bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive assessment of cancer stem cell like cells in prediction of pathologic complete response to preoperative dual anti–HER2 therapy for HER2–positive primary breast cancer.
Authors: Espinosa Fernandez Jose Rodrigo , Yamauchi Teruo , Imamura Chiyo K. , Yamauchi Hideko , Jinno Hiromitsu , Takahashi Maiko , Kitagawa Yuko , Nakamura Seigo , Lim Bora , Krishnamurthy Savitri , Reuben James M. , Liu Diane D , Tripathy Debu , Chen Helen X. , Takebe Naoko , Saya Hideyuki , Ueno Naoto T. 
Published: September 2018

e12123 Background: Chemotherapy for breast cancer destroys non–stem cells while sparing cancer stem cells (CSCs). In contrast, anti–HER2 therapy may eliminate resistant cells because HER2 may be a key driver of CSCs. CSC biomarkers have been found to be prognostic of poor outcome and predictive of resistance to therapy. However, there are no comprehensive studies of the impact of anti-HER2 therapies on CSC–related biomarkers. We conducted a prospective biomarker determination study of breast CSCs characterized by CD44v expression and increased aldehyde dehydrogenase 1 (ALDH1) enzymatic activity or expression. Methods: In a prospective trial (ClinicalTrials.gov: NCT01688609), 18 patients with operable primary HER2+ breast cancer (≥T2 excluding inflammatory, any N; median age of 54 yrs) were treated with preoperative anti–HER2 therapy following the NeoALTTO trial dual therapy arm regimen, with a goal of identifying novel predictive biomarkers for pCR. Proportions of tumor cells with CSC characteristics, defined as CD44v+ and ALDH1+, were estimated at baseline, at 6 weeks (after therapy with lapatinib/trastuzumab) and at 18 weeks (after therapy with lapatinib/trastuzumab and paclitaxel) to assess adaptive response. We determined changes in the quantity and characteristics of CSC–related biomarkers during preoperative therapy and correlated them to tumor response. Results: Out of 18 patients, 8 (44%) had a pCR; 5 of these 8 patients (62%) were positive for CD44v staining on tumor cells at baseline and none were positive on the 6–week biopsy. In contrast, 6 of the 10 patients without pCR exhibited persistent levels, or enrichment of CD44v proportion and expression at 6 and 18 weeks (p = 0.0128). ALDH1 expression and other biomarkers were not statistically significant predictors of pCR. Conclusions: Enrichment of CD44v+ tumor cells after double anti–HER2 therapy may predict poor response to dual anti–HER2 therapy with cytotoxic chemotherapy. A second biopsy after the start of preoperative therapy may reflect biological changes useful for the guidance and application of therapeutic strategies for patients with HER2+ breast cancer. Clinical trial information: NCT01688609.
Impact of neoadjuvant HER2-directed therapy on HER2 status in breast cancer.
Authors: Manguso Nicholas , Johnson Jeffrey , Basho Reva Kakkar , McArthur Heather L. , Tanaka Hisashi , Giuliano Armando E. 
Published: September 2018

e12130 Background: Neoadjuvant chemotherapy (NAC) with HER2-directed therapy has become standard-of-care for most women with potentially curable HER2-positive (HER2+) breast cancer and is associated with a high pathologic complete response (pCR) rate. The HER2 status of residual disease after NAC is not well characterized and could potentially inform clinical decisions about additional systemic therapy. We describe tumoral HER2 status before and after NAC with HER2-directed therapy. Methods: An institutional database was screened to identify patients with stage 1-3 HER2+ breast cancer by fluorescence in situ hybridization (FISH) and/or immunohistochemistry (IHC) who received NAC with HER2-directed therapy followed by resection between 2011 and 2015. Clinicopathologic data was collected. Change in HER2 status by FISH and IHC following treatment was described. Results: 99 patients were identified. Median age was 49 years (range 26-85). Pre-treatment median HER2/CEP17 copy number ratio (CNR) for all tumors was 6.3 (range 1.9-20.7) by FISH and 84 (84.8%) tumors were IHC 3+. 44 (44.4%) patients achieved a pCR. Of the 55 patients with residual disease, 35 had sufficient residual tumor to evaluate HER2 status and 14/35 (40%) were HER2- by FISH and IHC (table). Tumors converting from HER2+ to HER2- had lower pre-treatment median HER2 copy numbers (11.9, range 4.6-22) compared to tumors that remained HER2+ (18.3, range 5.1-48.6; p=0.04) after neoadjuvant therapy. Additionally, pre-treatment median HER2/CEP17 CNR was lower among tumors that converted from HER2+ to HER2- (3.0, range 2.2-8.2) compared to those remaining HER2+ (6.8, range 2-15.7; p=0.02). Conclusions: While pCR rates are high with NAC and HER2-directed therapy, many patients still have residual tumor. In this cohort, 40% of patients with evaluable residual disease after NAC had HER2+ tumors that became HER2-. HER2 conversion was associated with lower pre-treatment HER2 copy numbers and HER2/CEP17 CNR. Conversion from HER2+ to HER2- in patients undergoing neoadjuvant therapy may have clinical significance and biological implications. [Table: see text]
Obesity and survival in the neoadjuvant breast cancer setting: Role of tumor subtype and race.
Authors: Liu Ying , Catanese Benjamin Peter , Saraf Anurag , Lee Shing , Zhang Yuan , Connolly Eileen , Kalinsky Kevin 
Published: September 2018

e12136 Background: Obesity may adversely influence survival in breast cancer; however, studies are conflicting and limited in the neoadjuvant setting. Results may also vary by tumor subtype and race/ethnicity. Our study seeks to examine associations between obesity and survival in women receiving neoadjuvant chemotherapy (NAC) and the role of tumor subtype and race/ethnicity. Methods: In a retrospective review of women with operable invasive breast cancer administered Adriamycin/Taxane-based NAC at a single intuition from 2004-2016, we identified n = 273 women with completed BMI data at diagnosis. Obesity was defined as body mass index (BMI) > = 30. We assessed associations between obesity and progression-free survival (PFS), using STEEP criteria, and overall survival (OS), using all-cause mortality, both overall and stratified by tumor subtype in three groups: Hormone Receptor Positive (HR+)/HER2- (n = 135), HER2+ regardless of hormonal status (n = 94), and Triple Negative Breast Cancer (TNBC) (n = 44), examining race/ethnicity (Non-Hispanic White, Black and Hispanic) in each subtype. Results: There were 60 events and 33 deaths observed. Overall, obesity was associated with worse PFS (HR1.71 95% CI 1.03-2.85, p = 0.04) and a trend towards worse OS (HR 1.70 95% CI 0.86-3.37, p = 0.13). In HR+/HER2- disease, there was an interaction between obesity and hormonal therapy. In those receiving only tamoxifen (n = 35), obesity was associated with worse PFS (HR 2.96 95% CI 1.02-8.6, p = 0.047) and OS (HR 14.3 95% CI 1.67-123.1, p = 0.015). In those receiving an aromatase inhibitor (AI) (n = 96), there was no association between obesity and survival, p > 0.05. In TNBC, obesity was associated with worse PFS (HR 2.62 95% CI 1.03-6.66, p = 0.043) and OS (HR 3.00 95% CI 0.95-9.51, p = 0.062). In HER2+ disease, obesity was associated with worse PFS (HR 3.37 95% CI 0.97-11.72, p = 0.056) but not OS (HR 1.35 95% CI 0.22-8.19, p = 0.75). Race/ethnicity was not significantly associated with survival in any tumor subtype, and there were no interactions between race/ethnicity and obesity with survival. Conclusions: Obesity negatively impacts survival in all tumor subtypes, including TNBC, and may be influenced by hormonal therapy class in HR+/HER2- disease.
From the CLEOPATRA study to real life: An observational study from 11 Italian Centres; Preliminary report from the G.O.N.O. SUPER trial.
Authors: Garrone Ornella , Saggia Chiara , Beano Alessandra , Cicchiello Federica , Milani Andrea , Bertolini Ilaria , Coltelli Luigi , La Verde Nicla Maria , Collovà Elena , De Conciliis Enrico , Pedani Fulvia , Vandone Anna Maria , Donadio Michela , Cazzaniga Marina Elena , Michelotti Andrea , Merlano Marco Carlo 
Published: September 2018

e12510 Background: Approximately 20% of breast cancers (BC) are HER-2+. Trastuzumab (T) has substantially improved the outcome, both in early and in advanced settings, in HER-2+BC. Pertuzumab (P), combined with T and taxanes, ameliorated progression free survival (PFS) and overall survival (OS) in the phase III CLEOPATRA study. In order to verify the results of the trial in unselected patients (pts), we performed a multicenter, retrospective-prospective, observational study, in HER-2+ metastatic BC (MBC) pts. Methods: We analyze the outcome of all HER-2+ MBC pts treated with P+T and taxanes, as first line therapy since the availability of P in Italy, at 11 general and university hospitals. Results: Up to February 1stdata from 103 HER-2+ MBC pts were recorded. Main pts’ characteristics were: median (M) age 52 y (28-78), m ECOG PS 0 (0-2), ER/PgR positive 68 pts (66%). Most common metastatic sites: liver 51 pts (49.5%), bone 64 pts (62.1%), lung 26 pts (25.2%). Thirty pts (29.1%) had bone and soft tissue disease only; 78 pts (75.7%) had metastatic disease on presentation. m number of metastatic sites was 3 (1-7); 25 pts (24.3%) received neo/adjuvant chemotherapy (CT) + T and 36 pts (34.9%) adjuvant endocrine therapy; 71 pts (69%) and 32 pts (31%) received docetaxel (D) and paclitaxel (P) respectively. m number of CT cycles was 6 for both drugs (D range 3-12; P range 1-18).At the time of the present analysis 12 pts are still on CT and 78 on maintenance; response is available for 91 pts and ORR is 80.2% (22 pts and 51 pts obtained CR and PR respectively), 6 pts experienced PD during CT. Median PFS is 13.9 months (1.5+ - 33.8+).Among hematological toxicities leucopenia (any grade) was recorded in 29 pts (28.1%), g 3 febrile neutropenia in 6 pts (5.8%). No change of left ventricular ejection fraction (LVEF) was recorded during CT; 4 pts interrupted maintenance P due to drop in LVEF and 1 due to rash. Onicopathy, nausea, alopecia, rash and arthro-myalgia were the most common non-hematological toxicities. Conclusions: Our preliminary results highlight the activity and the safety of the combination of CT plus P and T in unselected HER2+ MBC patients. The study is ongoing and updated results will be presented.
Characteristics of HER2 3+ metastatic breast cancer patients with long-term benefit of trastuzumab.
Authors: Tomasevic Zoran , Tomasevic Zorica , Minic Ivana , Kolarevic Daniela 
Published: September 2018

e12523 Background: Because there is no cumulative dose, trastuzumab could be given until disease progression. However, characteristics of patients with long term benefit of trastuzumab treatment are seldom reported. Methods: Trastuzumab become available for HER2 3+ MBC at November 2005 at the Institute for Oncology and Radiology of Serbia. Since then, we have registered 42 patients with HER2 3+ MBC and/or inoperable loco-regional recurrent BC treated with first line trastuzumab for at least 24 months (range 24-123+). Results: Median age was 53 years (range 35-76). 30/42 patients (71%) had ER/PR positive BC. MBC was initial presentation in 14 patients (33%), and as relapse in 28 (67%) patients. Only 7/28 (25%) patients received neoadjuvant/adjuvant trastuzumab, therefore majority have been trastuzumab naive (83.3%). Metastases were present in the liver (9), lungs (9), bones (16), soft tissue (6), CNS (1), while 20 (48%) patients had multiple metastatic sites. After antracyclines based chemotherapy, patients have been treated with first line weekly taxane concurrently with three weekly trastuzumab. After taxanes (up to 24 doses), trastuzumab was continued +/-hormonal therapy. Objective response was achieved in 29 (69%) patients with 17 patients (40%) achieving complete response. Median duration of response was 32+ months; 11 patients are still in remission 5 years after trastuzumab initiation. The longest complete remission duration is 123+ months, in patient with initially inoperable BC and solitary cerebellar metastasis. During observational period 10 patients stopped trastuzumab predominantly because of disease progression (8/42 19%) and 2 (4.8%) because of decreased ejection fraction (EF≤ 50%) that occurred as a rather late effect, after 34 and 49 months of continuous trastuzumab treatment. Three patients are lost from follow-up (7%); 39 (93%) patients included in this analysis are alive, still receiving trastuzumab for median 37 cycles (range 29-172+). Conclusions: A subgroup of patient with HER2 3+ MBC has a long-term benefit of trastuzumab treatment. In this analysis majority (71%) had also ER/PR positive MBC and majority have not been treated with neoadjuvant/adjuvant trastuzumab (83.3%).
Incidence and risk of neutropenia with palbociclib in patients with cancer: A systematic review and meta-analysis.
Authors: Mao Yan , Lu Janice , Wang Haibo , Nie Gang 
Published: September 2018

e12530 Background: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 and has improved the progression-free survival of estrogen receptor positive, metastatic breast cancer (MBC). Its application in other cancers is also undergoing clinical evaluation. Neutropenia, especially high grade (grade 3 or 4), is one of the major side-effects of palbociclib, and the incidence was reported too vary in different studies. In order to better understand the overall risk of palbociclib associated neutropenia, we conducted a systematic review and meta-analysis. Methods: We conducted a systematic literature search (including Medline, Web of Science to November, 2016 and abstracts presented at the ASCO annual meetings from 2009 to 2016). Eligible studies include prospective clinical trials of patients with cancer treated with palbociclib on a 125mg daily 3/4 week schedule and have available data on neutropenia. The incidence and relative risk (RR) of neutropenia were calculated using a random-effects or fixed-effects model, depending on the heterogeneity of the included studies. Results: Eight studies published between 2012 and 2016 included a total of 1515 patients with cancer were eligible for analysis. For patients treated with palbociclib, the overall incidence of all-grade and high grade neutropenia were 77.4% (95% CI 70.9-82.8%) and 60.9% (57.8–63.8%), respectively. Surprisingly, the incidence of neutropenia was significantly different between MBC patients and non-MBC patients (all grade: RR 1.26 [95% CI 1.01–1.56], p = 0.041; high-grade: RR 1.57 [1.23–2.00], p = 0.000) who received palbociclib. Palbociclib was associated with a significantly increased risk of all-grade neutropenia in patients with cancer with an RR of 15.03 (10.17–22.21, p < 0.001) compared with controls. Conclusions: Patients with cancer who received palbociclib have a significant risk of developing neutropenia, especially MBC patients. It is strongly recommended to monitor these patients who are treated with palbociclib to adjust dose, treatment intervals, and avoid infections.
Dermatologic adverse events in breast cancer patients receiving endocrine therapies.
Authors: Freites-Martinez Azael , Belum Viswanath Reddy , Geller Shamir , Skripnik Anna , Ciccolini Kathryn , Shapiro Jerry , Kitts Sarah , Goldfarb Shari Beth , Lacouture Mario E. 
Published: September 2018

e12533 Background: Endocrine therapies are known to cause adverse events including hot flashes, arthralgias, and dyspareunia. Dermatologic adverse events (dAE), including alopecia are infrequently reported, despite their potential impact on quality of life (QoL). This study aims to characterize endocrine therapy-related dAE including alopecia, acne, xerosis, and onychodystrophy. Methods: A retrospective chart review (2005-2015) of patients referred to the dermatology service for dermatologic conditions developing during endocrine therapies was performed. Relevant data was abstracted from each patient’s medical record including demographics, primary cancer diagnosis, and dAEs by grade (CTCAE v4.03). The psychosocial impact of alopecia was assessed in a subset of patients using a QoL questionnaire (Hairdex), which includes the following domains: ‘emotions’, ‘functioning’, ‘symptoms’, ‘stigmatization’ and ‘self-confidence’. Results: A total of 74 breast cancer patients treated with endocrine therapies were included (median age 62yrs. [range, 34-85]). Alopecia was the reason for a dermatologic consultation in all patients, and was attributable to aromatase inhibitors (AI) in 49 patients (66.2%) and tamoxifen in 22 (29.3%). The mean duration of treatment at the time of alopecia diagnosis was 24 months (SD ±14.3). In 93.2% of the patients, alopecia was grade 1 in severity, and in 6.8% it was grade 2 (the latter was attributable to AIs only). All grade xerosis was identified in 34 (45.9%), onychodystrophy in 21 (28.4%) and acne in 9 patients (12.2%). In patients who completed the Hairdex questionnaire (n = 44), a high ‘emotions’ (52.6, p < 0.05) and ‘stigmatization’ (46, p < 0.05) domains score were found, while ‘symptoms’ (22.1, p < 0.05) and ‘functioning’ (24.5, p < 0.05) domains score were lower. Conclusions: Endocrine therapies are associated with alopecia and dAEs, with a greater severity with AIs. A psychosocial impact on emotions was seen in patients with alopecia. Moreover, xerosis, acne, and onychodystrophy were also observed. These findings underscore the need for increased attention to dAE in breast cancer patients receiving endocrine agents, in order to maintain quality of life and adherence to therapies.
Safety results of the Canadian Expanded Access Program (EAP) of palbociclib (PAL) plus letrozole (L) in postmenopausal patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) deemed appropriate candidates for first-line (1L) endocrine therapy (ET) with L.
Authors: Joy Anil A. , Verma Shailendra , Provencher Louise , Theall Kathy Puyana , Lu Dongrui (Ray) , Dequen Florence , Rayson Daniel 
Published: September 2018

e12534 Background: In the PALOMA-2 study, 1L PAL+L prolonged progression-free survival in women with estrogen receptor-positive/HER2- ABC vs placebo + L (hazard ratio 0.58; P< 0.001). Here we assess a cohort of Canadian pts treated with 1L PAL+L for ABC in an EAP study (NCT02142868). Methods: This was an open-label, single-arm study of US and Canadian postmenopausal women (N = 337) with HR+/HER2- ABC for whom 1L ET with L was deemed appropriate. The primary objective was to allow pt access to PAL in combination with L. PAL (125 mg/d orally [3 wk on, 1 wk off]) was administered with L (2.5 mg orally QD) until PAL was commercially available. Secondary objectives included safety and patient-reported outcomes (PROs). Results: 96/97 (99%) treated/enrolled Canadian pts were assessed for safety and PROs (treated pt characteristics: median age 62.5 y, white/Asian [89%/7%], metastatic sites bone/lung/liver [71%/25%/17%], ECOG PS 0-1/2 [93%/7%], 89% with prior systemic anticancer treatment [tx]). Median exposure was 4 x 28 d cycles of tx, and the median average PAL dose was 125 mg/d. All-causality treatment-emergent adverse events (AEs) were reported in 100% pts; 68% had grade 3/4 events, the most common events were neutropenia (61%), infections (3%), and alanine aminotransferase increase (3%). Grade 4 neutropenia and grade 3 febrile neutropenia were reported in 2% and 1% of pts, respectively. Due to AEs, PAL was temporarily discontinued in 59% and 31% had ≥1 dose reduction. The main reasons pts permanently discontinued from the study were sponsor study termination, 77%; objective progression, 11%; and AE related/unrelated to study drug, 6%/2%. All EQ-5D questions were completed by 96% pts at baseline and 85% by end of tx (EOT). At EOT, the median EQ-5D index and the EQ visual analog scale scores were not significantly changed from baseline. Conclusions: A safe and tolerable profile was observed for PAL+L in 1L treatment of Canadian pts with HR+/HER2− ABC, consistent with other studies. Sponsor Pfizer Clinical trial information: NCT02142868.
Real world experience with exemestane and everolimus for advanced HR-positive breast cancer.
Authors: Wang Ying , Le Dan , Camateros Pierre , Lohrisch Caroline A. 
Published: September 2018

e12538 Background: BOLERO-2 demonstrated a significant progression free survival (PFS) advantage for EvEx compared to Ex alone in the treatment of metastatic hormone receptor positive breast cancer (HP-MBC) following failure with aromatase inhibitor (AI) in menopausal patients. Benefits and harms reported in clinical trials do not always mirror real life, thus we examined the frequency of dose modifications for toxicity and PFS in a real-world population. Methods: Women with HP-MBC started on EvEx between Dec. 2, 2013 and Nov. 1, 2015 in any one of five cancer centres in British Columbia, Canada were identified via the provincial pharmacy database. Clinical and prior treatment details, adverse events, and outcomes were compared to those of the BOLERO-2 study participants. Results: We identified151 patients treated with EvEx: median age was 53 (range 25 – 85), and 60 (40%) were ≤49. ECOG performance status was 0-1 in 122 (81%) and 2-3 in 29 (19%). 135 (89%) received prior treatment for MBC, which included non-steroidal AI in 117 (87%) and chemotherapy in 74 (55%). 94 (62%) received EvEx as 3rd line treatment and beyond. Median follow-up was 714 days (range 10 – 1127); 66 (44%) were alive at time of analysis. Dose reductions, interruptions and discontinuations of everolimus due to toxicity occurred in 32%, 31%, and 30%, respectively, higher than reported in BOLERO-2. Median PFS was 6.1 months (95% CI: 4.9 – 7.7) in our cohort, similar to that of the investigator assessed EvEx arm of BOLERO-2. Majority, 52%, of dose reductions/interruptions occurred within the first month of treatment initiation. Conclusions: We observed similar PFS forEvEx in a real world population compared with BOLERO-2. Dose interruptions and reductions were frequent, but may have enabled patients to tolerate therapy for longer. Discontinuation rates for toxicity were high and may limit the efficacy of the combination in the real world. Recent findings of primary prophylaxis against mucositis may help enhance continuation and dose maintenance (Beck et al. JCO 2016). Alternately, starting at a lower dose of Ev and increasing to tolerance may be worth exploring, as despite higher rates of dose modifications, our PFS rate was similar to that in BOLERO-2.