Event-Free Survival in Patients with Early HER2-Positive Breast Cancer with a Pathological Complete Response after HER2-Targeted Therapy: A Pooled Analysis

Early breast cancer; Event-free survival; Pathologic complete responseCáncer de mama temprano; Supervivencia libre de eventos; Respuesta patológica completaCàncer de mama precoç; Supervivència lliure d'esdeveniments; Resposta patològica completaThe standard-of-care for patients with pathological complete response (pCR) after neoadjuvant human epidermal growth factor receptor 2 (HER2)-targeted therapy plus chemotherapy is continuation of HER2-targeted therapy in the adjuvant setting. Our objective was to evaluate risk of recurrence or death in these patients and determine if outcomes differed by the HER2-targeted regimen received in each setting. We analyzed patient-level data from five randomized trials evaluating trastuzumab, pertuzumab, or both as part of systemic neoadjuvant and adjuvant therapy for HER2-positive early breast cancer, and assessed event-free survival (EFS) in 1763 patients. Patients with pCR had decreased risk of an EFS event versus those with residual disease (unadjusted hazard ratio [HR] = 0.35; 95% confidence interval [CI]: 0.27–0.46). Regardless of pCR status, after adjusting for baseline factors, reduction in EFS event risk was greater in patients administered pertuzumab/trastuzumab in both settings versus those administered only trastuzumab in both settings (HR = 0.36; 95% CI: 0.26–0.49), or pertuzumab/trastuzumab in the neoadjuvant setting and only trastuzumab in the adjuvant setting (HR = 0.67; 95% CI: 0.47–0.96). Patients with pCR had longer EFS than those with residual disease. Patients treated with pertuzumab/trastuzumab in both the neoadjuvant and adjuvant settings had the lowest risk of breast cancer recurrence.The analysis was funded by F. Hoffmann-La Roche, Ltd

Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer.

BackgroundThe importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options.MethodsBreast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared.ResultsOf the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]).ConclusionsThis study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy

Prognostic value of lymphocyte vascular density and e-cadherin in inflammatory breast cancer

Background: We recently evaluated four laboratory assays, vascular endothelial growth factor D (VEGF-D), E-cadherin, lymphatic vessel density (LVD) measured by podoplanin, and intra-lymphatic tumor emboli (ILTE), which showed notable differences between inflammatory breast cancer (IBC) and non-inflammatory locally advanced breast cancer (LABC). In this study we investigated the potential of the three most quantitatively measured markers, E-cadherin, LVD and VEGF-D, to predict survival in the IBC patients. Materials and Methods: This study involved the 100 cases identified in the Inflammatory Breast Cancer Registry (IBCR) whose tumors were previously evaluated for the four assays noted above. Living patients were recontacted and survival data were available for up to 17 years. Overall survival (OS) was analyzed through the Kaplan-Meier method stratified by E-cadherin, LVD, VEGF-D, and response to chemotherapy. The differences in OS curves were compared using the log-rank test. Results: The median OS for patients with high LVD was 6.63 years (95% CI: 4.06 to 10.14), compared to median at 10 years not reached in those with low LVD (p = 0.03). There was a trend towards a longer median OS in patients with high E-cadherin (10.14, 95% CI: 6.63 to 11.67), compared with those with low E-cadherin (6.26, 95% CI: 3.42 to undeterminable). VEGF-D levels showed no correlation with survival. Conclusion: Low LVD significantly predicts better survival. High E-cadherin expression, as with non-IBC breast cancer and several other malignancies, tends to be associated with a better prognosis

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations

Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in E gypt and T unisia

The diagnosis of inflammatory breast cancer ( IBC ) is largely clinical and therefore inherently somewhat subjective. The objective of this study was to evaluate the diagnosis of IBC at two centers in N orth A frica where a higher proportion of breast cancer is diagnosed as IBC than in the U nited S tates ( U . S .). Physicians prospectively enrolled suspected IBC cases at the National Cancer Institute ( NCI ) –  C airo, E gypt, and the I nstitut S alah A zaiz ( ISA ), T unisia, recorded extent and duration of signs/symptoms of IBC on standardized forms, and took digital photographs of the breast. After second‐level review at study hospitals, photographs and clinical information for confirmed IBC cases were reviewed by two U . S . oncologists. We calculated percent agreement between study hospital and U . S . oncologist diagnoses. Among cases confirmed by at least one U . S . oncologist, we calculated median extent and duration of signs and S pearman correlations. At least one U . S . oncologist confirmed the IBC diagnosis for 69% (39/50) of cases with photographs at the NCI ‐ C airo and 88% (21/24) of cases at the ISA . All confirmed cases had at least one sign of IBC (erythema, edema, peau d'orange) that covered at least one‐third of the breast. The median duration of signs ranged from 1 to 3 months; extent and duration of signs were not statistically significantly correlated. From the above‐mentioned outcomes, it can be concluded that the diagnosis of a substantial proportion of IBC cases is unambiguous, but a subset is difficult to distinguish from other types of locally advanced breast cancer. Among confirmed cases, the extent of signs was not related to delay in diagnosis. The diagnosis of inflammatory breast cancer ( IBC ) is largely clinical and therefore inherently somewhat subjective. The objective of this pilot study was to evaluate the diagnosis of IBC at two centers in N orth A frica, where a higher proportion of breast cancer is diagnosed as IBC than in the U nited S tates ( U.S. ). The diagnosis of a substantial proportion of IBC cases at the study centers was unambiguous, but a subset was difficult to distinguish from other types of locally advanced breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97479/1/cam448.pd

Inflammatory breast cancer: dynamic contrast-enhanced MR in patients receiving bevacizumab. Initial experience

To retrospectively compare three dynamic contrast material-enhanced magnetic resonance (MR) imaging (dynamic MR imaging) analytic methods to determine the parameter or combination of parameters most strongly associated with changes in tumor microvasculature during treatment with bevacizumab alone and bevacizumab plus chemotherapy in patients with inflammatory or locally advanced breast cancer. MATERIALS AND METHODS: This study was conducted in accordance with the institutional review board of the National Cancer Institute and was compliant with the Privacy Act of 1974. Informed consent was obtained from all patients. Patients with inflammatory or locally advanced breast cancer were treated with one cycle of bevacizumab alone (cycle 1) followed by six cycles of combination bevacizumab and chemotherapy (cycles 2-7). Serial dynamic MR images were obtained, and the kinetic parameters measured by using three dynamic analytic MR methods (heuristic, Brix, and general kinetic models) and two region-of-interest strategies were compared by using two-sided statistical tests. A P value of .01 was required for significance. RESULTS: In 19 patients, with use of a whole-tumor region of interest, the authors observed a significant decrease in the median values of three parameters measured from baseline to cycle 1: forward transfer rate constant (Ktrans) (-34% relative change, P=.003), backflow compartmental rate constant extravascular and extracellular to plasma (Kep) (-15% relative change, P<.001), and integrated area under the gadolinium concentration curve (IAUGC) at 180 seconds (-23% relative change, P=.009). A trend toward differences in the heuristic slope of the washout curve between responders and nonresponders to therapy was observed after cycle 1 (bevacizumab alone, P=.02). The median relative change in slope of the wash-in curve from baseline to cycle 4 was significantly different between responders and nonresponders (P=.009). CONCLUSION: The dynamic contrast-enhanced MR parameters Ktrans, Kep, and IAUGC at 180 seconds appear to have the strongest association with early physiologic response to bevacizumab. Clinical trial registration no. NCT0001654

Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2–positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a \u3e 10% decline in left ventricular ejection fraction from baseline to a value \u3c 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function

NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone

Report on the International Colloquium on Cardio-Oncology (Rome, 12–14 March 2014)

Cardio-oncology is a relatively new discipline that focuses on the cardiovascular sequelae of anti-tumour drugs. As any other young adolescent discipline, cardio-oncology struggles to define its scientific boundaries and to identify best standards of care for cancer patients or survivors at risk of cardiovascular events. The International Colloquium on Cardio-Oncology was held in Rome, Italy, 12–14 March 2014, with the aim of illuminating controversial issues and unmet needs in modern cardio-oncology. This colloquium embraced contributions from different kind of disciplines (oncology and cardiology but also paediatrics, geriatrics, genetics, and translational research); in fact, cardio-oncology goes way beyond the merging of cardiology with oncology. Moreover, the colloquium programme did not review cardiovascular toxicity from one drug or the other, rather it looked at patients as we see them in their fight against cancer and eventually returning to everyday life. This represents the melting pot in which anti-cancer therapies, genetic backgrounds, and risk factors conspire in producing cardiovascular sequelae, and this calls for screening programmes and well-designed platforms of collaboration between one key professional figure and another. The International Colloquium on Cardio-Oncology was promoted by the Menarini International Foundation and co-chaired by Giorgio Minotti (Rome), Joseph R Carver (Philadelphia, Pennsylvania, United States), and Steven E Lipshultz (Detroit, Michigan, United States). The programme was split into five sessions of broad investigational and clinical relevance (what is cardiotoxicity?, cardiotoxicity in children, adolescents, and young adults, cardiotoxicity in adults, cardiotoxicity in special populations, and the future of cardio-oncology). Here, the colloquium chairs and all the session chairs briefly summarised what was said at the colloquium. Topics and controversies were reported on behalf of all members of the working group of the International Colloquium on Cardio-Oncology

Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart

Heart formation requires a highly balanced network of transcriptional activation of genes. The homeodomain transcription factor, Shox2, is essential for the formation of the sinoatrial valves and for the development of the pacemaking system. The elucidation of molecular mechanisms underlying the development of pacemaker tissue has gained clinical interest as defects in its patterning can be related to atrial arrhythmias. We have analyzed putative targets of Shox2 and identified the Bmp4 gene as a direct target. Shox2 interacts directly with the Bmp4 promoter in chromatin immunoprecipitation assays and activates transcription in luciferase-reporter assays. In addition, ectopic expression of Shox2 in Xenopus embryos stimulates transcription of the Bmp4 gene, and silencing of Shox2 in cardiomyocytes leads to a reduction in the expression of Bmp4. In Tbx5del/+ mice, a model for Holt-Oram syndrome, and Shox2−/− mice, we show that the T-box transcription factor Tbx5 is a regulator of Shox2 expression in the inflow tract and that Bmp4 is regulated by Shox2 in this compartment of the embryonic heart. In addition, we could show that Tbx5 acts cooperatively with Nkx2.5 to regulate the expression of Shox2 and Bmp4. This work establishes a link between Tbx5, Shox2 and Bmp4 in the pacemaker region of the developing heart and thus contributes to the unraveling of the intricate interplay between the heart-specific transcriptional machinery and developmental signaling pathways