Kevin Kalinsky

PIK3CA mutation associates with improved outcome in breast cancer.

Purpose: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer. Experimental Design: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer–specific survival were examined using Kaplan-Meier or competing risk methodology. Results: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer–specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004). Conclusion: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase–targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized. (Clin Cancer Res 2009;15(16):5049–59)

AKT in cancer: new molecular insights and advances in drug development

The phosphatidylinositol‐3 kinase (PI3K)–AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K–AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well‐characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT.

Presurgical Trial of Metformin in Overweight and Obese Patients with Newly Diagnosed Breast Cancer

Introduction: We conducted a presurgical trial to assess the tissue-related effects of metformin in overweight/obese breast cancer (BC) patients. Methods: Metformin 1,500 mg daily was administered to 35 nondiabetics with stage 0–III BC, body mass index (BMI) ≥ 25 kg/m2. The primary endpoint was tumor proliferation change (i.e., ki-67). Tumor proliferation change was compared to untreated historical controls, matched by age, BMI, and stage. Results: There was no reduction in ln(ki-67) after metformin (p = .98) or compared to controls (p = .47). There was a significant reduction in BMI, cholesterol, and leptin. Conclusion: Despite no proliferation changes, we observed reductions in other relevant biomarkers.

Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Optical biomarkers for breast cancer derived from dynamic diffuse optical tomography

Abstract. Diffuse optical tomography (DOT) is a noninvasive, nonionizing imaging modality that uses near-infrared light to visualize optically relevant chromophores. A recently developed dynamic DOT imaging system enables the study of hemodynamic effects in the breast during a breath-hold. Dynamic DOT imaging was performed in a total of 21 subjects (age 54±10  years) including 3 healthy subjects and 18 subjects with benign (n=8) and malignant (n=14) masses. Three-dimensional time-series images of the percentage change in oxygenated and deoxygenated hemoglobin concentrations ([HbO2] and [Hb]) from baseline are obtained over the course of a breath-hold. At a time point of 15 s following the end of the breath-hold, [Hb] in healthy breasts has returned to near-baseline values (1.6%±0.5%), while tumor-bearing breasts have increased levels of [Hb] (6.8%±3.6%, p<0.01). Further, healthy subjects have a higher correlation between the breasts over the course of the breath-hold as compared with the subjects with breast cancer (healthy: 0.96±0.02; benign: 0.89±0.02; malignant: 0.78±0.23, p<0.05). Therefore this study shows that dynamic features extracted from DOT measurements can differentiate healthy and diseased breast tissues. These features provide a physiologic method for identifying breast cancer without the need for ionizing radiation.

Uptake and Economic Impact of First-Cycle Colony-Stimulating Factor Use During Adjuvant Treatment of Breast Cancer

PURPOSE In 2002, pegfilgrastim was approved by the US Food and Drug Administration and the benefits of dose-dense breast cancer chemotherapy, especially for hormone receptor (HR) -negative tumors, were reported. We examined first-cycle colony-stimulating factor use (FC-CSF) before and after 2002 and estimated US expenditures for dose-dense chemotherapy. METHODS We identified patients in Surveillance, Epidemiology, and End Results-Medicare greater than 65 years old with stages I to III breast cancer who had greater than one chemotherapy claim within 6 months of diagnosis(1998 to 2005) and classified patients with an average cycle length less than 21 days as having received dose-dense chemotherapy. The associations of patient, tumor, and physician-related factors with the receipt of any colony-stimulating factor (CSF) and FC-CSF use were analyzed by using generalized estimating equations. CSF costs were estimated for patients who were undergoing dose-dense chemotherapy. RESULTS Among the 10,773 patients identified, 5,266 patients (48.9%) had a CSF claim. CSF use was stable between 1998 and 2002 and increased from 36.8% to 73.7% between 2002 and 2005, FC-CSF use increased from 13.2% to 67.9%, and pegfilgrastim use increased from 4.1% to 83.6%. In a multivariable analysis, CSF use was associated with age and chemotherapy type and negatively associated with black/Hispanic race, rural residence, and shorter chemotherapy duration. FC-CSF use was associated with high socioeconomic status but not with age or race/ethnicity. The US annual CSF expenditure for women with HR-positive tumors treated with dose-dense chemotherapy is estimated to be

Inhibition of the autocrine IL-6–JAK2–STAT3–calprotectin axis as targeted therapy for HR−/HER2+ breast cancers

38.8 million. CONCLUSION A rapid increase in FC-CSF use occurred over a short period of time, which was likely a result of the reported benefits of dose-dense chemotherapy and the ease of pegfilgrastim administration. Because of the increasing evidence that elderly HR-positive patients do not benefit from dose-dense chemotherapy, limiting pegfilgrastim use would combat the increasing costs of cancer care.

Cracking Open Window of Opportunity Trials

HER2-positive (HER2(+)) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR(-)/HER2(+) tumors, eliciting tumor dependency in these cells. Mechanistically, HR(-)/HER2(+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6-Janus kinase 2 (JAK2)-STAT3-calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR(-)/HER2(+) breast cancers, opening novel targeted therapeutic opportunities.

¡Cocinar Para Su Salud!: Randomized controlled trial of a culturally-based dietary intervention among Hispanic breast cancer survivors

Despite an increase in investment, only one in every 10 new molecular therapeutic agents that enters clinical development receives US Food and Drug Administration approval. The sequential phase I/II/III model that was developed in the 1960s for cytotoxic chemotherapy remains a common pathway for drug development, with anticancer agents often being investigated in metastatic disease before operable disease. However, with many new targeted therapies, there are limitations in measuring response by traditional methods, such as response rate defined by RECIST criteria, which may lead to erroneous conclusions about a drug’s benefit. Evaluating molecular end points can be hindered by difficulties in procuring tumor tissue before and after drug administration and by heterogeneity in previous exposure to cancer therapies. A method to circumvent this issue is to assess novel agents in presurgical (window of opportunity or phase 0) trials. In this model, women with newly diagnosed breast cancer, for instance, receive a study drug between the diagnostic breast biopsy and planned surgical resection. The goals of these trials include evaluation of target modulation after drug exposure and pharmacokinetic assessment of a potential anticancer agent. This is in comparison to neoadjuvant trials, in which an investigational agent is commonly given preoperatively along with cytotoxic chemotherapy or hormonal therapy for a longer period of time than in a presurgical trial, and the primary end point is often, but not always, pathologic or clinical response. The ultimate hope is that presurgical studies can expedite the drug development process by improving the understanding of an agent’s biologic effect early in its development, validating markers that may predict subsets of patients who will benefit, and targeting select patients in subsequent clinical trials that are powered to detect changes in clinical outcome. In the article by Bonanni et al that accompanies this editorial, 200 Italian, nondiabetic women with early-stage invasive breast cancer were randomly assigned to receive metformin or a placebo for 4 weeks before surgery. The authors should be commended on completing a large, randomized, double-blind presurgical trial, given the challenges in conducting these studies. Coordinating enrollment between diagnosis and surgery requires close collaboration between academic disciplines, including medical oncologists, surgeons, pathologists, and laboratory scientists. The authors chose to evaluate the effect of metformin on the basis of the benefit observed in preclinical population-based and retrospective singleinstitution studies. Proposed mechanisms of action include reduction in serum insulin levels, direct modulation of cellular protein synthesis, and growth through changes in AMP-activated protein kinase (AMPK) pathway signaling. In addition, metformin has a well-defined toxicity profile, is safe in healthy patients, does not interfere with surgery or wound healing, and reaches pharmacologic levels within a short intervention period. This is in comparison to drugs that have been evaluated in other presurgical trials, such as poly (ADPribose) polymerase and epidermal growth factor receptor inhibitors, which did not yield the same amount of safety data as metformin in healthy patients with cancer and in patients with other disease states. One must always balance the risks of treating curable patients with the potential yield of new information when designing presurgical trials with less well-studied pharmaceutical agents. The primary end point in the presurgical trial by Bonanni et al was reduction in the post-treatment mean of the proliferative marker Ki-67 (log transformed: lnKi-67) in surgical resection tissue. No difference in the lnKi-67 was observed between groups. Thus, this is a negative study for the primary end point. One may ask whether Ki-67 was the best end point to select. Ki-67 modulation has clearly been shown to be an appropriate end point for preoperative studies involving hormonal therapies. In the neoadjuvant, randomized, double-blind Immediate Preoperative Anastrazole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial, anastrazole was associated with a significantly greater reduction in tumor Ki-67 at 2 and 12 weeks compared with tamoxifen and the combination. The geometric mean percentage change in Ki-67 at 2 weeks strongly mirrored the results of the large, adjuvant Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. It has been argued that the ATAC trial could have been designed differently, potentially excluding the combination arm and reducing the sample size and expense. Although a decrease in the presurgical levels of Ki-67 serves as an appropriate surrogate marker for outcome in patients who are administered antiestrogen therapy, its usefulness in predicting disease-free survival outcome remains unproven with other targeted therapies. In addition, variability in results can come from the lack of uniformity for measuring Ki-67, particularly with a small sample size. Variability in Ki-67 staining can occur as the result of a number of factors, including the duration of ischemia, formalin quality, and time of fixation. There is also potential variability in the evaluation of Ki-67 staining by pathologists, with some estimating the percentage of nuclei staining and others counting hundreds of consecutive nuclei in different tumor locations to determine an overall average index. In this trial, there was a numerical increase in the overall lnKi-67 score in both the placebo and metformin groups, which emphasizes JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 21 JULY 2

Breast Cancer Chemoprevention among High‐risk Women and those with Ductal Carcinoma In Situ

BACKGROUND There is a need for culturally relevant nutrition programs targeted to underserved cancer survivors. OBJECTIVE Our aim was to examine the effect of a culturally based approach to dietary change on increasing fruit/vegetable (F/V) intake and decreasing fat intake among Hispanic breast cancer survivors. DESIGN Participants were randomized to Intervention and Control groups. Diet recalls, detailed interviews, fasting blood, and anthropometric measures were collected at baseline, 3, 6, and 12 months. PARTICIPANTS/SETTING Hispanic women (n=70) with stage 0 to III breast cancer who completed adjuvant treatment and lived in New York City were randomized between April 2011 and March 2012. INTERVENTION The Intervention group (n=34) participated in ¡Cocinar Para Su Salud!, a culturally based nine-session (24 hours over 12 weeks) intervention including nutrition education, cooking classes, and food-shopping field trips. The Control group (n=36) received written dietary recommendations for breast cancer survivors. MAIN OUTCOME MEASURES Change at 6 months in daily F/V servings and percent calories from total fat were the main outcome measures. STATISTICAL ANALYSES Linear regression models adjusted for stratification factors and estimated marginal means were used to compare changes in diet from baseline to 3 and 6 months. RESULTS Baseline characteristics were the following: mean age 56.6 years (standard deviation 9.7 years), mean time since diagnosis 3.4 years (standard deviation 2.7 years), mean body mass index (calculated as kg/m²) 30.9 (standard deviation 6.0), 62.9% with annual household income ≤