Non-metastatic HER2-positive Breast Cancer Research Articles

Outcomes of HER2-positive nonmetastatic breast cancer patients with or without deleterious BRCA mutations after trastuzumab treatment.

e12550 Background: Human epidermal growth factor receptor (HER2) overexpression or amplification occurs in 20–25% of all breast cancers and is associated with an aggressive form of the disease with reduced disease-free survival (DFS) and overall survival (OS). However, the outcome of patients with HER2+ tumor and BRCA mutation is poorly described. The purpose of this analysis was to analyze the clinical and pathological features and outcomes of patients with HER2+ breast cancer regards to their BRCA status. Methods: Patients who were referred for genetic counseling between 2004-2012 and who had a HER2+ breast cancer treated with trastuzumab were included in our analysis. Patients were considered Her2+ if immunohistochemistry was 3+ or had a ratio of ≥2 by FISH. Patients with metastatic breast cancer at diagnosis were excluded. Clinical and pathological and outcome data was extracted from a prospectively maintained research data base after IRB approval was obtained. Results: Ninety-four patients were identified. The median age at diagnosis was 39 years (range 21 – 58). The majority of the patients were White (76%). Tumors were invasive ductal carcinoma in 89% and had nuclear grading of 3 in 76% of patients. Hormone receptors were positive in 66% and BRCA 1 or 2 mutations were positive in 16% (N=15). The majority of the patients were treated with a combination of Anthracyclines plus Taxanes (76%). All patients received trastuzumab in the neoadjuvant or adjuvant setting. After a median follow-up of 4.4 years, OS and DFS in all patients were 97% and 88%, respectively. Three HER2-positive breast cancer patients had died (3.2 %). Recurrence had occurred in 11 patients; all of these patients were BRCA negative. OS and DFS of patients with BRCA mutations were then compared with OS and DFS of patients without BRCA mutation (both 100% vs. 96% and 81.9%, respectively). There was no statistically significant survival difference in BRCA mutation carriers compared with non-carriers (p=0.362). Conclusions: The presence of a BRCA mutation does not seem to offer prognostic information in this population. Further investigation with larger cohort are needed for confirmation.

Association of HER2 Ile655Val and Ala1170Pro polymorphisms with breast cancer prognosis factors

The human epidermal growth factor receptor‐2 (HER2) overexpression occurs in about 15% of human breast cancers and is a marker of poor survival. However, it is unclear if common HER2 polymorphisms are associated with breast cancer prognosis factors. This study aimed to evaluate the association between HER2 polymorphisms and breast cancer prognostic factors in non‐metastatic HER2‐positive breast cancer patients. Among 73 women, HER2 polymorphisms (Ile655Val and Ala1170Pro) were assessed using TaqMan assays in normal and tumor breast tissues. In normal breast tissue, the variant allele 1170Pro was associated with younger age (P=0.007) and the presence of lymphovascular invasion (P=0.06). Similar associations were observed when polymorphism was assessed in tumor breast tissue. No association was found between Ile655Val polymorphism and breast cancer prognostic factors. However, we observed a difference of Ile655Val or Ala1170Pro genotyping between normal and tumor breast tissues (P=0.03 and P=0.01, respectively). These preliminary results suggest that HER2 Ile655Val and Ala1170Pro polymorphisms may play a role in breast carcinogenesis, but only Ala1170Pro polymorphism is associated with breast cancer prognostic factors in non‐metastatic HER2‐positive breast cancer patients.

Cranial Magnetic Resonance Imaging in the Staging of HER2-positive Breast Cancer Patients

Aim: The aim of the current study was to evaluate whether early detection of brain metastases (BMs) could improve survival outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Material and Methods: HER2-positive breast cancer patients without BMs who had no neurological symptoms within 12 months from diagnosis or relapse time of the disease were included in the study. The patients were distributed into 2 groups: Group 1 comprised patients without metastases; group 2 comprised patients with metastases. The symptomatic historic control group with BMs was defined retrospectively for survival comparisons. Results: 55 (57.3%) and 41 (42.7%) patients were in groups 1 and 2, respectively. 11 of the 96 patients (11.5%) had occult BMs, and 9 of them were in group 2 whereas only 2 patients were in group 1 (22% vs. 3.6%, respectively; p = 0.008). While the median survival times from the first metastasis (28.7 vs. 22.5 months, respectively; p = 0.561) and BM (6.8 vs. 6.1 months, respectively; p = 0.511) were similar, cerebral death was numerically different (16.7% vs. 46.3%; p = 0.221) between asymptomatic (n = 9) and symptomatic patients (n = 53). Conclusions: BMs were detected very rarely in asymptomatic, non-metastatic HER2-positive breast cancer patients compared with asymptomatic, metastatic patients. Furthermore, although early detection of BMs decreases the cerebral death rate, it does not prolong the survival rate in metastatic patients.

An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for Human Epidermal Growth Factor Receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer

BackgroundLapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1–2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial. Patients and methodsPatients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m2). ResultsTwenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed. ConclusionsOur recommended dose for phase II is lapatinib 1000mg/day and docetaxel 100mg/m2 with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.

103IN - Is the Neoadjuvant Model an Accelerated Path Towards Breast Cancer Treatment Tailoring? Experience of the Neoaltto Trial

ABSTRACT Around 5% of oncology agents in the development pipeline receive regulatory approval. This procedure is very long and expensive, which results in delaying the availability of effective therapies to patients. Furthermore, one available, they are provided at a considerably high cost to compensate for the exhaustive development process. What is more frustrating is that after such a process we still have a crude idea on the subsets of patients who will “truly” benefit a given agent. Hence, there is a need to adopt innovative strategies to accelerate drug development in a more efficient and targeted way. In breast cancer (BC), the neoadjuvant setting emerge as an excellent opportunity to incorporate biomarkers within the drug development process, taking the advent of the presence of a robust short term surrogate endpoint, like pathological complete response (pCR). It also allows interrogating the effect of novel therapies on BC biology, via the collection of samples pre and post therapy. These advantages would help in accelerating drug and biomarker development via the conduction of trials that are relatively small in size and short in duration. This would possibly have a positive impact on the health-care economics dimension as well. NeoALTTO is a phase 3 trial, which included 455 patients with HER2-positive non-metastatic BC. Patients randomized to lapatinib and trastuzumab in combination with paclitaxel had nearly double the pCR rate compared to those randomized to paclitaxel with either drug alone. A similar trial but in the adjuvant setting (ALTTO) including nearly 8,000 patients has recently completed accrual. If the higher pCR rate in the NeoALLTO trial translated into improved long term outcome and this was confirmed in ALTTO, this could represent an important milestone in the way we develop targeted agents in BC, and hence conducting huge trials like ALTTO might not be needed in the future. The NeoALTTO trial also had an extensive translational research and molecular imaging programs with their results expected to be available very soon. It is fascinating to see the tremendous amount of information that can be generated and the possible impact this might have on patient care, with a study that included less than 500 patients. Hence, this model encourages the adoption of the neoadjuvant setting in investigating novel agents/treatment strategies, which could represent a smart, fast and cheap way in obtaining regulatory approval of effective agents. Disclosure All authors have declared no conflicts of interest.

387 - Cranial Magnetic Resonance Imaging (MRI) in the Staging of HER2-Positive Breast Cancer Patients

ABSTRACT Purpose The aim of the current study was to evaluate whether early detection of brain metastases could improve survival outcomes in HER2-positive breast cancer patients. Patients and methods HER2-positive breast cancer patients without neurological symptoms within 12 months from current stage of diagnosis were included in the study. The factors affecting the development of brain metastasis in the entire group and the metastatic patients were investigated, respectively. Survival durations after first metastasis and brain metastasis were compared between the asymptomatic and symptomatic patients Results Eleven of the 96 patients (11.5%) had occult brain metastasis. Of whom 9 patients were in the metastatic group, only 2 patients were in the non-metastatic group, (22% vs 3.6%, respectively, p = 0.008). Although median survival durations from first metastasis (27.4 vs 20.2 months, respectively, p = 0.858) and brain metastasis (5.2 vs 4.4 months, respectively, p = 0.710) similar, cerebral death was numerically different (22% vs 46%, p = 0.271) in the asymptomatic and symptomatic patients. Conclusion Present study suggests that routine cranial imaging do not bring any benefit to the non-metastatic HER2-positive breast cancer patients. Furthermore, although early detection of brain metastasis provides reduction in cerebral deaths, it does not prolong survival in metastatic patients. Disclosure All authors have declared no conflicts of interest.

Analysis of Fcγ Receptor IIIa and IIa Polymorphisms: Lack of Correlation with Outcome in Trastuzumab-Treated Breast Cancer Patients

The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high-affinity SNPs are associated with disease-free survival (DFS) among patients with HER2-positive nonmetastatic breast cancer. Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was conducted using Sanger sequencing and Sequenom mass spectrometry. Patient samples (N = 1,189) were successfully genotyped for FCGR3A and 1,218 for FCGR2A. Compared with the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms than control arm (HR, 0.842; P = 0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR, 0.74; P = 0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs. V/F vs. F/F, P = 0.98; 131H/H vs. H/R vs. R/R, P = 0.76; 158V/V and/or 131H/H vs. others, P = 0.67). This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not show a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab.

5087 New isolated mediastinal lymph node or pulmonary nodule during surveillance of breast cancer: clinical factors to differentiate metastasis from benign lesion

Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1–2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial.Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21 days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m2).Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7 days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed.Our recommended dose for phase II is lapatinib 1000 mg/day and docetaxel 100 mg/m2 with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250 mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250 mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.

5085 HER-2 positive locally advanced breast cancer: one or two entities?

Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1–2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial.Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21 days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m2).Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7 days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed.Our recommended dose for phase II is lapatinib 1000 mg/day and docetaxel 100 mg/m2 with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250 mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250 mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.