Jana Barinoff

Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer.

BACKGROUND Continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment. Here, we report the final analysis on overall survival. PATIENTS AND METHODS Patients with HER2-positive, advanced breast cancer who progressed during treatment with trastuzumab with or without 1st-line metastatic chemotherapy were prospectively randomised to X (2500mg/m(2) on days 1-14, q3w) or XH (6 (8)mg/kg, q3w). Overall survival was a pre-specified secondary end-point. RESULTS Median follow-up at June 2010 was 20.7months. Fifty nine of 74 and 60 of 77 patients died in the X and XH arm, respectively. Median overall survival was 20.6 and 24.9months with X and XH, respectively (HR=0.94 [0.65-1.35]; p=0.73). Performance status and metastatic site were independent prognosticators for overall survival. No difference between treatment arms was observed for patients who achieved clinical response or clinical benefit, respectively. Patients who continued/restarted anti-HER2 treatment (trastuzumab or lapatinib) after 2nd progression (N=52) had a post-progression survival of 18.8 compared with 13.3months for those who did not receive 3rd line treatment with anti-HER2 agents (N=88) (HR 0.63; p=0.02). CONCLUSIONS Final overall survival analysis of the GBG-26 study did not demonstrate a significant survival benefit for treatment beyond progression with trastuzumab. However, in a post-hoc analysis, patients receiving anti-HER2 treatment as 3rd line therapy showed a better post-progression survival than those not receiving this targeted treatment.

Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial

BACKGROUND The proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort. PATIENTS AND METHODS We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points [response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS)]. The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs). RESULTS A wide range of Ki67 cut points between 3%-94% (for pCR), 6%-46% (for DFS) and 4%-58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%-35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P < 0.0005), this effect was also present in six of eight molecular subtypes. In MSRD, Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors. CONCLUSIONS Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.

Ki67 measured after neoadjuvant chemotherapy for primary breast cancer

Purpose: The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. Experimental Design: Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0–15%), intermediate (15.1–35%), or high (35.1–100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively. Results: Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P < 0.0001) and death (P < 0.0001) compared with patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone–receptor-positive disease [hazard ratios (HR), 1.82–5.88] but not in hormone–receptor-negative disease (HR: 0.61–1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965). Conclusions: Posttreatment Ki67 levels provide prognostic information for patients with hormone–receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. Clin Cancer Res; 19(16); 4521–31. ©2013 AACR.

Diarrhea associated with afatinib: an oral ErbB family blocker

Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as HER1 or ErbB1) tyrosine kinase inhibitor therapy. GI AEs are among the most common and most impactful on a patient’s quality of life. Severe diarrhea can result in fluid and electrolyte losses, leading to dehydration, electrolyte imbalances and renal insufficiency. Afatinib is an irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to reversible tyrosine kinase inhibitors of EGFR, GI AEs – in particular, diarrhea – have frequently been observed in afatinib-treated patients. This article summarizes current data on afatinib-associated diarrhea and provides strategies for its management. Patient education, early identification, timely management and ongoing assessment will help to prevent aggravation, afatinib dose reductions or therapy discontinuation, encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent.

German Adjuvant Intergroup Node-Positive Study: A Phase III Trial to Compare Oral Ibandronate Versus Observation in Patients With High-Risk Early Breast Cancer

PURPOSE Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. PATIENTS AND METHODS The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. RESULTS Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). CONCLUSION Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Bevacizumab in the Treatment of Ovarian Cancer

IntroductionIn the past decade there have been many attempts to improve systemic treatment and thus the outcome of patients with ovarian cancer. However, neither the sequential addition of non cross-resistant drugs to standard chemotherapy comprising carboplatin and paclitaxel, nor triplet combination therapies with conventional chemotherapeutic drugs have improved outcomes. Instead, such approaches have led to an increase in the incidence of side effects. We are currently experiencing a shift toward the addition of molecularly targeted and biological anticancer therapies to standard treatment. Vascular endothelial growth factor (VEGF), which improves vitally important tumor vasculature, is secreted by a range of tumors, and a high level of VEGF is known to be an independent risk factor for aggressive disease in ovarian cancer. This finding led to the development in the 1990s of bevacizumab, a humanized monoclonal antibody against VEGF.DiscussionSeveral phase II trials and four phase III trials have demonstrated that bevacizumab is active in patients with advanced and recurrent ovarian cancer. Both phase III trials of bevacizumab as first-line therapy in advanced ovarian cancer (ICON 7/AGOOVAR 11 and GOG-0218) have shown that the addition of bevacizumab to chemotherapy and as maintenance therapy improves progressionfree survival (PFS). The phase III trials in platinum-sensitive (OCEANS) and platinumresistant, relapsed disease (AURELIA) have also demonstrated a benefit for bevazicumab with respect to PFS. The administration of bevacizumab to improve survival in patients with ovarian cancer is not without side effects and a broad discussion on the cost-effectiveness of this approach is ongoing.ConclusionThis article presents clinical trial data on bevacizumab in the treatment of ovarian cancer and discusses the indication and pitfalls in the application of bevacizumab in patients with this malignancy.

Intraoperative assessment of margins in breast conservative surgery--still in use?

A positive margin in breast conserving surgery is associated with an increased risk of local recurrence. Failure to achieve clear margins results in re‐excision procedures. Methods for intraoperative assessment of margins have been developed, such as frozen section analysis, touch preparation cytology, near‐infrared fluorescence optical imaging, x‐ray diffraction technology, high‐frequency ultrasound, micro‐CT, and radiofrequency spectroscopy. In this article, options that might become the method of choice in the future are discussed. J. Surg. Oncol. 2014 110:15–20.

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

BACKGROUND The 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. METHODS Eligible 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. RESULTS We 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 R(2) = 0.51 (95% CI 0.22-0.81). CONCLUSIONS In 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.

Clinicopathological differences between breast cancer in patients with primary metastatic disease and those without: A multicentre study

OBJECTIVE Approximately 6% of breast cancer (BC) patients present with primary metastatic disease (pmBC) at first diagnosis. The clinicopathological differences between tumours from patients who have metastatic disease and those who do not are unclear. METHODS This study was an exploratory analysis of patients with pmBC treated in 8 German breast cancer centres between 1998 and 2010. Phenotypes were defined using the following immunohistochemical markers: oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2). The control arm included the group of patients who had neither local recurrence nor distant metastases at a follow-up of at least 30 months after initial diagnosis. RESULTS A total of 2214 patients were included. Of these, 1642 had non metastatic BC, and 572 had pmBC. Eighty-five patients (15%) with pmBC were diagnosed at stage T1. On multivariate analysis, factors associated with pmBC were as follows: positive lymph node status, grade 3, lobular histology and Luminal B phenotype (Her 2 positive). Of the sample, 197 patients (34%) with pmBC were diagnosed as stage T2, 90 patients (16%) were diagnosed as stage T3, and 200 patients (35%) were diagnosed as stage T4. Only positive lymph node status and grade 3 were reported as risk factors for distant metastases in patients with stage T3 and T4 cancer. CONCLUSION There are differences in the clinicopathological features among breast cancer patients with primary metastases and those without. Receptor expression and histological type play a minor role in the risk for metastasis in patients with stage T3 and T4 disease when compared to patients with T1 pmBC tumours. On initial diagnosis, lobular histology and Luminal B positivity (Her 2 positive) in T1 pmBC were determined to be risk factors for primary metastatic disease.

Differences in the Receptor Status between Primary and Recurrent Breast Cancer - The Frequency of and the Reasons for Discordance

Objective: Receptor discordances between primary and recurrent breast cancer have been described for years, but only a few analyses have elucidated the factors that influence receptor changes. Methods: Explorative analyses of prospective data from a breast cancer database of a tertiary breast cancer unit. Results: Recurrent tumours that had expressed oestrogen (ER) and progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2) as primary tumours were negative for the respective receptor in 22.8, 41.4 and 40.8% of cases. ER, PR and HER2 expression was found in 19.8, 16.7 and 11.5% of recurrent tumours, although no expression had been observed in primary tumours. Receptor discordances in recurrent disease leading to different therapeutic approaches were noted in 126 of 411 patients (30.7%). In patients with tumours expressing primary ER and HER2, independent factors associated with discordance were endocrine therapy and treatment with trastuzumab. Conclusion: High rates of receptor discordance were found. The impact of factors that influence receptor changes is small so that no subgroup of patients with recurrent breast cancer should be excluded from biopsy. Whenever possible, a biopsy should be taken to confirm the diagnosis of a possible relapse as well as the receptor status of patients with breast cancer.