In Hae Park

Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer

BACKGROUND Although trastuzumab therapy improves survival in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, 40% of patients develop brain metastasis (BM) even when extracranial disease is under control. We studied whether trastuzumab therapy beyond or after BM was beneficial to patients with BM. PATIENTS AND METHODS The effect of trastuzumab on survival after BM was analyzed in 78 HER2-positive breast cancer patients. Patients were grouped according to trastuzumab therapy; no treatment and treatment before and after BM were diagnosed. RESULTS Overall survival after the diagnosis of BM as well as time to progression (TTP) of intracranial tumors was prolonged in patients who received trastuzumab after BM was diagnosed. Conversely, BM occurred much later in patients who received trastuzumab before BM. In the multivariate Cox regression model, age at BM <50 years, disease-free interval >or=24 months, TTP of intracranial tumor >or=4.8 months, and trastuzumab treatment after BM were significantly associated with longer survival after the onset of BM. CONCLUSIONS Trastuzumab therapy after the onset of BM in HER2-positive breast cancer patients is associated with a significant survival benefit after BM diagnosis compared with patients who never received or completed trastuzumab before the BM diagnosis.

MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Phase III, Multicenter, Randomized Trial of Maintenance Chemotherapy Versus Observation in Patients With Metastatic Breast Cancer After Achieving Disease Control With Six Cycles of Gemcitabine Plus Paclitaxel As First-Line Chemotherapy: KCSG-BR07-02

PURPOSE The primary purpose of our study was to evaluate whether maintenance chemotherapy with paclitaxel/gemcitabine (PG) was superior to observation in improving progression-free survival (PFS) in patients with metastatic breast cancer (MBC) who achieved disease control with an initial six cycles of PG as their first-line treatment. PATIENTS AND METHODS The study was a prospective, randomized, multicenter, phase III trial. Patients MBC with who achieved disease control after six cycles of PG chemotherapy were randomly assigned to maintenance chemotherapy or observation until progression. RESULTS Of 324 patients from 10 centers enrolled, 231 patients with MBC exhibited disease control (complete response + partial response + stable disease) with first-line PG and were randomly assigned to maintenance chemotherapy (n = 116) or observation (n = 115). The median age was 48 years (range, 28 to 76 years), median follow-up was 33 months, and median number of chemotherapy cycles in the maintenance group after random assignment was six. The median PFS time after random assignment was longer in the maintenance group than in the observation group (7.5 v 3.8 months, respectively; P = .026). The median overall survival (OS) time was longer in the maintenance group than in the observation group (32.3 v 23.5 months, respectively; P = .047). The rate of grade 3 or higher neutropenia after random assignment was higher in the maintenance group than in the observation group (61% v 0.9%, respectively; P < .001). CONCLUSION In patients with MBC who achieved disease control with an initial six cycles of PG chemotherapy, maintenance PG chemotherapy resulted in better PFS and OS compared with observation.

Metaplastic breast cancer: Clinicopathological features and its prognosis

Aims The prognosis of metaplastic breast cancer (MBC) is reportedly worse than that of triple-negative invasive ductal carcinoma (TN-IDC), but the determinants of poor prognosis are not yet known. Methods Patients from two Korean cancer centres were included in this study (67 MBC and 520 TN-IDC). Characteristics of the two disease groups, including clinical parameters, histological features, chemoresponsiveness, disease recurrence and survival estimates, were evaluated. Results MBC presented with larger tumours, more frequent distant metastasis and higher histological grade compared with TN-IDC (p<0.001). All but nine patients with MBC had triple-negative disease. Disease-free survival and overall survival (OS) of MBC were worse than TN-IDC (p<0.001). Multivariable analysis of disease-free survival revealed MBC type as an independent prognostic factor (HR 2.53; 95% CI 1.32 to 4.84) along with lymph node metastasis and implementation of breast conserving surgery. For OS, MBC type remained a significant prognostic factor (HR 2.56; 95% CI 1.18 to 5.54). Chemoresponsiveness of MBC and TN-IDC were similar in both neoadjuvant (p=1.000) and advanced disease settings (p=0.508). For a given MBC type, risk factors for disease recurrence included the presence of a squamous component (HR 4.0; 95% CI 1.46 to 10.99) and lymph node metastasis (HR 4.76; 95% CI 1.67 to 13.60); the risk factor for OS was initial distant metastasis (HR 10.77; 95% CI 2.59 to 44.76). Conclusions MBC had worse survival outcomes compared with TN-IDC. Poor prognosis for MBC was likely caused by frequent recurrence with high initial stage and the unique biology of MBC itself.

Protein and lipid MALDI profiles classify breast cancers according to the intrinsic subtype

BackgroundMatrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) has been demonstrated to be useful for molecular profiling of common solid tumors. Using recently developed MALDI matrices for lipid profiling, we evaluated whether direct tissue MALDI MS analysis on proteins and lipids may classify human breast cancer samples according to the intrinsic subtype.MethodsThirty-four pairs of frozen, resected breast cancer and adjacent normal tissue samples were analyzed using histology-directed, MALDI MS analysis. Sinapinic acid and 2,5-dihydroxybenzoic acid/α-cyano-4-hydroxycinnamic acid were manually deposited on areas of each tissue section enriched in epithelial cells to identify lipid profiles, and mass spectra were acquired using a MALDI-time of flight instrument.ResultsProtein and lipid profiles distinguish cancer from adjacent normal tissue samples with the median prediction accuracy of 94.1%. Luminal, HER2+, and triple-negative tumors demonstrated different protein and lipid profiles, as evidenced by permutation P values less than 0.01 for 0.632+ bootstrap cross-validated misclassification rates with all classifiers tested. Discriminatory proteins and lipids were useful for classifying tumors according to the intrinsic subtype with median prediction accuracies of 80.0-81.3% in random test sets.ConclusionsProtein and lipid profiles accurately distinguish tumor from adjacent normal tissue and classify breast cancers according to the intrinsic subtype.

Phase II Parallel Group Study Showing Comparable Efficacy Between Premenopausal Metastatic Breast Cancer Patients Treated With Letrozole Plus Goserelin and Postmenopausal Patients Treated With Letrozole Alone As First-Line Hormone Therapy

PURPOSE Goserelin and letrozole in premenopausal patients can result in clinical outcomes comparable to those obtained by letrozole alone in postmenopausal patients with metastatic breast cancer (MBC). PATIENTS AND METHODS A total of 73 patients with hormone-responsive MBC were included. Of those, 35 premenopausal patients received goserelin (3.6 mg subcutaneously every 28 days) plus letrozole (2.5 mg orally daily), and 38 postmenopausal patients received letrozole alone as their first-line endocrine therapy in a metastatic setting. RESULTS Baseline characteristics were similar in the two groups, except for a younger age (median, 41 v 53.5 years; P < .001) and a shorter disease-free interval (median, 1.8 v 3.3 years; P = .03) in the premenopausal group. Clinical benefit rates were comparable between the two groups (77% v 74%; P = .77). With the median follow-up of 27.4 months, there was no statistical difference in the median time to progression between the two groups (9.5 months [95% CI, 6.4 to 12.1 months] v 8.9 months [95% CI, 6.4 to 13.3 months]). In patients who did not receive bisphosphonate, letrozole +/- goserelin caused a greater loss of bone mineral density at 6 months compared with that of patients receiving bisphosphonate treatment (premenopausal group, -16.7% v 53.9%; P = .002 and postmenopausal group, -13.3% v 17.4%; P = .04 at the lumbar spine). CONCLUSION Clinical efficacies in premenopausal MBC patients with combined letrozole and goserelin therapy were comparable to those in postmenopausal patients treated with letrozole alone. Although letrozole +/- goserelin resulted in a modest increase in bone resorption, concurrent treatment with bisphosphonate could prevent bone loss at 6 months.

The invasive lobular carcinoma as a prototype luminal A breast cancer: A retrospective cohort study

BackgroundAlthough the invasive lobular carcinoma (ILC) is the second most frequent histologic subtype in Western countries, its incidence is much lower in Asia, and its characteristics are less well known.MethodsWe assessed the clinical characteristics and outcomes of 83 Korean patients (2.8%) with ILC for comparison with 2,833 (97.2%) with the invasive ductal carcinoma (IDC), including 1,088 (37.3%) with the luminal A subtype (LA-IDC).ResultsThe mean age of all patients was 48.2 years, with no significant differences among the groups. Compared to IDC, ILC showed a larger tumor size (≥T2, 59.8% vs. 38.8%, P = 0.001), a lower histologic grade (HG 1/2, 90.4% vs. 64.4%, P < 0.001), more frequent estrogen receptor positive (90.4% vs. 64.4%, P < 0.001), progesterone receptor positive (71.1% vs. 50.1%, P < 0.001) and HER2 negative (97.5% vs. 74.6%, P < 0.001) status, and lower Ki-67 expression (10.3% ± 10.6% vs. 20.6% ± 19.8%, P < 0.001), as well as being more likely to be of the luminal A subtype (91.4% vs. 51.2%, P < 0.001). Six (7.2%) ILC and 359 (12.7%) IDC patients developed disease recurrence, with a median follow-up of 56.4 (range 4.9-136.6) months. The outcome of ILC was close to LA-IDC (HR 0.77 for recurrence, 95% CI 0.31-1.90, P = 0.57; HR 0.75 for death, 95% CI 0.18-3.09, P = 0.70) and significantly better than for the non-LA-IDC (HR 1.69 for recurrence, 95% CI 1.23-2.33, P = 0.001; HR 1.50 for death, 95% CI 0.97-2.33, P = 0.07).ConclusionsILC, a rare histologic type of breast cancer in Korea, has distinctive clinicopathological characteristics similar to those of LA-IDC.

Prognostic Implications of Tumor-Infiltrating Lymphocytes in Association With Programmed Death Ligand 1 Expression in Early-Stage Breast Cancer.

BACKGROUND The immune system might influence breast cancer (BC) prognosis. However, the relationship between programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocyte (TIL) profiles remains unclear with respect to BC subtypes. PATIENTS AND METHODS We investigated the relationship between TIL profiles for CD8+ and forkhead box P3-positive (FOXP3+) and PD-L1 expression in primary tumor tissue using immunohistochemistry and the clinical outcomes in 2 patient cohorts at the National Cancer Center: 256 patients diagnosed with early-stage BC from January 2001 to December 2005 and 77 hormone receptor (HR)-negative BC patients diagnosed from January 2006 to December 2008. Clinical data were collected, including HR status, human epidermal growth factor receptor 2 expression, disease-free survival, and overall survival (OS). RESULTS The median patient age was 47 years (range, 28-78), and the median follow-up period was 9.8 years. Of the 333 patients, 186 (55.9%) had HR-positive and 125 (37.5%) had node-positive BC. We found a strong positive correlation between CD8+ TILs and FOXP3+ TILs (P < .001). CD8+ TILs were more abundant in tumors with low PD-L1 expression (P < .001), although no association was found between FOXP3+ TILs and PD-L1 expression. More CD8+ TILs were present in HR-negative than in HR-positive BC (P < .001), and PD-L1 expression was more frequent in HR-positive BC (P < .001). A greater number of CD8+ TILs (increase in quartile) was strongly associated with OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.95; P = .03) only in HR-negative BC when adjusted for various clinical factors. PD-L1 expression and FOXP3+ TILs did not exhibit such associations. CONCLUSION Higher CD8+ lymphocyte infiltration was related to lower PD-L1 expression and higher FOXP3+ TIL infiltration in BC. Higher CD8+ TIL expression was associated with prolonged survival only in those with HR-negative BC.

Correlation of HER2, p95HER2 and HER3 expression and treatment outcome of lapatinib plus capecitabine in her2-positive metastatic breast cancer.

Background Lapatinib plus capecitabine is an effective treatment option for trastuzumab-refractory HER2-positive metastatic breast cancer. We have investigated the correlation between quantitative measures of HER2, p95HER2, and HER3 and treatment outcomes using lapatinib and capecitabine. Methods Total HER2 (H2T), p95HER2 (p95), and total HER3 (H3T) expression were quantified in formalin-fixed paraffin-embedded samples using the VeraTag assays. Patients received lapatinib and capecitabine treatment following trastuzumab failure according to the Lapatinib Expanded Access Program. The association between the protein expression levels and clinical outcomes was analyzed. Results A total of 52 patients were evaluable. H2T level was significantly higher in responders (median 93.49 in partial response, 47.66 in stable disease, and 17.27 in progressive disease; p = 0.020). Longer time-to-progression (TTP) was observed in patients with high H2T [p = 0.018, median 5.2 months in high (>14.95) vs. 1.8 in low (<14.95)] and high H3T [p = 0.017, median 5.0 months in high (>0.605) vs. 2.2 in low (<0.605)]. Patients having both high H2T and high H3T had significantly longer TTP [adjusted hazard ratio (HR) 0.38 (95% CI 0.20–0.73), p = 0.004] and overall survival [adjusted HR 0.46 (95% CI 0.24–0.89), p = 0.020]. No significant association between p95 and response or survival was observed. Conclusions These data suggest a correlation between high HER2 and high HER3 expression and treatment outcome, while no significant difference was observed between clinical outcome and p95 expression level in this cohort of HER2-positive, trastuzumab-refractory metastatic breast cancer patients treated with lapatinib and capecitabine.

Locoregional Recurrence of Breast Cancer in Patients Treated With Breast Conservation Surgery and Radiotherapy Following Neoadjuvant Chemotherapy

PURPOSE Breast conservation surgery (BCS) and radiotherapy (RT) following neoadjuvant chemotherapy (NCT) have been linked with high locoregional recurrence (LRR) rates and ipsilateral breast tumor recurrence (IBTR) rates. The purpose of this study was to analyze clinical outcomes in patients who exhibited LRR and IBTR after being treated by BCS and RT following NCT. METHODS AND MATERIALS In total, 251 breast cancer patients treated with BCS and RT following NCT between 2001 and 2006 were included. All patients had been shown to be clinically node-positive. Clinical stage at diagnosis (2003 AJCC) was II in 68% of patients and III in 32% of patients. Of those, 50%, 35%, and 15% of patients received anthracycline-based, taxane-based, and combined anthracycline-taxane NCT, respectively. All patients received RT. RESULTS During follow-up (median, 55 months), 26 (10%) patients had LRR, 19 of these patients had IBTR. Five-year actuarial rates of IBTR-free and LRR-free survival were 91% and 89%, respectively. In multivariate analyses, lack of hormone suppression therapy was found to increase both LRR and IBTR rates. Hazard ratios were 7.99 (p<0.0001) and 4.22 (p=0.004), respectively. Additionally, pathology stage N2 to N3 increased LRR rate (hazard ratio, 4.22; p=0.004), and clinical AJCC stage III IBTR rate (hazard ratio, 9.05; p=0.034). Achievement of pathological complete response and presence of multifocal tumors did not affect LRR or IBTR. CONCLUSIONS In patients with locally advanced disease, who were clinically node-positive at presentation, BCS after NCT resulted in acceptably low rates of IBTR and LRR. Mastectomy should be considered as an option in patients who present with clinical stage III tumors or who are not treated with adjuvant hormone suppression therapy, because they exhibit high IBTR rates after NCT and BCS.