Relationship between tumor biomarkers and efficacy in TH3RESA,a phase III study of trastuzumab emtansine (T‐DM1) vs. treatment of physician's choice in previously treated HER2‐positive advanced breast cancer

In the phase III TH3RESA study (NCT01419197), 602 patients with HER2‐positive advanced breast cancer who received prior taxane therapy and ≥2 HER2‐directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T‐DM1) or treatment of physician's choice (TPC). A statistically significant progression‐free survival (PFS) benefit favoring T‐DM1 was demonstrated. Here, we examine the relationship between HER2‐related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 (n = 505) and HER3 (n = 505) mRNA expression, PIK3CA mutation status (n = 410) and PTEN protein expression (n = 358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and ≤median). For all biomarker subgroups, median PFS was longer with T‐DM1 vs. TPC. The PFS benefit favoring T‐DM1 vs. TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs. 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28–0.59; p < 0.0001) vs. ≤median subgroup (5.5 vs. 3.9 months; HR, 0.68; 95% CI, 0.49–0.92; p = 0.0131). The PFS benefit with T‐DM1 was similar among HER3, PIK3CA and PTEN subgroups. Consistent with other reports, benefit was seen with T‐DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2‐transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T‐DM1 (HR, 0.84; 95% CI, 0.75–0.94; interaction p value = 0.0027). In summary, T‐DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA >median vs. ≤median.     

Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients

Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25–0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06–3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13–2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29–6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43–0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48–7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25–7.58; p = 0.015). In conclusion: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways – AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.     

Phase 2 prospective open label study of neoadjuvant nab-paclitaxel,trastuzumab, and pertuzumab in patients with HER2-positive primary breast cancer

Background

The objective of this study was to evaluate the safety and efficacy of nab-paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy (NAT) in patients with human epidermal growth factor receptor 2 HER2+ breast cancer (HER2+ BC) to determine pathologic complete response (pCR), invasive disease-free survival (iDFS), and overall survival.

Methods

Forty-five patients with HER2+ BC Stages II–III were to be enrolled from 2013 to 2017. Patients were treated with weekly nab-paclitaxel (100 mg/m² intravenously), weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg), and six cycles of pertuzumab (840 mg loading dose, then 420 mg intravenously day 1 every 21 days).

Results

Median follow-up was 60 months (95% CI, 32.3–55.6) and pCR was 29/45 (64%). The 5-year iDFS for patients who achieved pCR (N = 29) was 96.3% (95% CI, 76.5–99.5) and non-pCR patients (N = 16) was 74.3% (95% CI, 39.1–91.0). The 5-year overall survival (N = 45) was 94.1% (95% CI, 77.6–98.5). Based on hormonal status, the 5-year iDFS for HR+ pCR patients (N = 14) was 92.3% (95% CI, 56.6–98.9) and for HR− (N = 15) was 100% (p = .3).

Conclusions

This anthracycline/carboplatin-free regimen with nab-paclitaxel achieved a pCR rate of 64% in patients with HER2+ BC. The 5-year iDFS in patients with and without pCR was 96.3% and 74.3%, respectively. The pCR rate is comparable with docetaxel, carboplatin, trastuzumab, and pertuzumab therapy in the NAT setting, but with fewer treatment-associated toxicities. This finding suggests the possibility of safe avoidance of anthracyclines and carboplatin as components of NAT in patients with HER2+ BC.     

PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab

BackgroundThis study was conducted to determine the frequency of PIK3CA mutations and human epidermal growth factor receptor-2 (HER2) phosphorylation status (pHER2-Tyr^1221/1222) and if PIK3CA, phosphatase and tensin homolog (PTEN), or pHER2 has an impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.Patients and methodsTwo hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m², epirubicin 60 mg/m², and fluorouracil 600 mg/m²) before administration of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing.ResultsFive-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent of patients had a PIK3CA mutation, 24% were PTEN low, 45% pHER2 high, and 47% patients had increased PI3K pathway activation (PTEN low and/or PIK3CA mutation). No significant correlations were observed between the clinicopathological variables and PIK3CA, PTEN, and pHER2 status. In both univariate and multivariate analyses, patients with PIK3CA mutations or high PI3K pathway activity had a significant worse OS [multivariate: hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.01–4.51, P = 0.046; and HR 2.35, 95% CI 1.10–5.04, P = 0.03].ConclusionPatients with PIK3CA mutations or increased PI3K pathway activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab.     

Multicenter phase II study of apatinib single or combination therapy in HER2-negative breast cancer involving chest wall metastasis

ObjectiveBreast cancer (BC) with chest wall metastasis (CWM) usually shows rich neovascularization. This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2 (HER2)-negative advanced BC involving CWM.MethodsThis trial involved four centers in China and was conducted from September 2016 to March 2020. Patients received apatinib 500 mg/d [either alone or with endocrine therapy if hormone receptor-positive (HR+)] until disease progression or unacceptable toxicity. Progression-free survival (PFS) was the primary endpoint.ResultsWe evaluated 26 patients for efficacy. The median PFS (mPFS) and median overall survival (mOS) were 4.9 [range: 2.0−28.5; 95% confidence interval (95% CI): 2.1−8.3] months and 18 (range: 3−55; 95% CI: 12.9−23.1) months, respectively. The objective response rate (ORR) was 42.3% (11/26), and the disease-control rate was 76.9% (20/26). In the subgroup analysis, HR+ patients compared with HR-negative patients had significantly improved mPFS of 7.0 (95% CI: 2.2−11.8) monthsvs. 2.3 (95% CI: 1.2−3.4) months, respectively (P=0.001); and mPFS in patients without or with chest wall radiotherapy was 6.4 (95% CI: 1.6−19.5) monthsvs. 3.0 (95% CI: 1.3−4.6) months, respectively (P=0.041). In the multivariate analysis, HR+ status was the only independent predictive factor for favorable PFS (P=0.014). ConclusionsApatinib was highly effective for BC patients with CWM, especially when combined with endocrine therapy. PFS improved significantly in patients with HR+ status who did not receive chest wall radiotherapy. However, adverse events were serious and should be carefully monitored from the beginning of apatinib treatment.     

Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer

Data characterizing demographics, treatment patterns, and clinical outcomes in black patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. registHER is a large, observational cohort study of patients (n = 1,001) with HER2-positive MBC diagnosed ≤6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up of 27 months). Demographics, treatment patterns, and clinical outcomes were described for black (n = 126) and white patients (n = 793). Progression-free survival (PFS) following first-line therapy and overall survival (OS) were examined. Multivariate analyses adjusted for baseline and treatment factors. Black patients were more likely than white patients to be obese (body mass index ≥30), to have diabetes, and to have a history of cardiovascular disease; they were also less likely to have estrogen receptor or progesterone receptor positive disease. In patients treated with trastuzumab, the incidence of cardiac safety events (grade ≥3) was higher in black patients (10.9 %) than in white patients (7.9 %). Unadjusted median OS and PFS (months) were significantly lower in black patients than in white patients (OS: black: 27.1, 95 % confidence interval [CI] 21.3–32.1; white: 37.3, 95 % CI 34.6–41.1; PFS: black: 7.0, 95 % CI 5.7–8.2; white: 10.2, 95 % CI 9.3–11.2). The adjusted OS hazard ratio (HR) for black patients compared with white patients was 1.29 (95 % CI 1.00–1.65); adjusted PFS HR was 1.29 (95 % CI 1.05–1.59). This real-world evaluation of a large cohort of patients with HER2-positive MBC shows poorer prognostic factors and independently worse clinical outcomes in black versus white patients. Further research is needed to identify potential biologic differences that could have predictive impact for black patients or that could explain these differences.     

The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis

BackgroundThe addition of HER2-targeted agents to standard treatment has been shown to improve outcomes for HER2 positive metastatic breast cancer patients. We undertook a meta-analysis to evaluate the efficacy of HER2-targeted therapy in addition to standard treatment in metastatic breast cancer patients.Patients and methodsEligible trials were randomised controlled trials (RCTs) comparing the addition of HER2 therapy to standard treatment (hormone or chemotherapy) reporting overall survival (OS), time to progression (TTP), progression-free survival (PFS) and/or response rates.ResultsEight trials comprising 1848 patients were eligible for inclusion. HER2-targeted agents were trastuzumab and lapatinib and therapeutic partners were taxanes (4 RCTs), anthracyclines (1), capecitabine (2), anastrozole (1) and letrozole (1). The addition of HER2-targeted agents improved OS [hazard ratios (HR) 0.78; 95% confidence interval (CI) 0.67–0.91], TTP (HR 0.56; 95% CI 0.48–0.64), PFS (HR 0.63; 95% CI 0.53–0.74) and overall response rate (relative risk 1.67; 95% CI 1.46–1.90).ConclusionsOur meta-analysis confirms the benefit of adding HER2-targeted therapy to standard treatment in HER2 positive metastatic breast cancer. Compared with OS, TTP, PFS and ORR overestimate treatment benefit. Trials in our meta-analysis differed in terms of partner drug or HER2 agents, yet delivered comparable outcomes.     

Clinical significance of p95HER2 overexpression,PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies

Background:

Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ∼30–40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively.

Materials and methods:

Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ², Fischer''s exact test and Mann–Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan–Meier method and survival curves of subgroups were compared with log-rank test.

Results:

Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5–13.4 months) and 22 months (95% CI, 9.9–34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6–34 months) and 12.1 months (95% CI, 7.9–16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3–40.4 months) and 29.1 months (95% CI, 8.6–43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5–40.1 months) and 26.8 months (95% CI, 8.1–42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2–4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1–3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18–4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14–3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis.

Conclusions:

Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.     

PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab

BackgroundThe predictive value of PIK3CA mutations in HER2 positive (HER2+) breast cancer treated with neoadjuvant anti-HER2 and chemotherapy has been reported, but the power for subgroup analyses was lacking.Patients and methodsWe combined individual patient data from five clinical trials evaluating PIK3CA mutations and associations with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to a taxane-based chemotherapy. PIK3CA was genotyped in tumour biopsies taken before therapy.ResultsA total of 967 patients were included in this analysis; the median follow-up is 47 months. Overall, the pCR rate was significantly lower in the PIK3CA mutant compared with the wild-type group (16.2% versus 29.6%; P < 0.001). Within the hormone-receptor positive (HR+) subgroup, the PIK3CA mutant group had a pCR rate of only 7.6% compared with 24.2% in the wild-type group (P < 0.001). In contrast, in the HER2+/HR– group, there was no difference in pCR (27.2% versus 36.4%; P = 0.125) according to PIK3CA mutation status (interaction test P = 0.036). According to treatment arm, the pCR rate for mutant versus wild-type was 20.3% versus 27.1% for T (P = 0.343), 11.3% versus 16.9% for L (P = 0.369) and 16.7% versus 39.1% for T/L (P < 0.001). In the HR+ T/L group, the pCR rate was 5.5% versus 33.9% (interaction between HR and PIK3CA genotype P = 0.008). DFS and OS were not significantly different by mutation status, though the incidence rate of events was low. However, HR+/PIK3CA mutant patients seemed to have significantly worse DFS {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.00–2.45], P = 0.050; P_interaction = 0.021}. T/L tended to improve DFS compared with T in the wild-type cohort, especially in the HR– group [HR 0.72, 95% CI (0.41–1.25), P = 0.242].ConclusionOverall PIK3CA mutant/HER2+ tumours had significantly lower pCR rates compared with wild-type tumours, however mainly confined to the HR+/PIK3CA mutant population. No definite conclusions can be drawn regarding survival.     

Expression of truncated HER2 and its prognostic value in HER2-positive breast cancer patients

Purpose

The purpose of this work was to assess the truncated form of human epidermal growth factor receptor 2 (HER2) such as p95-HER2 expression in HER2-positive breast cancer (BC) patients who developed metastatic disease after adjuvant treatment with a trastuzumab-containing regimen.

Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive,HER2-negative,locally recurrent,or metastatic breast cancer: interim analysis of the multicentre,placebo-controlled,phase II randomised PEGGY study

BackgroundApproximately 40% of hormone receptor-positive, HER2-negative breast cancers (BCs) are associated with activating mutations of the phosphatidylinositol 3-kinase (PI3K) pathway. Pictilisib, a potent and highly specific class I pan-PI3K inhibitor, demonstrated preclinical activity in BC cell lines and may potentiate the effect of taxanes, benefiting patients with or without aberrant activation of the PI3K pathway. PEGGY (NCT01740336), a randomised, placebo-controlled phase II trial, examined whether pictilisib augments the anti-tumour activity of paclitaxel in patients with hormone receptor-positive, HER2-negative locally recurrent or metastatic BC (mBC). We report results from the protocol-specified interim analysis.Patients and methodsOne hundred and eighty-three eligible patients were randomised (1:1) to receive paclitaxel (90 mg/m² weekly for 3 weeks in every 28-day cycle) with either 260 mg pictilisib or placebo (daily on days 1–5 every week). The primary end point was progression-free survival (PFS) in the intention-to-treat (ITT) population and patients with PIK3CA-mutated tumours. Secondary end points included overall response rate (ORR), duration of response, and safety.ResultsIn the ITT population, the median PFS was 8.2 months with pictilisib (n = 91) versus 7.8 months with placebo (n = 92) [hazard ratio (HR) for progression or death, 0.95; 95% confidence interval (CI) 0.62–1.46; P = 0.83]. In patients with PIK3CA-mutated tumours, the median PFS was 7.3 months for pictilisib (n = 32) versus 5.8 months with placebo (n = 30) (HR, 1.06; 95% CI 0.52–2.12; P = 0.88). ORR was similar between treatment arms. The safety profile of pictilisib was consistent with previous reports, with no new safety signals. Proportions of patients with grade ≥3 adverse events (AEs), serious AEs, and dose reductions/discontinuations due to AEs were higher with pictilisib.ConclusionsPEGGY did not meet its primary end point, revealing no significant benefit from adding pictilisib to paclitaxel for patients with hormone receptor-positive, HER2-negative locally recurrent or mBC.Clinical trial numberNCT01740336.     

PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis

The implications of Phosphatidylinositol 3-kinase (PIK3CA) mutations and its aberrant protein expression in breast cancer (BC) different molecular subtypes and patients’ outcome remain controversial. The aims of this study were to assess the prevalence and clinical significance of PIK3CA protein expression in BC and to determine its association with its different molecular classes. PIK3CA protein expression was assessed in a well-characterized series of early stage BC (n = 1,394) with long-term follow-up, using tissue microarrays and immunohistochemistry. Associations between PIK3CA expression and clinicopathological variables, molecular classes, and patients’ outcome were investigated. Positive PIK3CA expression was associated with poor prognostic variables including higher grade, larger size, nodal involvement, vascular invasion, and higher proliferative fraction (P < 0.001). Increased PIK3CA expression was associated with the basal-like breast cancer (BLBC) and HER2-positive classes as well as triple negative non-basal (TNnon-B) tumors (P < 0.001). The luminal class showed reduced PIK3CA expression relative to other classes. Patients with PIK3CA positive tumors had shorter BC specific and disease free survival, independent of other prognostic factors except grade. Similar associations with outcome were found when the analysis was restricted to the large luminal class of tumors. PIK3CA is an oncogenic biomarker associated with poor prognosis in BC. Although, PIK3CA over-expression was more prevalent in BLBC and HER2-positive tumors it appeared to be a marker of poor differentiation rather than of a particular subtype. Thus, targeting of PIK3CA using specific inhibitors could potentially be beneficial, particularly for patients with more aggressive poorly differentiated tumors, irrespective of their molecular subtype.     

Trends in neoadjuvant chemotherapy versus surgery-first in stage I HER2-positive breast cancer patients in the National Cancer DataBase (NCDB)

Background

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced HER2?+?breast cancer (BC). Optimal sequencing of treatment (NAC vs. surgery first) is less clear cut in stage I (T1N0) HER2?+?BC, where information from surgical pathology could impact adjuvant treatment decisions. Utilizing the NCDB, we evaluated the trend of NAC use compared to upfront surgery in patients with small HER2?+?BC.

Methods

We identified NCDB female patients diagnosed with T1 N0 HER2?+?BC from 2010 through 2015. Prevalence ratios (PR) using multivariable robust Poisson regression models were calculated to measure the association between baseline characteristics and the receipt of NAC. Analysis of trends over time was denoted by annual percent change (APC) of NAC versus surgery upfront.

Results

Of the 14,949 that received chemotherapy and anti-HER2 therapy during the study period, overall 1281 (8.6%) received NAC and 13,668 (91.4%) received adjuvant treatment. Patients receiving NAC increased annually from 4.2% in 2010 to 17.3% in 2015, with the most rapid increase occurring between years 2013 (8.5%) and 2014 (14.2%). The greatest increase was seen in patients with cT1c tumors with an APC of 37.8% over the study period (95% CI 29.0, 47.3%, p?<?0.01), although a significant trend was likewise seen in patients with cT1a (APC?=?26.1%,95% CI 1.59, 56.6%), and cT1b (APC?=?27.4%, 95% CI 18.0, 37.7%) tumors. Predictors of neoadjuvant therapy receipt were age younger than 50 (PR?=?1.69, 95% CI 1.52, 1.89), Mountain/Pacific area (PR?=?1.24, 95% CI 1.05, 1.46), and estrogen receptor negativity (ER??PR?+?: PR?=?2.01, 95% CI 1.51, 2.68; ER??PR??: PR?=?1.49, 95% CI 1.32, 1.69).

Conclusions

Neoadjuvant therapy for T1 N0 HER2?+?BC increased over the study period and was mostly due increased use in clinical T1c tumors. This may be consistent with secular change in Pertuzumab treatment following FDA approval in 2013.

     

Dose-dense adjuvant chemotherapy in HER2-positive early breast cancer patients before and after the introduction of trastuzumab: Exploratory analysis of the GIM2 trial

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52–1.89; OS: HR, 0.95; 95% CI 0.37–2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab.     

Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer

BackgroundThe gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC.MethodsEligible trials accrued HER2+ MBC patients in 1992–2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy.ResultsWe identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21–23 months] and the median PFS was 5.7 months (95% CI 5.5–6.1 months). At the individual level, the Spearman correlation was equal to ρ = 0.67 (95% CI 0.66–0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R² = 0.51 (95% CI 0.22–0.81).ConclusionsIn trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting.     

Leptomeningeal disease and breast cancer: the importance of tumor subtype

Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. We aimed to characterize clinical features and outcomes of patients with LMD based on BC subtypes. We retrospectively reviewed records of 233 patients diagnosed with LMD from BC between 1997 and 2012. Survival was estimated by the Kaplan–Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Of 190 patients with BC subtype available, 67 (35 %) had hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative BC, 56 (29 %) had HER2+BC, and 67 (35 %) had triple-negative BC (TNBC). Median age at LMD diagnosis was 50 years. Median overall survival (OS) from LMD diagnosis was 4.4 months for HER2+BC (95 % CI 2.8, 6.9), 3.7 months (95 % CI 2.4, 6.0) for HR+/HER2?BC, and 2.2 months (95 % CI 1.5, 3.0) for TNBC (p = 0.0002). Older age was associated with worse outcome (p < 0.0001). Patients with HER2+BC and LMD were more likely to receive systemic therapy (ST) (p = 0.001). Use of intrathecal therapy (IT) (52 %) was similar (p = 0.35). Both IT (p < 0.0001) and ST (p < 0.0001) administration were associated with improved OS. After adjusting for age, IT, extracranial disease, and ST, patients with HER2+BC had better OS compared with HR+/HER2?BC (HR 1.72; 95 %CI 1.07–2.76) and TNBC (HR 3.30; 95 %CI 1.98–5.52). LMD carries a dismal prognosis. Modest survival differences by tumor subtype were seen. Patients with HER2+BC had the best outcome. There is an urgent need to develop effective treatment strategies.     

First‐Line Treatment Patterns and Clinical Outcomes in Patients With HER2‐Positive and Hormone Receptor‐Positive Metastatic Breast Cancer From registHER

Background.

Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting.

Methods.

registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors.

Results.

HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89).

Conclusions.

These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.     

Efficacy and safety analysis of trastuzumab and paclitaxel based regimen plus carboplatin or epirubicin as neoadjuvant therapy for clinical stage II-III,HER2-positive breast cancer patients: a phase 2, open-label,multicenter, randomized trial

This trial was designed to compare the efficacy and safety between epirubicin (E) and carboplatin (C) in combination with paclitaxel (P) and trastuzumab (H) in neoadjuvant setting. In 13 Chinese cancer centers, 100 patients with HER2-positive, locally advanced breast cancer were 1:1 randomized to receive medication as follows: trastuzumab and paclitaxel weekly combined with carboplatin weekly for PCH group, or epirubicin every 3 weeks for PEH group. Patients were given 4 to 6 cycles of chemotherapy. The primary endpoint was pathologic complete response (pCR) rate, which was no significant difference in PCH and PEH regimen (39.1% vs. 48.8%; p=0.365). However, PEH regimen achieved higher pCR in luminal-B (HER2-poitive) subgroup (55.0% vs. 24.0%; p = 0.033), but not in ERBB2+ subgroup (42.9% vs. 57.1%; p = 0.355). PEH regimen showed a favorable efficacy in PIK3CA mutated subgroup (69.2% vs.23.5%, p=0.012). No significant difference was observed in the subgroup analysis of TP53 mutation status, PTEN expression, FCGR2A SNP and FCGR3A SNP. Both regimens as neoadjuvant chemotherapy achieve similar efficacy and safety. PEH might improve pCR rate, especially in the luminal-B subtype and PIK3CA mutation subtype. PEH is feasible and less likely to increase the incidence of acute cardiac events compared to PCH.     

Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer

We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease-free survival. Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER-positive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC <50%). In conclusion, reactive stroma in HER2-positive/ER-negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy.