setting. The trastuzumab-anthracycline induced decline in LVEF could be prevented with concurrent treatment with lisinopril, which was tolerable even in patients without hypertension. Clinical trial information: NCT01009918.

Real-world outcomes of neoadjuvant treatment for HER2 positive early-stage breast cancer.

e18791 Background: Patients with HER2 positive early-stage breast cancer (ESBC) with residual disease (RD) following neoadjuvant therapy derive benefit from treatment escalation. However, treatment modifications for patients who achieve a complete pathologic response (pCR) remains controversial. The Neo-Bioscore is a validated prognostic tool used for patients with ESBC treated neoadjuvantly. To understand the impact of pCR on outcomes in a real-world setting, and better refine patient selection for treatment escalation or de-escalation, we investigated the use of the Neo-Bioscore and/or other prognostic variables. Methods: Patients diagnosed from 2005 to 2014 with stage I-III HER2 positive breast cancer and treated with neoadjuvant systemic therapy were identified from the BC Cancer Breast Cancer Outcomes Unit database. Outcomes of interest included breast cancer specific survival (BCSS), overall survival (OS), distant disease- free survival (DRFS), and locoregional recurrence free survival (LRFS), and were assessed using the Kaplan-Meier method, comparing the pCR and RD groups. Multivariate analysis was used to assess clinical and pathologic prognostic factors beyond pCR. Results: Of the 417 patients meeting inclusion criteria, median age was 50, including 38.1% with clinical stage 2 and 58.3% with clinical stage 3 disease and 59.5% with hormone receptor (HR) positive tumors. 98.1% received chemotherapy and 92.6% received trastuzumab. Median follow-up was 9.6 years (9.2, 10.0). Overall, 193 patients (46.3%) achieved a pCR. Those with RD had higher clinical T stage (p &lt; 0.01) and more HR positive disease (p &lt; 0.01). Patients who achieved a pCR had significantly better 5-year BCSS (91.2% vs. 74.8%, p&lt; 0.0001), OS (90.7% vs. 69.9%, p&lt; 0.0001), DRFS (87.9% vs. 66.3%, p&lt; 0.0001) and LRFS (98.9% vs. 92.5%, p= 0.007) in univariate analyses. In multivariate analyses, the neo-bioscore (1 vs 5: HR 0.05, 95% CI 0.003,0.666, p = 0.02), higher pathological T stage (ypT3 vs ypT0: HR 7.2, 95% CI 1.3, 40.9, p = 0.03) and pathological N stage (ypN1 vs ypN0: HR 2.2, 95% CI 1.1, 4.5, p = 0.03) were associated with BCSS, whereas patients’ age, ER status and baseline clinical T and N stage were not. Conclusions: In a real-world population, ESBC patients with HER2 positive tumors treated with neoadjuvant systemic therapy who achieved pCR derived significant improvements across all survival parameters compared to those with RD. However, distant relapses still occurred in 12% of patients who achieved pCR. Further analyses to identify patients with pCR who relapsed are underway to determine who may benefit from treatment escalation. The final pathological stage and neo-bioscore for patients with RD were prognostic in a real-world cohort and should be considered for adjuvant treatment decisions. Validation of these results in an independent cohort are also ongoing to better understand predictive and prognostic variables.

P090 - Pathological complete response in early stage HER-2 positive breast cancer patients, receiving neoadjuvant chemotherapy/ Trastuzumab, in a single breast unit in Johannesburg

P090 - Pathological complete response in early stage HER-2 positive breast cancer patients, receiving neoadjuvant chemotherapy/ Trastuzumab, in a single breast unit in Johannesburg

Prognostic and predictive value of neutrophil/lymphocyte ratio in patients with triple-negative and HER2-positive breast cancer undergoing neoadjuvant systemic therapy.

e12620 Background: Preoperative neutrophil-lymphocyte ratio (NLR) have been suggested to be correlated with the prognosis of patients with breast cancer (BC). However, the results still remain controversial. The goal of our study was to evaluate the predictive and prognostic value of NLR in early stage triple negative and HER2-pos breast cancer patients undergoing NAC. Methods: 96 female patients (pts) with histologically proven breast cancer (51 TNBC, and 45 HER2 pos) were analysed in this retrospective analysis. The NLR before the initiation of NAC was documented. Histopathological response in surgically removed specimens was evaluated using the Residual Cancer Burden (RCB) Calculator (by MD Anderson Cancer Center). The pCR was defined as no invasive tumor in primary tumor bed and lymph nodes. The NLR variable was analyzed as both continuous and categorical. The impact on pCR and RCB was tested using Mann-Whitney, Kruskal-Willis or the Chi-2 test, respectively. Results: Only 4 categories of NAC were used: in TNBC 4 x ACdd followed by 12 x PCL (38 pts) or 4 x ACdd followed by 12 x PCL+ carboplatin AUC 1.0-2 (13 pts), in HER2-pos 39 pts received 6 x TCH (docetaxel + tratuzumab + carboplatin AUC 6) and 6 pts 4 x ACdd followed by 12 x PCL iv + 4 x trastuzumab. In 27 pts (53%) with TNBC and 24 pts (53%) with HER2-pos breast cancer pCR was obtained after NAC. RCB distribution was: 0-53.1%, 1-22%, 2-17.6%, 3-7.3%. No association with NLR and pCR could be observed (p &gt; 0.26). No association with NLR and RCB could be observed (p &gt; 0.18). Conclusions: In our retrospective analysis we could not demonstrate predictive or prognostic value of NLR in the cohort of early stage triple negative and HER2-positive breast cancer patients treated with NAC. Further studies are planned in a group of patients with Luminal B, HER2 – negative breast cancer, who received NAC.

Post-Mastectomy Radiation Therapy in Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer Patients: Analysis of the HERA Trial

Postmastectomy radiation therapy (PMRT) improves recurrence rates and overall survival in breast cancer patients. However, it remains unclear whether these findings can be applied to human epidermal growth factor receptor 2 (HER-2) positive patients treated with trastuzumab. The Herceptin Adjuvant (HERA) trial is a phase III randomized clinical trial that established the efficacy of trastuzumab in HER-2 positive early stage breast cancer. The present study is a retrospective analysis of prospective data of 1633 trial patients treated with mastectomy and adjuvant trastuzumab. The primary objective of the study was to determine the effect of PMRT on loco-regional recurrence rates (LRR). Hazard ratios were estimated from Cox models, and LRR curves were generated by the Kaplan-Meier method. Our analysis included 940 patients (57.6%) who received PMRT and 693 patients (42.4%) who did not. Patients in the PMRT group had worse prognostic disease characteristics. At a median follow-up of 11 years, no significant difference in LRR was noted after PMRT in node negative (N0) patients (P = .96). Patients with 1 to 3 positive lymph nodes had a LRR-free survival of 97% in the PMRT group compared with 90% in the no PMRT group (hazard ratio = 0.28, P = .004) and a nonsignificant improved overall survival after PMRT (hazard ratio = 0.63, P = .06). PMRT delivery in HER-2 positive breast cancer patients with 1 to 3 positive lymph nodes decreases the risk of LRR. Although the magnitude of PMRT benefit is lower than historic studies, the present findings are in favor of PMRT for HER-2 positive breast cancer patients with 1 to 3 involved nodes. Future studies are needed to determine which HER-2 positive breast cancer patients benefit the most from PMRT.

De-escalating adjuvant trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer: A systemic review and meta-analysis.

524 Background: One year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage HER2 positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results. Methods: A search of PubMed and conferences identified randomized trials that compared abbreviated trastuzumab therapy to one year of treatment in early-stage HER2 positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for disease free survival (DFS) and overall survival (OS). Data on the number of DFS and distant relapse events were also collected as were the number of patients at risk in each group. Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor (ER) expression and the duration of abbreviated trastuzumab (9-12 weeks versus 6 months). Odds ratios (ORs) and 95% CI were computed for pre-specified cardiotoxicity events including cardiac dysfunction and congestive heart failure (CHF). Results: Analysis included 6 trials comprising 11603 patients. In most studies adjuvant chemotherapy included anthracyclines and taxanes. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI 1.05-1.25, p = 0.002) and OS (HR = 1.15, 95% CI 1.02-1.29. p = 0.02). The effect on DFS was not influenced by ER status (p for the subgroup difference = 0.23), nodal involvement (p = 0.44) or the different duration of trastuzumab in the experimental arm (p = 0.08). In absolute terms, after an estimated median follow-up of 71 months, shorter treatment with trastuzumab was associated with an absolute increase in DFS events of 2.3%. Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI 0.55-0.81, p &lt; 0.001) and CHF (OR = 0.66, 95% CI 0.50-0.86, p = 0.003). Conclusions: Compared to one year, shorter duration of adjuvant trastuzumab is associated with significantly worse DFS and OS, despite favorable cardiotoxicity profile. One year of trastuzumab should remain the standard adjuvant treatment in early-stage HER2 positive breast cancer with appropriate cardiac monitoring.

P208 - Time – Driven Activity – Based Costing: cost analysis of trastuzumab in the treatment of early stage HER-2 positive breast cancer in southern of Brazil

P208 - Time – Driven Activity – Based Costing: cost analysis of trastuzumab in the treatment of early stage HER-2 positive breast cancer in southern of Brazil

Abstract P2-08-46: Prognostic value of tumor-infiltrating lymphocytes (TILs) and clinical values for prediction of breast cancer recurrence in HER2 positive early breast cancer after surgery in King Chulalongkorn Memorial Hospital

Abstract Background:Tumor-infiltrating lymphocytes (TILs), one of immunological biomarkers have been investigated in breast cancer and other cancers. High levels of TILs or lymphocyte-predominant breast cancer subgroup (LPBC) were associated with better prognosis in HER2 positive and triple negative breast cancers from various studies. Recently, TILs is also the predictive biomarker for response to neoadjuvant chemotherapy. Clinical utility of TILs has been recommended in routine clinical practice for breast cancer patients. However, limitation of TILs in HER2 positive women in Thai ethnicity was reported. So, the aim of this study was to evaluate TILs in combination with clinical values as the prognostic value for predicting the recurrent breast cancer in Thai population. Methods: Four hundred and eighty-six patients with early stage HER-2 positive breast cancer who were diagnosed and treated at King Chulalongkorn Memorial Hospital from January 2005 to December 2016 were reviewed retrospectively. Clinico-pathological features, stromal TILs classified as low, intermediate and high, and survival outcomes were analyzed. Results: The median age was 52 years (26-85). Of the 486 HER2 positive women, 56% had postmenopause, 54.5% had T2 tumor, 47.7% had node negative, 66.8% had stage I-II, 44.6% had lymphovascular invasion, and 47.5% had positive hormonal receptor. For the primary treatment, 67.3% underwent modified radical mastectomy, 96.5% received neoadjuvant/adjuvant chemotherapy, 69.7% received adjuvant trastuzumab, 46.7% received adjuvant hormonal therapy. In 92 recurrent patients (18.9%), distant metastasis was identified in 67.4%. In 100 available tissues for evaluating stromal TILs, only 14 (14%) had high stromal TILs (at least 50%) and 46 patients (46%) had recurrent disease. Twenty three of 39 (59%)in low stromal TILs group had disease recurrence while only 4 out of 14 (28.6%) in high stromal TILs had recurrent disease. Median percentage of stromal TILs in recurrent and non-recurrent group was 17.5% and 27.5%, respectively. From multivariate analysis, high stromal TILs (HR 0.52 [95%CI 0.32-0.85]; p = 0.01) and trastuzumab used (HR 0.39 [95%CI 0.25-0.61]; p &amp;lt;0.001) were associated with decreased risk of recurrences. After median follow up of 4.1 years, 5-years disease free survival (DFS) and 5-years overall survival (OS) were 80.9%, 86.8%, 69% and 92.6%, 91.5%, 94.5% in overall populations, trastuzumab and non-trastuzumab used group, respectively. Additionally, 5-year DFS and 5-year OS were 34.3%, 60.8%, 75.7% and 86.2%, 82.5%, 83.1% in low, intermediate and high stromal TILs subgroup, respectively. Conclusion: High stromal TILs and trastuzumab used were statistically significant prognostic values for predicting disease recurrence in HER-2 positive early breast cancer. Stromal TILs together with clinical values established clinical utility in Thai HER2 positive breast cancer women. Level of Stromal TILs in Overall PatientsStromal TILsTotal (n = 100)No recurrence (n = 54)Recurrence (n = 46)P valueLow (0-15%)39(39%)16(41%)23(59%)0.03Intermediate (20-40%)47(47%)28(59.6%)19(40.4%) LPBC (50-90%)14(14%)10(71.4%)4(28.6%) Citation Format: Prapatsornvichit S, Atikankul T, Sriuranpong V, Poovorawan N, Parinyanitikul N. Prognostic value of tumor-infiltrating lymphocytes (TILs) and clinical values for prediction of breast cancer recurrence in HER2 positive early breast cancer after surgery in King Chulalongkorn Memorial Hospital [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-46.

Pharmacokinetics of CT-P6 and reference trastuzumab by clinical factors in patients with HER2 positive early-stage breast cancer (EBC).

591Background: CT-P6 is a proposed biosimilar to reference trastuzumab, Herceptin (H) (Genentech, S San Francisco, CA, USA). A randomized phase III trial showed efficacy equivalence and comparable ...

Abstract P5-20-14: Cardiotoxicity in 1 year of treatment with reference trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early stage breast cancer (EBC) patients

Abstract Background CT-P6 is a proposed biosimilar to reference trastuzumab. This trial (NCT02162667) evaluated the similarity of CT-P6 and reference trastuzumab for both efficacy and safety in HER2 positive EBC patients. The primary endpoint, pathological complete response (pCR) rate was entirely within the pre-defined equivalence margin (Stebbing et al., Lancet Oncology 2017). Efficacy and safety were similar between the two treatment groups. We aimed to investigate the cardiotoxicity in the 1 year treatment and follow-up period. Methods A total of 549 patients with HER2 positive EBC were randomized to receive CT-P6 (n=271) or reference trastuzumab (n=278) in combination with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC, Cycles 5-8) in the neoadjuvant setting. CT-P6 or reference trastuzumab was administered at 8 mg/kg (Cycle 1 only) followed by 6 mg/kg every 3 weeks. After surgery, patients received monotherapy of CT-P6 or reference trastuzumab up to 10 cycles in the adjuvant setting. Left ventricular ejection fraction (LVEF) was evaluated by ECHO or MUGA at baseline, every 3 or 4 cycles during treatment and every 6 months thereafter. If LVEF decreased by ≥10 points from baseline and &amp;lt;50%, a reassessment was performed within 3 weeks and the patient was withdrawn from the study treatment if the cardiac toxicity was confirmed. Results Median follow-up period was 19 months. In total, 96% of patients completed 8 cycles of taxane and anthracycline combination therapy during the neoadjuvant period and 90% of patients in each group received 1-year treatment of CT-P6 or reference trastuzumab. The relative dose intensity of study drug was similar, indicating good tolerability of CT-P6 and reference trastuzumab (97.5% and 97.3% during the neoadjuvant period; 98.5% and 98.8% during the adjuvant period). Docetaxel and FEC combination therapies were administered approximately 96% of dose intensity in the two groups. All patients had normal LVEF (≥55%) at baseline. Mean LVEF value was maintained more than 60% during 1-year treatment and follow-up period. Heart failure cases with LVEF decrease (≥10 points from baseline and &amp;lt;50%) were reported to be similar between two groups. Three patients in each group were withdrawn due to LVEF decrease. Adverse events of cardiac disorders were reported to be similar between two groups. All cases were mild or moderate except two cases. Table 1. Summary of heart failure with LVEF decrease and cardiotoxicity CT-P6 (N=271)Reference Trastuzumab (N=278)LVEF decrease ≥ 10 points and below 50%9 (3.3%)7 (2.5%)- Asymptomatic9 (3.3%)6 (2.1%)- Symptomatic01 (0.4%)- Confirmed2 (0.7%)4 (1.4%)- Withdrawn3 (1.1%)3 (1.1%)Cardiac disorder by AEs31 (11.4%)38 (13.7%)- Grade 1 to 230 (11.0%)37 (13.3%)- Grade 3 to 51 (0.4%)11 (0.4%)21 Grade 3 of Adams-Strokes syndrome occurring 5 months after the completion of 1-year treatment; 2 Grade 5 of acute myocardial infarction occurring 10 days after Cycle 1 of the neoadjuvant therapy Conclusions Combination therapy of CT-P6 with taxane/anthracycline and monotherapy of CT-P6 over 1 year period were well tolerated and cardiotoxicity was similar to reference trastuzumab. Citation Format: Esteva FJ, Chung HC, Royce ME, Lee SY, Lee SJ, Stebbing J. Cardiotoxicity in 1 year of treatment with reference trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early stage breast cancer (EBC) patients [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 P5-20-14.

Abstract P5-20-17: Safety of continuing chemotherapy in overt left ventricular dysfunction using antibodies to human epidermal growth factor receptor-2: A retrospective study

Abstract Introduction: Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor (HER)-2 and significantly improves survival in HER-2 positive early stage breast cancer. However, trastuzumab is also known to cause cardiotoxicity. Guidelines recommend withholding or discontinuing trastuzumab if left ventricular ejection fraction (LVEF) falls ≥15% from baseline, or to &amp;lt;50%, but there is little evidence to support this strategy. Additionally, premature discontinuation of trastuzumab may lead to poorer cancer outcomes. Trastuzumab cardiotoxicity is frequently reversible, and the use of angiotensin converting enzyme-inhibitors (ACE-I) and beta blockers is highly effective at treating impaired LVEF in other patient populations. We therefore hypothesize that it is safe to continue trastuzumab in patients with asymptomatic or mildly symptomatic fall in LVEF, when concomitantly treated with ACE-I and beta blockers. Methods: In this retrospective chart review, we identified 18 consecutive patients with stage 1-3 HER-2 positive breast cancer patients who had a decline in LVEF meeting the criteria above to withhold trastuzumab, and who were referred to our cardio-oncology service from the beginning of 2015 to March 2017. These patients were offered and consented to receive ongoing trastuzumab accompanied by ACE-I and/or beta blocker. Data on patient demographics, cancer therapies, clinical features, LVEF, and cardiac medications were extracted from medical charts. Results: Among the 18 patients identified, all were women, 12 (67%) were estrogen receptor positive, and 7 progesterone receptor positive (39%). 11 (61%) of patients had a left-sided breast cancer, 6 (33%) had right-sided breast cancer, and 1 (5%) had an unspecified side breast cancer. 17 (94%) of patients had previously undergone radiation therapy, and 4 (22%) had experienced a recurrence. 16 patients had received a prior anthracycline regimen (10 sequentially, 6 concurrently). The patients were treated with one or a combination of the following medications: carvedilol (n=13), ramipril (n=12), bisoprolol (n=1), candesartan (n=2), rosuvastatin (n=2), atorvastatin (n=2). The patients were followed up for an average of 7 months after starting cardiac therapy. Table 1 summarizes the mean±SD LVEF values over the follow up time period. All patient except one (94%) completed trastuzumab treatment successfully. This patient with concomitant moderate-severe mitral regurgitation was hospitalized for pulmonary edema. Trastuzumab was discontinued and LVEF has subsequently returned to normal values. Table 1: LVEF progression from baseline to end of follow-upMean±SD LVEF at baseline57.59±5.49%Mean±SD LVEF on referral to cardio-oncology clinic50.75±4.76%Mean±SD LVEF at end of follow-up56.35±3.50% Conclusion: Treating cardiac dysfunction related to trastuzumab in a cardio-oncology clinic, using beta blockers and ACE-I may enable completion of trastuzumab therapy. Randomized trials are necessary before it can be widely recommended, however findings from our experience suggest this may be a promising new treatment strategy. Citation Format: Bharaj UK, Leong D, Dhesy-Thind S, Ellis P, Mukherjee S, Bordeleau L, Phillips C, Brown M, Kumar Tyagi N. Safety of continuing chemotherapy in overt left ventricular dysfunction using antibodies to human epidermal growth factor receptor-2: A retrospective study [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 P5-20-17.

Abstract P5-20-05: Impact of type of (neo)adjuvant systemic therapy (AdjTx) and total exposure to trastuzumab (TET) on long-term outcome of HER2-positive (HER2+) early stage breast cancer (ESBrCa)

Abstract Background Trastuzumab (T) administered for 12 months (mos) as part of a taxane (Tax)– or Tax+anthracycline (Anthra)–based AdjTx is the standard of care as (neo)AdjTx of HER2+ ESBrCa. Several prospective randomized trials have investigated a shorter duration of Adj T (i.e. 9 weeks or 6 mos) compared to standard 12 mos of T. However, the results have not been conclusive so far. The impact of administering non-Tax/non-Anthra-based AdjTx and single-agent T on long-term outcome of HER2+ ESBrCa is not fully known. Methods We conducted a retrospective analysis on a prospectively maintained departmental database of all patients (pts) with Stage I-III HER2+ ESBrCa treated with at least one dose of (neo)Adj T. Pre-planned duration of T was 12 mos for all pts. TTE was defined as the interval in weeks between the first and the last dose of T. In order to ensure that most pts had a minimum FU of 3 yrs we included all pts who received 1st T before March 31st 2014. The database was locked for outcome analyses on March 31st 2017. Results 506 pts treated between October 2001 and March 2014 were included in the study. Main pts characteristics: median age: 55 years (range: 26-85), oestrogen (ER) and/or progesterone (PR) receptors positive: 321 (63%), axillary lymph nodes positive: 266 (52%), Adj T: 386 (76%), neoAdj T: 120 (24%), Tax- and Tax/Anthra–based AdjTx: 457 (90%), non-Tax/non-Anthra AdjTx and single-agent T (without chemotherapy): 49 (10%). Median FU is 73.3 months (range: 1.4-176.3). In the overall population, DFS and OS rates are 83% and 91%, respectively. Pts treated with non-Tax/non-Anthra AdjTx had a significantly higher risk of BrCa relapse [DFS: HR 3.54 (95%CI:1.24 to 10.06, p=0.018)], and death [OS: HR 2.73 (95%CI:0.63 to 11.77 p=0.176)] compared to those treated with Tax–based AdjTx (e.g. TCH [docetaxel/carboplatin/T]). Pts who received single-agent T also had highly significantly worse DFS [HR 4.21 (95%CI:2.18 to 8.38, p&amp;lt;0.0001)] and OS [HR 6.75 (95%CI:3.13 to 14.6 p=&amp;lt;0.0001)] compared to those treated with Tax-based AdjTx. When adjusted for age (&amp;lt;55 vs &amp;gt;55 yrs), the detrimental impact of type of AdjTx remained highly statistically significant (p&amp;lt;0.0001). Patients with TTE&amp;lt;24 weeks had a highly significantly worse DFS [HR 4.7 (95%CI:2.34-9.47, p&amp;lt;0.0001)] and OS [HR 5.36 (95%CI:2.39-12.01, p&amp;lt;0.0001)] compared to pts with TTE&amp;gt;24weeks. In most cases, shorter duration of T was due to reduction in LVEF or patients refusal. In the multivariate model, positive lymph nodes, type of (neo)AdjTx and TET (&amp;lt;24 weeks vs &amp;gt;24 weeks) remained all significant and independent variables associated with worse DFS and OS. Conclusions Our mature results indicate that the administration of non-Tax/non-Anthra-based AdjTx and single-agent T is associated with a significant increase in the risk of disease relapse and death and should not be considered as therapeutic options for pts with HER2+ ESBrCa. The administration of T for &amp;lt;24weeks irrespective of the type of AdjTx is also associated with significantly worse outcome. Citation Format: Gullo G, Walsh N, Fennelly D, Walshe J, O'Mahony K, Silva N, Ballot J, Calzaferri G, Quinn C, McDonnell D, Crown J. Impact of type of (neo)adjuvant systemic therapy (AdjTx) and total exposure to trastuzumab (TET) on long-term outcome of HER2-positive (HER2+) early stage breast cancer (ESBrCa) [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 P5-20-05.