Therapy In HER2-positive Patients Research Articles

Abstract 6439: Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer

Abstract Purpose: Achieving pathologic complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis for HER2 positive breast cancer. However, clinical and biological heterogeneity of HER2 positive disease significantly affect prognosis and treatment response. Early prediction of treatment benefit could enable tailored anti-HER2 therapy. Next-generation sequencing (NGS) based genomic tests including copy number (CN) detection are widely used in breast cancer patients. We aim to evaluate the association of HER2 copy number detected by NGS with pCR rate of HER2 positive breast cancer after neoadjuvant chemotherapy. Methods: HER2 positive breast cancer patients underwent neoajuvant chemotherapy in Henan Cancer Hospital From January 2022 to March 2023 were included in the study. Pretreatment tumour specimens were subjected to pan-cancer 1021-gene panel genomic sequencing. Copy number of HER2 was obtained from the panel. Copy number of >=4 was classified as HER2 amplified and HER2 copy number <4 was classified as HER2 non-amplified. All patients underwnt definitive surgery after receieveing neoadjuvant chemotherapy containing taxanes, trastuzumab and pertuzumab. pCR was defined as pathological stage ypT0/Tis ypN0. Results: In total, 299 HER2 positive breast cancer patients were eligible for the analysis. 87 were classified as HER2 non-amplified (29.1%) by copy number and 212 patients were classified as amplified group (70.9%). The HER2 non-amplified group tends to have a higher proportion of hormone receptor positive (HR+) patients (71.3% vs. 50.5%, p=0.002). Other clinicopathological parameters were well distributed between the groups. 91.3% of patients in HER2 amplified group had strong positive HER2 expression (IHC 3+), while only 10.5% of patients in HER2 non-amplified group had HER2 expression of IHC 3+. Patients with HER2 IHC 3+ had a PCR rate of 75.8% and Patients with HER2 IHC 2+ had a pCR rate of 20.0% (20.0% vs. 75.8% p<0.001). Patients in the amplified group had a pCR rate of 76.9% and pCR rate of the non-amplified group was12.6% (12.6% vs. 76.9% p<0.001). In a multivariable logistic regression with HER2 copy number by NGS, HR status and HER2 IHC, the HER2 copy number predicted pCR rate independently of HER2 IHC and HR status. Conclusions: NGS based detection of HER2 copy number could predict response to neoadjuvant therapy in HER2 positive patients. The discordance between IHC/FISH and NGS based detection of HER2 amplification may reflect HER2 heterogeneity. HER2 heterogeneity promotes resistance to anti-HER2 therapy. Noval antibody-drug conjugates (ADC) with bystander effect, such as Trastuzumab deruxtecan, have shown anti-tumor effect even in HER2 low expression tumors. Thus, prospective study is needed to optimize anti-HER2 therapy for patients with HER2 heterogeneity. Citation Format: Hao Dai, Dechuang Jiao, Xuhui Guo, Jianghua Qiao, anfang Li, Zhenduo Lu, Xiuchun Chen, Chengzheng Wang, Min Yan, Zhenzhen Liu. Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6439.

Update Breast Cancer 2022 Part 5 - Early Stage Breast Cancer.

The treatment of patients with early stage breast cancer has changed in recent years due to the introduction of pembrolizumab, olaparib, and abemaciclib. These and other drugs with the same class of active ingredient are currently in trial for various indications. This review article summarizes the latest results that have either been presented at major conferences such as the ESMO 2022 or published recently in international journals. This includes reports on newly discovered breast cancer genes, atezolizumab in neoadjuvant therapy in HER2-positive patients, long-term data from the APHINITY study, and on how preoperative peritumoral application of local anesthetics can influence the prognosis. We also present solid data on dynamic Ki-67 from the ADAPT studies.

Combination of Nab-Paclitaxel with Trastuzumab as Neoadjuvant Chemotherapy for HER2-positive Breast Cancer Patients: Experience from a Single Center

Background: Several phase II and pilot studies showed that neoadjuvant nab-paclitaxel-based chemotherapy and trastuzumab treatment was effective and safe. However, combination of nab-paclitaxel alone with trastuzumab has not been investigated. Methods: This is a retrospective analysis. From July 2009 to June 2014, Patients with histologically confirmed, nonmetastatic HER2-positive breast cancer who received a 3-week regimen of nab-paclitaxel with trastuzumab in Guangdong General Hospital were screened. Baseline and pathological data and blood test results were collected from the electronic patient medical records. Survival data, severe adverse events and cardiac events were collected by telephone follow-up. The primary endpoint was pCR. The secondary endpoints included pCR in breast, DFS during follow-up period, breast conserving rates, tolerance, adverse events and symptomatic cardiac events. Results: 23 patients who met the eligibility criteria were indentified. 21 (91.3%) patients completed NC courses and received surgery. The breast conserving rates were 19.0%. 10 (47.6%) patients achieved a pCR and 13 (61.9%) achieved a pCR in breast. 7 (53.8%) of the 13 patients with clinical stage IIB-IIIC before surgery achieved a pCR. The pCR rates among hormone-receptor-negative and hormone-receptor-positive patients were 58.3% (7/12) and 33.3% (3/9) respectively. During a median follow-up of 31.3 months, no death was indentified and the 3-year estimated DFS was 81.2%. Two patients reported cardiac events during and after adjuvant chemotherapy. No severe adverse events that required hospitalization were identified during NC period. Grade 3 events were rare. Conclusion: The combination of nab-paclitaxel and trastuzumab as NC lead to related high pCR rates and was well tolerated. No cardiac events or severe adverse events were indentified during NC period. The studied regimen may be a potential NC therapy for HER2-positive patients. Further study is recommended in the future.

Abstract P3-12-11: Clinical outcome in patients with surgically resected brain metastases from breast cancer: prognostic considerations regarding molecular status and established prognostic classification systems.

Abstract Introduction: Incidence of brain metastases (BM) from breast cancer (BC) is increasing, paralleling increasing life expectancy of patients. However, biology, prognostic evaluation and treatment strategy are still a matter of debate. We analysed here a series of patients with resected brain metastases from BC to assess the actual prognostic factors in this specific population and the relevancy of widely accepted BM prognostic classification systems. Methods: we reviewed retrospectively all patients (n = 49) referred to our institution between December 2001 and July 2011 with available tumor tissue from resected breast cancer brain metastases. All patients underwent initial breast tumor surgery and surgical resection of the BM. Patients, tumor and treatment characteristics were recorded. Prognostic value of ER, PR, HER2 status of BM, age, Karnofsky performance status, Mini Mental Score (MMS), clinical features, number and topography of BM, systemic disease characteristics (response, metastatic sites), delay between primary tumor and BM diagnoses and treatment after neurosurgery were analyzed using uni- and multi-variate analyses. Results: Median age was 54 years (28–75). Median KPS was 80 (50–90). MMS was abnormal for 7 pts (14.3%). At BM diagnosis, 12 pts (24.5%) did not present extracranial disease and 15 (20.6%) had only one systemic metastatic site. After surgery, 83.7% of pts benefited from whole-brain radiotherapy and 79.6% from systemic therapy. Median follow-up was 25.6 months. Median cerebral progression-free survival (C-PFS) was 11.3 months (IC95:6.0–16.6) and median overall survival (OS) was 19.4 months (IC95:16.1–22.7). By univariate analysis, neither hormonal or HER2 BM status impacted survival. Similarly, molecular subtyping by IHC approximation (“basal”, ER− and PR−/HER2−;”luminal A”, ER and/or PR+/HER2−; “luminal B”, ER and/or PR+/HER2+; “HER2”, ER and PR−/HER2+) was not significantly associated with survival(p = 0.946). Abnormal MMS and multiple systemic metastases were associated with poor C-PFS (p = 0.009 for both) and poor OS (p = 0.006 and p < 0.001 respectively). Use of anti-HER2 therapy in HER2 positive patients (p = 0.003) impacted positively OS. Use of postoperative chemotherapy trend to be significant for C-PFS (p = 0.088) and OS (p = 0.100). By multivariate analyses, MMS (p = 0.012 for C-PFS, p = 0.009 for OS) and multiple systemic metastases (p = 0.020 for C-PFS, p < 0.001 for OS) remained significant, while the use of post-operative chemotherapy appeared relevant (0.013 for C-PFS and p = 0.006 for OS. Prognostic scoring systems (RPA, Nieder's Sperduto's and Niwinska's scores) were not significantly correlated to survival. Conclusions: Surgery seems to be bean effective treatment in oligometastatic brain disease of breast cancer patients whatever the hormonal receptor, HER2 or molecular subtype status of BM. MMS, presence of systemic metastases and use of postoperative systemic treatment are associated with better OS in this population whereas conventional established scoring systems are not significantly correlated to outcome. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-11.

Evaluation of Ile655Val HER2 polymorphism associated with cardiac toxicity following the administration of trastuzumab in women with breast cancer.

634 Background: Trastuzumab is well tolerated without major side effects except for cardiac toxicity. Although a number of clinical parameters have been associated with trastuzumab-associated cardiac toxicity (TACT), there is some indication that genetic variation of the HER2 gene may play a toxic role in a population of metastatic breast cancer patients. However, this finding needs confirmation and we looked at a population of non-metastatic breast cancer. This study aimed to evaluate the association between cardiac toxicity and HER2 [Ile655Val] polymorphism in non-metastatic breast cancer patients treated with trastuzumab. Methods: The Ile655Val HER2 polymorphism was assessed in 73 women using TaqMan technology. For this study, the genotyping was performed using DNA extracted from normal breast tissue located at more than 1 cm of any other lesions. Charts review was used to collect information on TACT which was defined as any decline in LVEF > 10 % from the baseline to < 55 % or a decline in LVEF > 5 % to < 50 % (lower limit of normal). The Fisher exact test was used to evaluate the association between cardiac toxicity and HER2 polymorphism. Results: No deviation from the Hardy-Weinberg equilibrium has been observed for the allele and genotype frequencies. The distribution of HER2 polymorphism was 3 Val/Val (4%), 18 Ile/Val (25%) and 52 Ile/Ile (71%). In this population, 19% (14/73) developed a cardiac toxicity. We found that 29% (6/21) of Ile/Val or Val/Val carriers compared to 15% (8/52) of Ile/Ile carriers showed TACT, but this association did not reach statistical significance (P = 0.21). Conclusions: HER2 Ile655Val polymorphism may be an efficient marker of TACT considering this tendency with this small cohort of patients. Larger sample is needed to strengthen this conclusion, since this result may influence on prescribing decision for adjuvant chemotherapy and anti-HER2 therapy in HER2 positive patients.

P1-12-12: Evaluation of Ile655Val HER2 Polymorphism Associated with Cardiac Toxicity Following the Administration of Trastuzumab in Women with Non-Metastatic Breast Cancer.

Abstract Background: Trastuzumab is well tolerated without major side effects except for cardiac toxicity. Although a number of clinical parameters have been associated with trastuzumab-associated cardiac toxicity (TACT), there is some indication that genetic variation of the HER2 gene may be associated with TACT in a population of metastatic breast cancer patients. However, this finding needs confirmation and we looked at a population of non-metastatic breast cancer. Purpose: This study aimed to evaluate the association between cardiac toxicity and HER2 [Ile655Val] polymorphism in non-metastatic breast cancer patients treated with trastuzumab. Method: The Ile655Val HER2 polymorphism was assessed in 41 women using TaqMan technology. For this study, the genotyping was performed using DNA extracted from normal breast tissue located at more than 1 cm of any other lesions. Charts review was used to collect information on TACT which was defined as a decrease in the left ventricular ejection fraction (LVEF) of ≥15% or ≥10% with a resulting LVEF < 50% or any follow-up LVEF of < 45%. The Fisher exact test was used to evaluate the association between cardiac toxicity and HER2 polymorphism. Results: No deviation from the Hardy-Weinberg equilibrium has been observed for the allele and genotype frequencies. The distribution of HER2 polymorphism was 10 Ile/Val (24%) and 31 Ile/Ile (76%). In this population, 22% (9/41) developed a cardiac toxicity. The Val655Ile genotype was associated with cardiac toxicity (0.03). In this preliminary study, 50% (5/10) of Ile/Val carriers compared to 13% (4/31) of Ile/Ile carriers showed TACT. Conclusion: HER2 Ile655Val polymorphism may be an efficient marker of TACT considering this tendency with this small cohort of patients. Larger sample is needed to strengthen this conclusion, since this result may influence on prescribing decision for adjuvant chemotherapy and anti-HER2 therapy in HER2 positive patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-12.

Management of early-stage breast cancer: Are we headed in the right direction?

284 Background: The understanding of breast cancer (BC) as a heterogeneous disease consisting of distinct subtypes based on variation in expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) has led to more personalized treatment. We postulated that with increased adoption of chemotherapy and targeted therapy for HER2 positive patients, the outcomes of ER/PR+, HER2- and of HER2+ subtypes of breast cancer would be similar. Methods: A chart review was performed of female patients >18 years old seen by a medical oncologist at an academic cancer centre in Toronto, Canada, between January 1, 2005 and December 31, 2006, for stage I-III invasive breast cancer. Clinical features, 5-year overall (OS) and relapse-free survival (RFS) of three BC subtypes were compared: ER/PR+, HER2- (hormone receptor positive, HR), HER2+ (HER2), and ER/PR-, HER2- (triple negative, TN). Results: Of 870 patient charts reviewed, 525 were analysed. There were 341 HR, 101 HER2 and 83 TN patients. TN patients were younger (p<0.001), and had higher stage (p<0.001) and higher histological grade tumors (p<0.001). The 5-year RFS and OS were: HR: 88.2% and 96.6%, HER2: 76.7% and 92%, TN: 79.8% and 83.9%. Chemotherapy was used in 41.1%, 84.2% and 83.1% of HR, HER2 and TN patients. Anthracycline plus taxane regimens were used in 48.6%, 52.9% and 68.1% of HR, HER2 and TN patients, respectively. Among HER2 patients, only 74.3% received trastuzumab. The 5-year RFS and OS for HER2 patients who received trastuzumab were 79.9% and 91.8%, and for those who did not: 69% and 91.6%. Conclusions: HR+ patients have an excellent outcome. Despite significant improvement in outcomes of HER2+ patients with early stage breast cancer, they still remain at higher risk of recurrence along with TN patients. Trastuzumab was underutilized among HER2+ patients in this cohort, which may have contributed to decreased 5 year RFS. Ongoing prospective follow up of early BC outcomes by breast cancer subtypes is important.