bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary results from the international neoadjuvant melanoma consortium (INMC).
Authors: Menzies Alexander M. , Rozeman Elisa A. , Amaria Rodabe Navroze , Scolyer Richard A. , Tetzlaff Michael T. , Guminski Alexander , Davies Michael A. , Blank Christian U. , Wargo Jennifer Ann , Long Georgina V.
Published: September 2018

9581

Background: For several cancers, response to neoadjuvant therapy (NAT) correlates with survival. Targeted and immune therapies achieve high response rates and durable survival in many patients with metastatic melanoma. Their role as NAT for stage III disease is not clear, and whether pathological response following NAT correlates with relapse-free (RFS) or overall survival (OS) in melanoma is unknown. Methods: Pooled clinical data from four ongoing NAT clinical trials (NCT02437279, NCT02231775, NCT02519322, NCT01972347) at three large melanoma centers participating in the INMC were examined. All trials included only patients with surgically resectable clinical stage III melanoma. NAT regimens included dabrafenib/trametinib (DT) and nivolumab (nivo) [single agent or in combination with ipilimumab (ipi/nivo)]. Patients who had undergone surgery prior to 27th January 2017 are included in this preliminary analysis. A pathological complete response (pCR) was defined as no viable melanoma cells in the resected specimen by hematoxylin and eosin evaluations by dedicated dermatopathologists. Results: 58 patients with clinical stage III melanoma (AJCCv7: 18 IIIB, 40 IIIC) have completed NAT and undergone surgery. 18 received neoadjuvant immunotherapy (IT): ipi/nivo x2 doses (N = 10), ipi/nivo x3 doses (N = 4) or nivo x4 doses (N = 4). 40 received neoadjuvant DT, either for two (N = 10) or three months (N = 30). Median age is 55 years (range 22-84). A pCR was observed in 50% of patients, 7 (39%) with IT and 22 (55%) with DT. Median follow-up is 10.2 months (95% CI 8.7-12.5). 14 (24%) patients have recurred (5 local, 8 distant, 1 both), 2 (11%) after IT, 12 (30%) after DT. For those with pCR, 14% have recurred, 0/7 (0%) after IT, 4/22 (18%) after DT. In contrast, for those without pCR, 34% have recurred, 2/11 (18%) after IT and 8/18 (44%) after DT. Two deaths have occurred, both after neoadjuvant TT. Early data suggests improved RFS in those with pCR. Conclusions: Neoadjuvant targeted and immunotherapy are active regimens in clinical stage III melanoma patients and are associated with high pCR rate. Preliminary data suggest pCR correlates with improved RFS. Updated data will be presented. Clinical trial information: NCT02437279, NCT02231775, NCT02519322, NCT01972347.
Outcomes of women with small, early-stage breast cancer in Manitoba from 2006-2011.
Authors: Zhang Hanbo , Lambert Pascal J , Lalani Aly-Khan A. , Fradette Katherine , Ahmed Rashid , Grenier Debjani , Pitz Marshall W.
Published: September 2018

e12000

Background: The incidence of early-stage breast cancers has increased dramatically over the past decades. Treatment decisions for patients with stage I breast cancers are challenging, as there are significant variations in outcomes based on biologic subtypes. The objectives were to describe the distribution, molecular phenotypes, management, and long-term outcomes of women with early-stage breast cancer (T1mic/T1a/T1b N0 M0) in Manitoba from 2006-2011. Methods: Using the Manitoba Cancer Registry, we created a retrospective cohort of patients with primary breast cancer of ≤1.0 cm, diagnosed between 2006 and 2011. Data included patient demographics, tumour size, treatment modalities (surgery, radiotherapy, chemotherapy and trastuzumab), estrogen-receptor (ER) and progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status. Node-positive cancers were excluded. Patient outcomes were evaluated, including rates of recurrence and overall survival using univariate and multivariable models. Kaplan-Meier curves and cumulative incidence curves were used to illustrate overall survival and recurrence, respectively. Results: Our study included 733 women. Mean age at diagnosis was 62. ER/PR positivity and HER2 positivity (HER2+) were 84% and 8.9%, respectively. Tumours were: T1mic in 14.0%, T1a in 19.1%, and T1b in 66.9%. 98% of patients had surgery, 60% had adjuvant radiation, 3.8% received trastuzumab, and 11% received chemotherapy. The adjusted hazard ratio (HR) for disease recurrence for patients with HER2+ versus HER2- status was 4.31 (95% CI, 2.18 to 8.50; P = 0.0001), and the HR for overall survival was 1.63 (95% CI, 0.72 to 3.67; P = 0.2402). The HR for disease recurrence in HER2+ patients receiving trastuzumab versus HER2+ patients who did not receive trastuzumab was 1.92 (95% CI, 0.61 to 5.97; P = 0.2621). Conclusions: HER2-positivity appears to be an important risk factor for recurrence in small, early-stage breast cancers. In our cohort, trastuzumab did not appear to reduce the risk of recurrence compared to those who did not receive it. This may be due to limited power and selection bias, in which patients with higher risk cancers received trastuzumab.
Outcome analysis of time from diagnosis to treatment in breast cancer patients treated at Edward Comprehensive Cancer Center, Huntington, West Virginia.
Authors: Raufi Ali Mehmood , Srivastava Roma , Jafri Hassaan , Gress Todd W. , Tirona Maria R. B. Tria
Published: September 2018

e12005

Background: Cancer is the second leading cause of death in the USA. In multiple cohorts, adverse outcomes were observed among early breast cancer (BC) patients when time from diagnosis to treatment was 91 days or beyond. Multiple patient and system related factors can lead to delays in treatment initiation.This retrospective study was doneto determine the relationship between diagnosis and time to treatment on OS in BC patients treated at ECCC from 2006 to 2015. Methods: 721 charts of BC patients were retrospectively reviewed. Time interval between diagnosis and initial treatment modality was determined and set at 30 day increments, (0-30 days, 31 to 60 days, and 61 to 90 days and > than 90 days).Time from diagnosis to surgery (TTS) and surgery to adjuvant chemotherapy (TTC) was also calculated. Statistical analysis was done and Kaplan Meier curves were generated to assess the OS. Results: Median age at diagnosis of BC was 58 years. 82% of the BC patients were started on treatment (any modality) within 60 days of diagnosis whereas 35% within 30 days of diagnosis, respectively. Patients who received initial treatment (any modality) > 90 days since diagnosis, had the worst survival outcome (hazard ratio of 2.5, 95% CI 1.315 to 4.91, p value = 0.005). Patients treated after 60 days since diagnosis did show numerical trend towards the worse survival outcome but was not statistically significant. There was a declining trend in survival when TTC was more than 90 days . A similar trend was noted when TTS was > 60 days when adjusted for age, stage and hormone status. Conclusions: The relationship between TTS and BC outcome continues to be a modern health concern. The survival outcome in BC is affected by the length of the interval between diagnosis and treatment. All efforts should be directed towards minimizing them.
Treatment patterns and patient profiles for docetaxel-based adjuvant chemotherapy in early-stage breast cancer in China: A pooled analysis of four observational studies.
Authors: Xu Binghe , Shao Zhimin , Wang Shui , Jiang Zefei , Hu Xichun , Zhang Xiaohua , Li Xi Ru , Liu Jinping , Li Mengquan , Wang Shu
Published: September 2018

e12017

Background: Adjuvant docetaxel-based chemotherapy is frequently used for operable breast cancer. This study investigated the patterns of use of docetaxel (T) in real-life clinical practice in China. Methods: This retrospective pooled analysis included female Chinese adults (≥18 years) with operable breast cancer treated with docetaxel-based adjuvant chemotherapy enrolled in the Asia-Pacific Breast Initiatives (APBI) I (2006-2008) and II (2009-2011) registries, and two Chinese observational studies; BC STATE (2011-2014) and BC Local Registry (2007-2010). Patients with metastatic disease were excluded. The primary endpoint was assessment of treatment patterns and patient profiles. Patient profiles for treatment regimen selection were investigated using regression analysis. Results: Data from 3020 patients were included. The most commonly used regimen was docetaxel/anthracycline combination (n=1421 [47.1%]; of whom 52.0% received T/epirubicin (E)/cyclophosphamide (C)), followed by docetaxel/other (n=705 [23.3%]; of whom 72.8% received TC), docetaxel/anthracycline sequential (n=447 [14.8%]; of whom 40.9% and 39.6% received 5-Fu/EC-T and EC-T), and ‘Other’ (n=447 [14.8%]; of whom 91.5% received T). Multivariate regression analysis revealed a significant association between selection of docetaxel/anthracycline combination and patient weight, menopausal status, and estrogen receptor and HER-2 status (Table). Conclusions: Data from real clinical practice show docetaxel/anthracycline combination is the most commonly used docetaxel-based adjuvant therapy for operable breast cancer in China; of which TEC is the most popular specific regimen. Several patient profile factors were significantly associated with the selection of docetaxel/anthracycline combination. [Table: see text]
Genomic profiling of metaplastic breast cancer: A single center experience.
Authors: Afkhami Michelle , Amanam Idoroenyi Usua , Aoun Patricia A. , Schmolze Dan , Yost Susan , Frankel Paul Henry , Nguyen Kim , Yu Wai (Kim) Wai , Luu Thehang H. , Yuan Yuan
Published: September 2018

e12041

Background: Metaplastic breast cancer (MpBC) is a rare malignancy with aggressive clinical presentation and poor prognosis. The goal of this study is to characterize MpBC at the genomic level with targeted exome sequencing and correlate with clinical-pathological characteristics. Methods: We have Identified 23 patients (pts) with a diagnosis of MpBC through the COH Cancer Registry from 1995 to 2013. A next generation sequencing based panel (Onco48) was performed on 21 pts on using the Ion AmpliSeq™ Kit. Molecular testing for two pts was performed at FoundationOne®. Patient’s clinical-pathological characteristics were also captured (age, race, stage, chemotherapy, radiation therapy history, and 5-year relapse free survival (RFS)). Results: Of the 21 specimens tested with COH Onco48, 3 failed to yield results. Of the 20 pts included in the analysis, 1 pt did not have survival information available. The median age at time of diagnosis was 68 years (range 35-93). All of the tumors were TNBC. The subtypes of MpBC were: squamous (35%), spindle (30%), mixed squamous and spindle (15%) and chondroid (20%). A total of 70% of pts received (neo)adjuvant chemotherapy, and 65% received radiation therapy. Median follow-up of alive pts is 63 months. Median RFS and OS have not been reached for entire cohort with a lower 95% of PFS of 22.2 months. The most commonly mutated genes included TP53 (65%), PIK3CA (45%), PTEN (15%).In a univariate analysis, the association of p53, PTEN, PIK3CA mutations and breast cancer specific survival. RFS at 2 years was 33% (0.03-0.64) for those with PIK3CA mutations, and 100% for those without (p<0.01, log-rank). Overall survival was 56% at 2 years in pts with PIK3CA mutations (95% CI 0.23-0.88) compared with 100% in pts without PIK3CA mutations (p<0.02). There are no statistically significant association between P53, PTEN mutation and survival. Conclusions: PIK3CA mutation confers poor prognosis in this small cohort of patients with MpBC. A larger cohort of pts is needed to verify these findings.
Tumor-infiltrating lymphocytes as a prognostic factor in patients with stage I to III breast cancer.
Authors: Richardet Eduardo , Acosta Luciana Paola , Paradelo Martin , Pairola Martin , Di Tada Cecilia , Molina Matias , Dicalbo Luciano Salvador , Villavicencio Rocio Paola , Richardet Martin Eduardo
Published: September 2018

e12042

Background: Current evidence makes reference to the potential role that tumor-infiltrating lymphocytes (TILs) as a prognostic factor in breast cancer and numerous types of tumors. Different studies have shown that the interaction with the immune response of the host is relevant to the response to chemotherapy. TILs are cell phenotype T CD3 +, which can, in turn, stratify in cytotoxic T lymphocytes (CD8), and regulatory T cells (CD4+ CD25+ FOXP3+).Our aim was to identify whether there was a relationship between TILs and SLE in patients with stage I to III breast cancer who have undergone chemotherapy adjuvant treatment. The secondary endpoint was to analyze the association between subtype infiltrating lymphocytes (CD4 and CD8) and SLE. Methods: Retrospective and analytical study in our institution IONC. Patients with stage I to III breast cancer was analized which had standard risk factors and required adjuvant treatment with chemotherapy. 87 patients completed with the selection criteria. The infiltration degree by H/E was evaluated and CD4 and CD8 by IHQ was marked. SLE was analyzed through the Kaplan-Meier method. Results: 87 samples were analyzed, in 46 patients (52,8 %) evidenced TILs and in 41 patients (47.12%) there were no TILs in their tumor samples. SLE was higher for those patients who had TILs with respect to those patients who did not have any TILs, 45.3 months as opposed to 30.85 months respectively (p: 0,038) and these differences were statistically different. In the TILi analysis, it could observed that 91% patients not revealed infiltrations in their tumor samples.When correlating CD4 and CD8 was carried out, 33% of the patients showed CD4 TILs in their tumor samples and 49.4% evidenced CD8 TILs. There were no SLE differences regarding the presence or the absence of CD4. The high number of CD8 was associated to a higher SLE; 39.06 months as opposed to 37.5 months, but these differences were not statistically different. Conclusions: We could conclude that patients who had showed TILs in their tumor samples had a higher SLE with respect to those who did not show any infiltration and this was statistically significant. There were no differences when samples were analyzed on the presence or absence of CD4 and CD8.
Detection of sentinel lymph node in patients with breast cancer: Application of 3D contrast enhanced ultrasound (3D-CEUS).
Authors: Lu Man , Hu Ziyue , Li Juan
Published: September 2018

e12095

Background: Sentinel lymph node biopsy (SLNB) has became widely accepted as the gold standard procedure for axilla nodal staging .The main methods for the detection of Sentinel lymph nodes (SLNs) are dye-guided and g-probe-guided method.Currently, studies suggest that 2D - Contrast Enhanced Ultrasound(2D-CEUS) may be as good as the accepted techniques for SLNs detection .But the 2D-CEUS can not image the spatial relationship of the lymph vessel and SLNs.The objective of this study was to explore whether three-dimensional contrast enhanced ultrasonography (3D-CEUS) poses higher diagnostic value of in SLNs and lymphatic drainage routes of breast cancer than conventional ultrasonography (US) or 2D-CEUS.To our knowledge, this is the first study to investigate the value of 3D-CEUS in the preoperative diagnosis of SLN metastases in patients with early breast cancer. Methods: By using postoperative pathological results as gold standard, the accuracy and sensitivity of conventional US, 2D-CEUS and 3D-CEUS for SLNs were retrospectively tested in 73 patients with early breast cancer confirmed by pathology between December 2015 and June 2016, all patients underwent US, 2D-CEUS and 3D-CEUS before operation. Injection of the Blue dye was performed half an hour before the operation. Results: According to the postoperative pathology, 25 of 73 patients were with lymphatic metastasis. The lymph nodes detection rate of 2D-US,2D-CEUS and 3D-CEUS was 35.2%, 73.4%, 79.4% ,respectively.The correct rate of 2D-US,2D-CEUS and 3D-CEUS was 74%,90.4%,91.8%, respectively(p<0.05).The lymph drainage route of SLNs are divided into 7 types by 3D-CEUS and the enhancement modes of the lymphatic vessels and the lymph nodes are divided into six categories by 2D-CEUS. Conclusions: The 2D-CEUS and 3D-CEUS can clearly display the SLNs and the lymph drainage routes. 3D-CEUS possesses advantages over 2D-CEUS in displaying lesions with spatial relationship which is informative to preoperative assessment of the stage, the operative type and surgical prognosis in patients with breast cancer, and can contribute greatly to the easy detection of SLNs during SLNB. Clinical trial information: Approval NO,SCPPHEC-D-2015-75.
TARGIT E(lderly): Prospective phase II study of intraoperative radiotherapy (IORT) in elderly patients with small breast cancer—3 year local control and overall survival.
Authors: Wenz Frederik K. ,   TARGIT E Trialists
Published: September 2018

e12105

Background: To investigate the efficacy of a single intraoperative radiotherapy treatment within elderly low risk patients with breast cancer (≥ 70 years, <3.5cm, cN0, cM0, invasive-ductal histology) which is followed by whole breast radiotherapy (WBRT) only when risk factors are present. This prospective, multicentric single arm phase II study (NCT01299987) is based on the experimental arm of the randomized protocol of the international TARGIT A study. Here we present 3 year data on local control and overall survival after a median follow-up of 24 months. Methods: 541 patients from 28 international centers were recruited between February 2011 and September 2014. Sixty-three patients were excluded from the analysis because of screening failure, drop-out or loss to follow-up. During breast conserving surgery a single dose of 20 Gy of intraoperative radiotherapy was given using the INTRABEAM system (Carl Zeiss Meditec, Germany). Additional postoperative WBRT (46 – 50 Gy) was prescribed only in patients with risk factors (larger size, other histology, small free margin, lymphvessel invasion, positive nodes, multifocality/multicentricity, extensive intraductal component (EIC)). Systemic therapy was given according to international standards. The primary outcome was local relapse. Overall survival was a secondary outcome. Discontinuation of the trial was scheduled if rates of local relapse rates rise to 3/4/6% after 2.5/5/7.5 years. Results: After a median follow-up of 24.0 months (120 pts with 3 year f/u), one ipsilateral in-breast recurrence and nine deaths were observed resulting in an actuarial local relapse free survival of 99.7% and actuarial overall survival of 96.6% after 3 years. Conclusions: The results of the prospective TARGIT E trial consolidate earlier reports from the randomized TARGIT A trial supporting the use of accelerated partial breast radiotherapy (APBI) in selected patients. The observed local relapse rate after 3 years is well below the prospectively defined stopping rules (Neumaier et al. BMC Cancer 2012). Further follow-up will be performed. Clinical trial information: NCT01299987.
The first report of multicenter validation study on curebest 95GC breast, a multi-gene assay to predict prognosis of node negative and ER positive breast cancer patients.
Authors: Ito Ken-ichi , Oba Takaaki , Aogi Kenjiro , Ohsumi Shozo , Takahashi Mina , Shiroma Noriyuki , Oda Miyo , Arihiro Koji , Tsukamoto Fumine , Shiino Sho , Yoshida Masayuki , Kishi Kazuki , Kinoshita Takayuki
Published: September 2018

e12107

Background: Curebest™ 95GC Breast (95GC) is one of the multi-gene assays to predict prognosis of node negative and estrogen receptor (ER) - positive breast cancer patients, developed using 95 gene-set without overlap with that used in Oncotype DXⓇ(ref 1). It has been shown to have the capability to classify the “intermediate” patients determined using Recurrence Online (microarray-based simulation model for Oncotype DXⓇ) but was validated only using the data from single institute and public database. Here we report the result of the first multi-center validation study for this multi-gene assay. Methods: ER-positive and T1-2/N0/M0 breast cancer patients who received adjuvant hormonal therapy were enrolled retrospectively. Fresh frozen tissues were applied to the assay, resulting classification into “L” and “H”, which was used for the validation on 5 year recurrence free survival (5Y-RFS) data of each patient. Results: 73 cases out of 150 enrolled cases were eligible and analyzed. 46 patients were classified as “L” whose 5Y-RFS was 96.5% (95%CI:89.5-98.9) while 27 patients were classified as “H” whose 5Y-RFS was 79.0% (95%CI:63.6-88.5). There was a statistically significant difference between RFS of “L” and “H” group by Log-Rank test (p = 0.0016). Significant association with 95GC were seen in histological grade (p = 0.0012), Recurrence Online (p < 0.001) and PAM50 (p < 0.001). The assay could classify the patients of histological grade 2, intermediate group by Recurrence Online (RS > 17, RS < 31) and Luminal B patients into “L” and “H”. Conclusions: Curebest™ 95GC Breast was well validated by this first multi-centered retrospective study on 5Y-RFS of the ER positive, node-negative patients who received only hormonal therapy in adjuvant setting. This result indicates the usefulness of 95GC as a novel multi-gene assay, as it can classify target patients into 2 groups, “H” and “L” according to predicted prognosis of 5Y-RFS. Reference: 1. Naoi et al. Breast Cancer Res Treat (2011) 128:632-641
Exercise training during anthracycline-based chemotherapy for breast cancer.
Authors: Fraser Steve , Bigaran Ashley , Selig Steve , LaGerche Andre
Published: September 2018

e12110

Background: Breast Cancer is the most common female malignancy in Australia and worldwide. Medical advancements in breast cancer detection, diagnosis, and treatment have increased the 5 year-survival rate to 90%, so a focus on non-breast cancer related causes of morbidity and mortality have emerged. Anthracycline-chemotherapy has had considerable success in reducing tumour size, cancer recurrence and improving survival rates but significant adverse effects including reductions in VO2peak and cardiac function. Exercise training may provide a treatment option to reduce the cardiotoxic and fitness declines seen in women treated with anthracycline-based chemotherapy. Therefore this study aims to investigate the effects of exercise training for women recently diagnosed with breast cancer undergoing anthracycline chemotherapy Methods: 20 women recently diagnosed with breast cancer were evenly split into either usual care (UC, n = 10, age 49.2 ± 13.4yrs, Ht 164 ± 0.09cm, Wt 77.4 ± 19.7kg, BMI 23.5 ± 5.4) or three months of AEP led aerobic and resistance training designed to reduce the adverse effects of chemotherapy treatment (Ex, n = 10, age 50.9 ± 7.4 yrs, Ht 161 ± 0.09cm, Wt 70.7 ± 23kg, BMI 21.9 ± 6.9). Key measures including cardiac function, VO2peak, strength and cancer related fatigue were assessed pre and post intervention. Results: Baseline VO2peak (UC 22 ± 6.6 ml/kg/min, Ex UC 26.3 ± 6.7 ml/kg/min were below predicted values. Breast cancer patients tolerated exercise training during chemotherapy treatment and preliminary result suggest a decline in VO2peak and cardiac function during chemotherapy treatment and that exercise training was able to ameliorate this. More complete data will be presented at the conference. Conclusions: An Exercise Physiologist led aerobic and resistance training program was well tolerated in women recently diagnosed with breast cancer. The program appears to minimise some of the adverse effects of treatment, notably fitness declines and cardiotoxicity and should be considered in the oncology setting. Clinical trial information: ACTRN1261600160241.
Efficacy of taxanes followed by anthracyclines as neoadjuvant therapy in HER2-negative breast cancer (BC): Analysis of everyday clinical practice.
Authors: Alanya Rodríguez Enrique , Falo Zamora Catalina , Gil Gil Miguel J. , Anna Petit , Ortega Raul , Fernandez Adela , Morilla Idoia , Stradella Agostina , Cobo Sara , Pernas Simon Sonia
Published: September 2018

e12112

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy for BC has been related with survival, and the sequence of anthracyclines followed by taxanes (AT) has been the strategy to achieve this response. Some studies suggest that the reverse sequence (TA) might improve cancer outcomes. The aim of our study was to compare clinical response, toxicity and efficacy in terms of pCR rate (ypT0/pTis, ypN0) between both sequences Methods: A retrospective cohort study was designed. TA cohort received Docetaxel (100 mg/m2) x 4, followed by AC (60/600 mg/m2) x 4. AT cohort received the reverse sequence at the same doses. To be included, it was necessary to have received at least one cycle in the planned sequence. Logistic regression analysis was performed to obtain a model adjusted by age, menopausal status, tumor size, nodal status, grade, estrogen receptor (ER), progesterone receptor, and Ki67 Results: From June 2008 to December 2015, 135 consecutive patients with stage II – III HER2 negative BC were treated: TA (n = 48) and AT (n = 87). No significant differences in patient characteristics between groups were found, except for histological grade 3 (63.2% to AT vs. 35.4% to TA), and ER negative (41.4% to AT vs. 22.9% to TA). The pCR rate for TA was 16.7% (8 of 40) vs. 14.9% (13 of 74) for AT. Multivariate logistic regression analysis found OR = 3.65 to achieve pCR for TA (95%CI 1.03 – 12.94; p = .045). We also performed the same analysis for two clinical parameters of response: Neoadjuvant response index (NRI) with cut-off > 0.5 (OR 3.96, 95%CI 1.42-11.08; p = .009) and Clinical response (CR) > 50% (OR 3.65, 95%CI 1.03 – 12.94; p = .045). These parameters were correlated in our series with DFS (p = .011 to NRI and p = .00023 to CR) and OS (p = .034 to NRI and p = .0014 to CR) using the Kaplan-Meier method. No significant differences between rates of either, hospitalizations, neutropenia or dose intensity were found Conclusions: Sequence of T followed by A was slightly significantly more effective to achieve pCR as well as better clinical outcomes in our series of HER2 negative BC than classical sequence of A followed by T, and support the design of large prospective studies to confirm these results
Prognostic factors in breast cancer patients evaluated by PET/CT prior to neoadjuvant chemotherapy.
Authors: Farrugia Mark K , Jacobson Geraldine M. , Salkeni Mohamad Adham
Published: September 2018

e12113

Background: Neoadjuvant chemotherapy (NAC) is an important modality in breast cancer treatment. We sought to identify pre-treatment prognostic factors in patients who had positron emission tomography paired with diagnostic quality contrast-enhanced CT (PET/CT) prior to neoadjuvant chemotherapy with respect to pathologic complete response (pCR) , survival and relapse-free survival (RFS). Methods: We retrospectively analyzed 118 breast cancer patients who had pre-treatment PET/CT imaging and received NAC from 2008-2014. We collected data on molecular markers, PET/CT, pCR, survival, and disease status. Results: The median follow up was 44 months(range 7.3-101.5),median age was 51 years; 47% were stage II, 53% stage III. 52% of patients had hormone receptor (HR) positive/HER2 negative disease, 31% of tumors were HER2 positive, and 17% of tumors were triple-negative. 92.5% with HER2 positive tumors received NAC containing at least one HER2 targeted agent. Pre-treatment standard uptake value (SUV) max of the primary breast tumor showed no statistically significant relationship to survival, RFS, or pCR. PET avid (>2 SUV) extra-axillary nodes such as internal mammary and supraclavicular was associated with a non-statistically significant trend towards reduced RFS (p=0.06, HR=0.13-1.06). pCR overall was 37.5% for HER2 positive tumors, 15% in triple-negative tumors, and 8% in HR positive/HER2 negative tumors. Log-rank analysis with post-hoc pairwise comparisons showed a significant difference between the RFS of triple-negative tumors and HER2 positive tumors (p=0.001), while comparison between HR positive/HER2 negative and HER2 positive was not statistically significant (p=0.11). Multivariate cox regression analysis, which included grade and stage of tumors, showed HER2 positivity to be associated with a favorable outcome (p=0.04, HR=0.22 (0.05-0.94)). Conclusions: Within this cohort, pre-treatment SUV max of the primary tumor showed no prognostic value with regard pCR or RFS. PET avid extra-axillary metastasis trended towards reduced RFS. Patients with HER2 positive tumors had the highest pCR and RFS comparable to classically favorable subgroups such as HR positive/HER 2 negative.
Prognostic value of Ki-67 labeling index according to age in patients with non-metastasic triple-negative breast cancer.
Authors: Zenzola Victor , Cabezas-Quintario María Antonia , Correa Andrea , Moreno Irene , Pedregal Manuel , Rojo Federico , Arguelles Miguel , Perez Fernandez Elia , Garcia-Foncillas Jesus
Published: September 2018

e12118

Background: The prognostic value of Ki67 in triple negative breast cancer (TNBC) is yet unclear because the cut-off points employed differ widely and its predictive effect may vary according to age. The purpose of this study was to analyze the role of Ki-67 among patients with TNBC, and determined the optimal Ki-67 cut-off point to demonstrate its prognostic relevance associated with patient age and treatment strategy. Methods: 201 patients treated for primary TNBC from 1999 to 2014 were identified from the breast surgery database. Clinicopathologic characteristics and outcomes were compared between patients treated with neoadjuvant or adjuvant chemotherapy. We used time-dependent receiver operating characteristic (ROC) curve and time-dependent area under the ROC curve (AUC) to evaluate the discriminative ability of Ki-67 at 3 and 5 years of follow up. A Ki-67 cut-off point was set up to maximize sensitivity and specificity. Interaction effect between age and Ki-67 on disease-free survival (DFS) and overall survival (OS) was evaluated by stratified analysis. Results: There was a non-significant Ki-67 cut off value to predict OS and DFS at 3 and 5 years neither in the whole serie (201) nor in the adjuvant group (125), and only a slightly better threshold for DFS in the neoadjuvant one (N = 46) at 5 years (AUC = 0.697). According to the coordinates of the ROC curves, the best cut-off point for Ki-67 was 60%. In the multivariate analysis (COX proportional hazards regression), high Ki-67 ( > 60%), was a poor prognostic factor for DFS in patients > 40 yo. Among the patients < 40 yo, high Ki-67 was a better prognosis factor. Conclusions: Our data suggest that a threshold of Ki-67 of 60% could provide a usefull tool to define patients with significantly different outcome in TNBC.
Association between ER±36 and PR A/B overexpression in trastuzumab resistant HER2+ breast cancer cell lines.
Authors: Contreras Sergio , Torres Eduardo Rey , López José Anselmo , García Eric Alejandro , Ventura José Luis , Badillo Ernesto , Lara - Torres Cesar , Aguilar Diana Elodia , Ibarra María de los Ángeles , Zentella Dehesa Alejandro , Aguayo Alvaro
Published: September 2018

e12501

Background: Clinical importance of the ERa36 isoform is poorly understood. It is present in 40% of the cells that lack the ERa66 and has also been linked to proliferation and invasion. It is also related to expression of phospho-src. Coincidently, phospho-src over-expression is associated to trastuzumab-resistance. We analyzed the possible link between trastuzumab-resistance and over expression of estrogen and progesterone receptors in HER2+ cell lines with trastuzumabTM chronic treatment. Methods: BT-474 and SKBR-3 cells were treated with trastuzumabTM with 4 ug/ml for 8 weeks, then 10 ug/ml for 2 weeks and with 20 ug/ml for the last 2 weeks. Protein extracts for western blot analysis where obtained from paternal cell lines and at 4, 8 and 12 weeks during treatment. Western blots were done for total and phosphorylated HER2, total and phosphorylated Src, aER and PR A/B. Densitometry analysis was applied to the western blots with the image-jTM software. Surface HER2 status was determined by flow citometry. Results: Treatment led to increase in T-HER but no changes in p-HER, T-Src and p-Src where increased, 5.27% and 18.01% respectively compared to baseline. 36KDa and 46KD aER isoforms increased with treatment. The most significant increase was in PR A expression. Western Blot for total HER2 and flow citometry for surface HER2 status revealed a link between HER2 and hormone receptor over-expression in TrastuzumabTM resistant BT-474 cells while both where absent in trastuzumabTM resistant SKBR-3 cells. Conclusions: A variety of trastuzumabTM-resistance mechanisms have been established, some of which include over-expression of p-Src. So far, none of them had been associated with expression of hormone receptors. We observed two molecular phenotypes associated to trastuzumabTM resistance: over-expression of HER2 linked to over-expression of hormone receptors in BT-474 cell and down-regulation of HER2 with no change in the hormone receptor status in the SKBR-3 cells. Our results suggest that over-expression of ERa36, ERa46 and PR A/B could represent a novel mechanism of trastuzumabTM resistance.
Efficacy of pertuzumab in combination with trastuzumab and a taxane in first-line treatment for metastatic breast cancer (MBC): A multicenter, retrospective, observational study.
Authors: Gamucci Teresa , Mentuccia Lucia , Sperduti Isabella , Gelibter Alain , D'Onofrio Loretta , Cassano Alessandra , Iezzi Laura , Botticelli Andrea , Pizzuti Laura , Moscetti Luca , Barchiesi Giacomo , Scinto Fedele , Carbognin Luisa , Cursano Maria Concetta , Foglietta Jennifer , Rossi Ernesto , Barni Sandro , Graziano Vincenzo , Magnolfi Emanuela , Vici Patrizia
Published: September 2018

e12504

Background: Pertuzumab (P) , Trastuzumab (T) and Docetaxel (D) is standard first-line treatment in patients (pts) with HER2 + metastatic breast cancer (MBC). This multicenter retrospetive observational study was performed to evaluate the activity of P and T in combination with D or Paclitaxel (Tx) in real world HER2 + MBC pts. Methods: We identified HER2 + MBC pts treated with P, T and D or Ptx optionally followed by P, T and endocrine therapy (ET) maintenance in hormone positive (HR+) BC, in 17 Italian cancer centres between 09/2012 and 08/2016. Overall Survival (OS) and Progression Free Survival (PFS) were calculated by the Kaplan-Meier product-limit method. Log-rank test was used to assess differences between subgroups. Results: 191 pts were included in our analysis. Pts characteristics: median age 54 years (range 29-80); PS 0 in 127 (67%) pts and PS 1 in 54 (28%); 107 (56%) had visceral metastases (mts), 23 (12%) only bone mts and 28 (15%) brain mts, 130 (68%) were ER/PgR +. 76 pts (40%) were metastatic at diagnosis; 148 (78) were treated with D while 43 (22%) with Tx. The ORR was 78% (CI 95% 72-84), RC 18% and RP 60%, only 10 (5%) had PD. To date, of the 54 pts treated with ET maintenance, 26% had a further improvement of response (7 pts had RC). At median follow-up of 17 months (mo) (range 6- 52), median PFS was 20 mo (95% CI 14-26) and median OS at 2 years was 80%. No differences in PFS were found for age (p = 0.92), PS (p = 0.18), receptor status (p = 0.57), visceral mts (p = 0.54) and chemotherapy (cht) type (p = 0.47), whereas number of mts site (1 vs > 1) affected PFS (28 vs 16 mo, p = 0.002). Moreover median PFS in naïve pts and in pts pretreated with only cht was 28 mo (95% CI, 20-36) and 27 mo (95% CI, 16-38) respectively, whereas in pts pretreated with T it was 12 mo (95% CI 16-38 p 0.002). In HR+ pts ET maintenance together with P and T had an impact on PFS (28 vs 15 mo, p = 0.01). Conclusions: Our analysis confirms, in real world HER2 MBC pts, the efficacy of P, T and a taxane combination in first line treatment; in this population PFS was shorter in pts pretreated with T. ET maintenance in association with P and T in HR+ pts improved PFS. Data collection is ongoing and update results will be presented.
Inter-laboratory evaluation of a novel DEPArray-HER2 FISH assay.
Authors: Gerber Amanda , Koenig Lisa , Millner Lori , Strotman Lindsay , Sero Valeria , Manaresi Nicolò , Kasimir-Bauer Sabine , Bischoff Farideh Z.
Published: September 2018

e12506

Background: Fluorescent in Situ Hybridization (FISH) is a method currently used for detection and assessment of HER2 gene amplification. Although clinical guidelines set forth by CAP/ASCO exist to ensure accuracy, limitations in HER2test results due to sample preparation, assay-conditions and tumor heterogeneity remain unresolved. We have successfully demonstrated analytical confidence in performing HER2 FISH on DEPArray™ sorted and recovered tumor cells. In this study, we aimed to evaluate inter-laboratory concordance of the DEPArray™ HER2-FISH assay. Methods: Three laboratories equipped with the DEPArray™ were designated as testing sites for this study. Positive control SKBr3 cells embedded in paraffin as well as 20 invasive breast carcinoma FFPE samples were blinded and evaluated by each of the three labs. Control and patient samples were processed through the DEPArray™ beginning with dissociation of the FFPE curls followed by single-cell image-based cell sorting to separate and recover pure distinct tumor cell populations prior to HER2 FISH analysis. Data was only obtained when ∼200 intact cytokeratin+/vimentin-/DAPI+ tumor cells from each sample were recovered and used for subsequent FISH using a standard dual-color HER2/CEP17 FISH procedure. Results: Overall, 80% concordance between DEPArray™-HER2 and conventional HER2 (6 HER2 negative and 10 HER2 positive) was observed between lab(s) and the conventional HER2 method. In each of 4 cases, a discordant HER2 result was reported by one of three sites. In three of these discordant cases, the DEPArray™ HER2 ratio was reported as amplified while the conventional result was negative. In the remaining discordant case, the converse was observed by one site; however, this case was initially evaluated 15 years ago. All three sites correctly scored the SKBr3 positive control cells. Conclusions: The results showed a high concordance rate of correct HER2 status classification. This data further supports the understanding that tissue heterogeneity can indeed give rise to discordant results that may consequently affect treatment options for patients. We demonstrate that sample preparation by DEPArray™ may aid in a more precise classification for tumor biomarker status.
A real-world retrospective study of apatinib plus chemotherapy in metastatic breast cancer.
Authors: Zhu Anjie , Yuan Peng , Wang Jiayu , Ma Fei , Luo Yang , Fan Ying , LI Qing , Zhang Pin , Xu Binghe
Published: September 2018

e12507

Background: Antiangiogenic therapy in combination with chemotherapy has shown improved clinical outcome in advanced breast cancer(ABC). Apatinib is an orally administered tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2), which exhibited objective efficacy in metastatic breast cancer(MBC). We performed a retrospective observational analysis to evaluate the efficacy and safety of apatinib plus chemotherapy in the real-world practice of patients with MBC. Methods: Patients who have failed at least one prior chemotherapy regimen for metastatic disease were included in this study. The primary endpoint was progression free survival(PFS). Secondary end points included objective response rate(ORR), clinical benefit rate(CBR), overall survival(OS) and safety. Data analysis included association between clinicopathological characteristics or treatment choice and PFS. Results: Of the 23 patients analyzed, 14(60.9%) received plant-derived anticancer agents combined therapy and 9(39.1%) combined with non-plant-derived agents. Objective response rate(ORR) was 34.7% and clinical benefit rate(CBR) reached 52.2% on last tumor assessment. With a median follow-up of 9.0 months, the estimated median PFS and OS were 5.4 months (95%CI 3.5-7.3) and 8.2 months (95%CI 4.7-11.7), respectively. Toxicities were tolerable or could be clinically managed.The most frequently observed adverse events (AEs) of all grade were hypertension, myelosuppression, hand-foot syndrome, proteinuria, fatigue and gastrointestinal reaction. The most common grade 3/4 treatment-related AEs were myelosuppression(39.1%) and gastrointestinal reaction(17.4%). Conclusions: In this retrospective observational study, combination of apatinib with chemotherapy demonstrated clinically relevant efficacy and tolerability in metastatic breast cancer.
Circulating tumor cells and genomic profiling of patients with ERBB2 mutant, HER2 non-amplified metastatic breast cancer treated with neratinib.
Authors: D'souza Anishka , Shishedo Stephanie , Spicer Darcy V. , Welter Lisa , Jiang Yuanfei , Hyman David Michael , Solit David B. , Ma Cynthia X. , Bose Ron , Cutler Richard E. , Eli Lisa , Hicks James B , Kuhn Peter , Lu Janice M.
Published: September 2018

e12554

Background: ERBB2 mutations in the absence of gene amplification are rare, with an incidence of 2-4%. Neratinib is a HER2/EGFR tyrosine kinase inhibitor being evaluated for use in ERBB2 mutated breast cancer. Neratinib has been found to have clinical activity on heavily pre-treated ERBB2 mutant breast cancer patients. We are evaluating the response and genomic profiles of 3 postmenopausal patients with metastatic ERBB2 mutant/non-amplified breast cancer receiving neratinib and fulvestrant NCT01953926, NCT01670877. Methods: Samples were collected at different points during treatment and CTCs were identified. Other representative cells were tracked but not classified as CTCs. CD45-CK+ cells with cytoplasmic and/or nuclear apoptosis were defined as CTC-Apoptotic. CD45- cells expressing little to no CK but otherwise meeting morphological criteria for CTCs are CTC-LowCK. CD45-CK+ cells with small nuclear size are CTC-SmallCK. Single CTCs will be analyzed using whole genome copy number variation to determine chromosomal alterations. Results: The patients had an average of 4.7 lines of therapy for metastatic disease before neratinib. Two had stable disease and one had progression. The patient who progressed had a rise in the number of CTCs from 37 to 52 cells/ml and drop in apoptotic cells from 5 to 0 cells/ml. Conclusions: The high CTC count of the patient who progressed may suggest more aggressive disease. The drop in the apoptotic cell count may correlate with a failure to respond to therapy. Samples have been sent for copy number variation profiling. The goal is to identify any genomic amplifications or deletions associated with clinical response and progression after targeted therapy. We hope to demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the use of fluid biopsies to monitor disease progression. [Table: see text]
Nab-paclitaxel in clinical practice: Preliminary data from the mantel study.
Authors: Garrone Ornella , Saggia Chiara , Bergnolo Paola , Beano Alessandra , Castiglione Federico , Vanella Paola , Turletti Anna , De Conciliis Enrico , Vellani Giorgio , Denaro Nerina , Bellini Elisa , Miraglio Emanuela , Merlano Marco Carlo
Published: September 2018

e12561

Background: Metastatic breast cancer (MBC) is an incurable disease. The main goals of treatment are palliation, symptoms control, preserving QoL and prolonging survival. New drugs have contributed to ameliorate the outcome of MBC patients (pts) by increasing response rates (RR) progression free survival (PFS) and, in some setting, overall survival (OS). Taxanes are the most effective drugs in the management of MBC. Nab-Paclitaxel (Nab-P), a solvent-free albumin-bound taxane with high tumor retention, showed antitumor efficacy, and limited toxicity in MBC pts. Aim of the present study is to evaluate the activity and safety of Nab-P in clinical practice. Methods: MANTEL is a retrospective, multicenter, observational study, designed to collect biological and clinical data of MBC treated with Nab-P, from its availability in Italy. Objectives of the study are PFS, correlation between response and tumor biological characteristics and safety. Results: Up to date 137 cases were collected from 9 centers. Main patients’ characteristics were: median age 58 y (32-82) including 40 pts over 65, median ECOG PS 0 (0-2), ER/PgR positive 118 pts (86.1%), Triple Negative 11 pts (8%), most common metastatic sites: bone 100 pts (73%), liver 77 pts (56.2%), soft-tissues 72 pts (52.5%), lung 38 pts (27.7%), CNS 7 (5.1%) median number of organs involved: 2 (1-5), median number of previous chemotherapy regimens for advanced disease: 2 (0-9). Preliminary results were: 4 CR (3%), 34 PR (24.8), 35 SD (25.5%), 54 PD (39.4%) and 10 NE (7.3%), CB was observed in 52 pts (37.9%). Median number of cycles administered was 5 (1-15). Six pts are still on treatment. Median PFS is 4.2+ months (0.3+ - 34). G3-4 leucopenia and neutropenia were observed in 6 (4.3%) and 11 pts (8%) respectively, anemia (all grades) in 51 pts (37.2%). 65 pts (47.4%) experienced neuropathy (G3 in 6 pts), 87 (63.5%) fatigue (G3 in 4) and 20 pts (14.6%) G1-2 arthro-myalgia. 99 pts (72.2%) received standard every 3-weeks schedule. 34 pts (24.8%) required dose reduction due to toxicity. Conclusions: Nab-P is feasible in unselected MBC pts. No concerns about toxicity in this real life population including large number of elderly and heavily pretreated pts. The study is ongoing.
Treatment patterns and associated adverse events among patients with metastatic triple-negative breast cancer.
Authors: Kaklamani Virginia G. , Schultz Neil M. , Irwin Debra E. , Fulcher Nicole , Noxon Virginia , Wu Jun , Pandya Bhavik J. , Kim Ruth , Barlev Arie , Flanders Scott
Published: September 2018

e12576

Background: Triple-negative breast cancer (TNBC) accounts for 10–20% of all breast cancers and about 4% are metastatic (mTNBC) at diagnosis. This research aims to describe treatment patterns and associated adverse events (AEs) among mTNBC patients. Methods: MarketScan Commercial Claims and Encounters and Medicare Supplemental Database, linked to an oncology EMR database, was used to identify patients with mTNBC. Demographic factors, clinical characteristics, mTNBC treatment patterns (treatment type and initial regimen), and the incidence of associated AEs (rates per 100 person-years) were tabulated. Patients seen in oncology practices between January 1, 2011 and June 30, 2015 were included in the study and were required to have continuous enrollment overlap in the administrative claims data for 6 months before the first diagnosis and throughout the variable-length follow-up period. Follow-up ended due to death, end of continuous enrollment, or end of study (whichever occurred earlier). Results: The study identified 163 mTNBC patients with a mean age of 55 years. The average length of follow-up was 569 days and 34% died during the study period. Diabetes mellitus (22%) and anemia (16%) were the most common comorbid conditions at baseline. During the follow-up period, the majority of mTNBC patients received treatment (76%); the most common first-line treatments included cyclophosphamide (60%), paclitaxel (56%), doxorubicin (52%), carboplatin (25%), and docetaxel (23%), averaging 96 days in duration. In 47% of patients, treatment ended due to a switch. Over 96% of the patients experienced at least one AE during treatment, the most common being hematological (neutropenia, leukopenia, and anemia), gastrointestinal (nausea and vomiting), and other (pyrexia, fatigue, and dyspnea) [see table]. Conclusions: Several different chemotherapy agents were used to treat mTNBC. Adverse events were common among mTNBC patients initially treated with chemotherapy; the highest incident AEs were hematological. [Table: see text]