bluuebunny/crossref_metadata_2025 huggingface dataset:
SWOG S1400F (NCT03373760): A phase II study of durvalumab plus tremelimumab for previously treated patients with acquired resistance to PD-1 checkpoint inhibitor therapy and stage IV squamous cell lung cancer (Lung-MAP Sub-study).
Authors: Leighl Natasha B. , Redman Mary Weber , Rizvi Naiyer A. , Hirsch Fred R. , Mack Philip C. , Schwartz Lawrence Howard , Wade James Lloyd , Irvin William Johnson , Reddy Sreekanth , Crawford Jeffrey , Bradley Jeffrey D. , Stinchcombe Tom , Ramalingam Suresh S. , Miao Jieling , Minichiello Katherine , Gandara David R. , Herbst Roy S. , Papadimitrakopoulou Vassiliki , Kelly Karen
Published: May 2020

9623

Background: The Lung Cancer Master Protocol (Lung-MAP) is designed to evaluate novel targeted therapies in patients with advanced squamous lung carcinoma. In the S1400F sub-study (non-match), we tested whether combined CTLA-4 and PD-1 inhibition with durvalumab plus tremelimumab (D+T) could overcome primary or acquired resistance to anti-PD-(L)1 therapy. Response, progression-free (PFS) and overall survival, and safety in the acquired resistance cohort are reported herein. Methods: Patients with previously treated squamous lung carcinoma, performance status (PS) 0-1, and adequate organ function that developed disease progression after ≥24 weeks of anti-PD-(L)1 monotherapy were eligible. Prior severe immune-related toxicities, intervening systemic therapy and combination chemo-immunotherapy were not permitted. Patients received D1500 mg + T75 mg IV q28 days for 4 cycles then D maintenance until disease progression. The primary endpoint was best objective response (RECIST 1.1). Interim analysis for futility was planned after 20 patients evaluable for response were enrolled. If no responses were observed, the cohort would stop enrolment. Results: 30 eligible patients were accrued to the acquired resistance cohort. Median age was 68 years, 60% of patients were male, 33% PS 0 and had received a median of 2 prior lines of therapy (maximum 4). Best response to prior anti-PD-(L)1 therapy was CR/PR/SD in 3/7/20 patients, with a median duration of anti-PD-(L)1 therapy of 8.6 months (5.2-30.4). No objective responses were seen with D+T; 47% had SD as best response. Median PFS was 2.0 months (95% CI 1.6-2.9) and survival 7.5 months (95% CI 5.3-8.7). Among the 14 patients with SD as best response, the median PFS calculated from first disease assessment is 2.8 months (95% CI: 1.4-3.9). Grade≥3 adverse events at least possibly related to protocol therapy were seen in 10/30 patients. These include 1 treatment-related death due to pneumonitis and 1 death not otherwise specified. Other adverse events include grade 3 confusion (1), dehydration (2), diarrhea (3), encephalopathy (1), weakness (1), hyperglycemia (1), hypoxia (1), lymphopenia (1), nausea, (1), neutropenia (1), thrombocytopenia (1), rash (1), vomiting (1), grade 4 dyspnea (1), leucopenia (1) and lymphopenia (1). Conclusions: D+T did not demonstrate activity in patients with acquired resistance to PD-1 checkpoint inhibitors and pretreated advanced squamous lung carcinoma. Clinical trial information: NCT03373760 .
Efficacy and safety of pegfilgrastim in prophylaxis of chemotherapy-induced neutropenia in breast cancer patients.
Authors: Xia Wen , Xu Fei , Yuan Zhongyu , Xu Ruilian , Jiang Yi , Wu Zhiyong , Lu Qianyi , Zheng Qiufan , Hong Ruoxi , Jiang Kuikui , Huang Jiajia , An Xin , Bi XiWen , Hong Yun , Pang Danmei , Zhang Anqin , Wang Xianming , Zhang Qing , Zhang Haibo , Wang Shusen
Published: May 2020

e12511

Background: The role of secondary prophylaxis with pegfilgrastim (brand name: Jinyouli) in Chinese breast cancer patients has not been fully evaluated. We assessed the efficacy and safety of pegfilgrastim in secondary prophylaxis of chemotherapy-induced neutropenia in breast cancer patients. Methods: In the open-label, single-arm, multicenter trail, 319 patients were enrolled. Breast cancer patients who developed grades 3/4 neutropenia in the previous chemotherapy cycle were given a fixed dose of subcutaneous pegfilgrastim, 24-48 hours after receiving the same chemotherapy regimen in the subsequent cycle. A dose of 6mg/cycle was given to patients weighed ≥45kg, and a dose of 3mg/cycle was given to patients weighed <45kg. The primary end point was the incidence of grade 3/4 neutropenia and secondary end point was the incidence of febrile neutropenia (FN). Results: In patients who received prophylactic pegfilgrastim, the incidence of grade 3/4 neutropenia was reduced to 12.53% (95% CI, 9.1 to 16.7) and the incidence of FN was reduced from 6.58% (95% CI, 4.1 to 9.9) in the screening cycle to 0.94% (95% CI, 0.2 to 2.7)(Table). Among the 40 patients who still developed grades 3/4 neutropenia after receiving pegfilgrastim, the absolute neutrophil count (ANC) was not significantly different between patients with (n=10) or without (n=30) additional filgrastim treatment. The most common adverse events (AEs) associated with pegfilgrastim were bone pain and myalgia, which were prevalent in 10% to 15% of the patients. However, both AEs were mild or moderate (grades 1/2). Conclusions: Prophylactic administration of pegfilgrastim is effective and safe in reducing the risk of grades 3/4 neutropenia and FN in breast cancer patients after receiving chemotherapy. [Table: see text]
Predictors of adjuvant radiation therapy in the treatment of male breast cancer and its impact on outcomes: A propensity matched analysis.
Authors: Bakalov Veli , Jayakrishnan Thejus Thayyil , Abel Stephen , Hilton Christie , Rusia Bindu , Wegner Rodney E.
Published: May 2020

e12516

Background: Male breast cancer (MBC) accounts for 1% of all breast cancers and there is a paucity of data on factors impacting the treatment strategies and outcomes. We hypothesized that adjuvant radiation therapy (Adj-RT) may improve survival outcomes and sought to examine predictive factors for Adj-RT receipt. Methods: We queried the National Cancer Database (NCDB) for patients with stages I-III MBC treated with surgery (breast conservation surgery- BCS or mastectomy-MS) within 180 days of diagnosis (years 2004-2015). Multivariable logistic regression identified predictors of adjuvant radiation therapy receipt. Multivariable Cox regression evaluated predictors of survival. Propensity matching for adj-RT accounted for indication biases. Results: We identified 6,217 patients meeting the eligibility criteria (1457 BCS vs. 4760 MS). The majority of patients were white (85%) and within the age range of 50-80 years (74%). Although Adj-RT was omitted for 30% of BCS patients, the utilization was higher compared to MS (OR=26, p-value=0.001). The predictors of Adj-RT use were – African American race, higher stage, higher grade, presence of lymphovascular invasion and ER/Her-2 positivity for the entire cohort and higher age, urban location and higher income for BCS. Adj-RT was associated with lower mortality in the propensity matched model (overall HR for BCS=0.28, p-value<0.001; overall HR for MS=0.62,p-value=0.001) and is shown in the table. Conclusions: This study demonstrates there may be an association between decreased mortality and Adj-RT in MBC undergoing BCS. Although this implies that Adj-RT should be routinely delivered, it appears to be omitted frequently and its use requires further investigation. The study also suggests a benefit to Adj-Rt after MS for stage-III MBC. [Table: see text]
Factors associated with the use of adjuvant neratinib in stage I-III HER2-positive breast cancer.
Authors: Stoen Ericson , Kagihara Jodi , Kabos Peter , Fisher Christine M. , Diamond Jennifer Robinson
Published: May 2020

e12517

Background: HER2-positive breast cancers have a higher risk of recurrence, though systemic chemotherapy in combination with HER2-targeted agents significantly reduces this risk. Neratinib (N) is a small molecule inhibitor of HER2 that was shown in the ExteNET trial to improve invasive disease-free survival in patients with stage II-III breast cancer. The purpose of this study was to investigate factors associated with the use of adjuvant N in patients with HER2-positive breast cancer treated in the University of Colorado Health system (UCH). Methods: We performed a retrospective chart review of women diagnosed with stage I-III breast cancer who received adjuvant trastuzumab (T) between July 2016 and April 2019 at UCH to coincide with the approval of N in July 2017. We collected patient demographics, baseline characteristics, and cancer treatments. Results: A total of 350 patients were identified who received adjuvant T for treatment of stage I-III HER2-positive breast cancer within the inclusion timeframe. 234 patients (74.1%) were either ≥ T2 and/or node-positive at diagnosis as in the inclusion criteria of ExteNET. Of these, only 31 (13.3%) were prescribed adjuvant N within 2 months of completing adjuvant T. 81 (34.6%) received adjuvant pertuzumab (P) in addition to T. Of those who received N, 78.8% were ≥ T2 and 78.8% were node-positive. The average age of those receiving N was 49.3 versus 54.9 years in those not receiving N. Hormone receptor (HR)-positive disease was noted in 72.7% of those receiving N and 68.6% in those who did not (P = 0.624). The vast majority (97.0%) of patients were prescribed diarrheal prophylaxis with N. Patients receiving adjuvant N were less likely to have had a pathologic complete response (pCR) following neoadjuvant chemotherapy than those who did not receive N (23.1% versus 51.0%, P = 0.008). Of those who received N, 18 (54.5%) were treated at an academic hospital, where 34.2% of the total studied patient population was treated. Conclusions: The use of adjuvant N in patients with ≥ T2 or node-positive HER2-positive breast cancer in our patient population was low. Patients who did receive adjuvant N were more likely to have residual disease following adjuvant chemotherapy and be treated at an academic hospital. Despite the greater benefit of adjuvant N in HR-positive HER2-positive breast cancer in ExteNET, HR status did not correlate with the use of adjuvant N in our study. Trials assessing the additional benefit of adjuvant N in patients receiving adjuvant P or trastuzumab emtansine will likely be required prior to widespread use of adjuvant N.
A novel approach for 21-genes testing associated with prognosis in Chinese patients with ER-positive/HER2-negative breast cancer: A real-world study.
Authors: Zeng Yinduo , Li Qian , Wu Jiannan , Deng Heran , Wang Ying , Wu Wenjing , Zhao Jianli , Dinglin Xiao-Xiao , Qin Tao , Liu Qiang , Su Fengxi , Jia Weijuan , Yao Herui
Published: May 2020

e12528

Background: We previously reported a Chinese version of 21-genes Recurrence Score (RS) provides reduction chemotherapy prescription in patients with ER-Positive/HER2-Negative node negative breast cancer, while Oncotype Dx was hardly to be reached. However, the impact on clinical outcome was not mentioned. Herein, we explored whether this 21-genes recurrence score (RS) impacted on prognosis in patients with this molecular subtype of breast cancer. Methods: From Jan 2013 to Aug 2018, 378 patients with ER-Positive/HER2-Negative early stage breast cancer were enrolled. All patients received a Chinese version of 21-genes RS test, which is a new method using RNA extracted from formalin-fixed paraffin-embedded tissue performed by SurExam Campany, Guangzhou, China. . The RS score for each patient was calculated based on expression level of 21-genes used in a prosperctively defined algorithm and calculate a recurrence score range from 0 to 100 and divided three risk groups according to TAILORs study.Distant metastases-free survival (DMFS) were correlated with the 21-genes RS by Kaplan-Meier (log-rank method), and Cox regression. Multivariable logistic regression was performed to determine factors correlated with RS testing and receipt of a high-risk RS. Results: Median patient age was 46 years (18 to 77 years). The Chinese version of 21-gene RS was generated for 378 patients: 61 (16.1%) low risk ( < 11), 241 (63.8%) intermediate risk (11 to 25), and 76 (20.1%) high risk (≥ 26). At a median follow-up of 40 months, the 4-year-rate of estimated DMFS was 100%, 98.7% and 92.9% in low risk, intermediate risk and high risk groups. Meanwhile, there was no difference in RFS among three risk groups. For all patients, 21-gene RS was associated with DMFS ( P = .021). In multivariable Cox regression models, 21-gene RS was independently prognostic factor of DMFS (hazard ratio, 5.375; 95% CI, 1.00 to 28.84; P = .05). Tumor size (>2cm vs ≤2cm, OR = 2.31, P = .005), high grade ( OR = 2.15, P = .013), ki67 index ( > 14% vs ≤14%, OR = 4.24, P = .002), progesterone receptor expression ( < 20% vs ≥20%, OR = 5.07, P < .001) were predictor of high risk of RS. Conclusions: The Chinese version of 21-genes RS is independently prognostic factor for DMFS patients with ER–positive/HER2-negative node negative breast cancer. Future study was needed to explore the impact of 21 gene RS on long-term prognosis.
Usage and factors associated with adjuvant bisphosphonate therapy among postmenopausal women diagnosed with early-stage breast cancer.
Authors: Panuganty Veera Durga Sravanthi , Lakkunarajah Suganija , Shanmuganathan Sumugan , Black Morgan , Nasreen Sharifa , Karp Igor , Vandenberg Theodore A. , Raphael Jacques , Fernandes Ricardo , Blanchette Phillip S.
Published: May 2020

e12532

Background: Early Breast Cancer Trialist Collaborative Group meta-analysis suggested significant reduction in bone metastasis and breast cancer mortality among post-menopausal women diagnosed with early breast cancer when treated with an adjuvant bisphosphonate. Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline published in 2017, recommends the use of an adjuvant bisphosphonate in postmenopausal women who are candidates for adjuvant systemic therapy. Our goal was to evaluate trends and factors associated with adjuvant bisphosphonate usage since the guideline’s publication. Methods: This study is a retrospective review of postmenopausal women treated for early breast at the London Regional Cancer Program from 2017-2018. Univariate and a multivariable logistic regression models were used to investigate factors potentially associated with adjuvant bisphosphonate use including age, stage, grade, estrogen receptor, progesterone receptor, HER2 receptor status and previous use of adjuvant chemotherapy. The percentage of patients offered, receiving and declining therapy was also recorded and the time interval from surgery to start of bisphosphonate therapy (< 6 months, 6-12 months or >12 months). Results: We identified 286 postmenopausal breast cancer patients, of whom 75 (28%) received adjuvant bisphosphonate therapy. In our multivariable model, cancer stage [odds ratio (OR) stage II vs. I=2.26, 95% confidence interval (CI) 1.08-4.74) and OR Stage III vs. I=4.94, 95% CI 1.84-13.17] and previous use of adjuvant chemotherapy (OR=2.76, 95%CI 1.37-5.55) were significantly associated with adjuvant bisphosphonate use. Among 133 patients who received adjuvant systemic chemotherapy, 51% were offered adjuvant bisphosphonate and of these 81% patients accepted therapy. Among a total of 75 patients receiving adjuvant bisphosphonate therapy 19% initiated therapy within 6 months of surgery, 48% within 6-12 months of surgery, and 33% after 12 months following surgery. Conclusions: Stage and previous use of chemotherapy were significantly associated with adjuvant bisphosphonate therapy. Our study observes the potential underutilization of adjuvant bisphosphonate therapy and possible need to start treatment earlier in some patients. Further education and awareness of the clinical practice guidelines regarding adjuvant bisphosphonate therapy may be warranted and additional population-based study investigating treatment patterns and real-world effectiveness.
Effects of cardioprotective medications on breast cancer survival: A retrospective study from an academic center from Southern Illinois.
Authors: Regmi Manjari Rani , Parajuli Priyanka , Cheema Asad , Lara Garcia Odalys Estefania , Tandan Nitin , Maini Ruby , Sahib Hamsa , Mirihagalle Noupama , Koester Cameron , Niaz Zurain , Abedrabo Sabree , Johnson Alexander , Ibrahim Abdisamad M. , Bhandari Bishal , Delfino Kristin , Robinson Kathy , Desai Meghna R. , Kulkarni Abhishek
Published: May 2020

e12540

Background: Cardiovascular disease is one of the leading causes of deaths in breast cancer patients. Pre-existing cardiac conditions and cardiovascular risks associated with chemotherapy affect the overall mortality of these patients. Cardio protective medications like beta-blocker, ACEIs, ARBs, statin, and potassium-sparing diuretics have shown to increase the survival odds. In our study, we investigated the survival of breast cancer patients who were on cardio protective medications. Methods: Our retrospective cohort study included breast cancer patients from Simmons Cancer Institute, Springfield, Illinois from January 1st, 2014 to December 31st, 2017. The first step comprised of screening patients using ICD code of breast cancer. Next, a retrospective chart review led to selecting eligible patients with biopsy proven breast cancer diagnosis within the aforementioned dates. We excluded patients who were diagnosed outside the give time frame. Data on age, gender, medical comorbidities, medications, and survival status were also collected. Comparisons between categorical variables were compared with the Chi-Squared test. Survival curves were estimated using Kaplan-Meier methodology and analyzed with a log rank test. Predictors of survival are assessed with Cox proportional hazards regression analyses. Results: Screening using ICD codes resulted in 1618 patients. Of those, 478 had biopsy proven diagnosis within the dates mentioned. 301 out of 478 patients were on some kind of cardio protective medication (88 on beta-blockers, 73 on ACEIs, 41 on ARBs, 87 on statins, and 12 on potassium sparing diuretics). We looked into survival analysis in patients on different cardioprotective medications. ARBs and potassium sparing diuretics showed increased likelihood of survival as the hazard ratio (HR) was found to be 0.512 (95% Cl: 0.068-3.832, p-value:0.0919) and HR 0.390 (95% CI: 0.130-1.66, p-value:0.514) respectively. In contrast, other cardio protective medications showed decreased trends for survival. The HR of beta blocker was 1.734 (95% CI: 0.508-5.919, p-value: 0.379) and of ACEIs was 1.350 (95% CI: 0.395-4.613, p-value: 0.632). Similarly, statins had a hazard ratio of 1.534 (95% CI: 0.512- 4.594, p-value:0. 444). Conclusions: We found that the cardio protective medications showed no statistically significant difference in survival in breast cancer patients. Given the smaller sample size and single center study, further multi-center clinical trial is warranted to establish a stronger association.
Radiation therapy following breast conserving surgery (BCS) in women with early-stage breast cancer and low oncotype scores.
Authors: Damico Nicholas , Kharouta Michael , Lyons Janice A. , Harris Eleanor Elizabeth
Published: May 2020

e12547

Background: Clinical trials have demonstrated radiation therapy (RT) significantly reduces local recurrence following BCS, but that omission of RT does not compromise survival in the majority of women with early stage, low risk breast cancer. Criteria for omission of RT have been based on clinical factors such as age, stage, tumor size, surgical margins and estrogen receptor (ER) status. The utility of Oncotype DX RS in determining benefit of RT is not well defined. Methods: The National Cancer Database (NCDB) was queried for women ages 50-69 with T1N0M0, grade 1-2, ER+, Her2- breast cancer who underwent BCS with negative margins and had Oncotype DX RS of 0-18. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between patients who received RT and endocrine therapy (ET) versus ET alone using logrank analysis. Propensity matching was performed to reduce the impact of potential confounders and balance sample bias. Cox proportional hazards regression was used to identify predictors of OS. Results: A total of 13,648 women met inclusion criteria. The median age was 60 years. 13,389 women had adjuvant RT+ET, while 259 women had ET alone. Five year OS was 98.6% in patients who underwent RT+ET compared to 95.5% in those that had ET alone (p = 0.0012). Propensity-matching by age, Charlson Deyo Comorbid Condition score, tumor size, Oncotype RS, and race. Five year OS in the propensity matched cohort was 99.6% for women receiving RT+ET, and 98.3% for ET alone, which was not significantly different (p = 0.095). On multivariate analysis receipt of radiotherapy was not predictive of survival. Age and comorbidity score were the only significant predictors of survival. Conclusions: Patients who receive adjuvant RT with low risk, early stage ER+/Her2- breast cancer had higher OS than women who received ET alone on univariate analysis. However, results from both multivariate analysis and propensity score matching suggest no survival benefit to the addition of RT. Prospective studies are underway assessing omission of RT on the basis of multigene assays rather than clinical features alone. [Table: see text]
Prognostic value of circulating nucleosomes in primary breast cancer.
Authors: Mego Michal , Kalavska Katarina , Karaba Marian , Minarik Gabriel , Benca Juraj , Sedlackova Tatiana , Manasova Denisa , Pindak Daniel , Mardiak Jozef , Celec Peter
Published: May 2020

e12553

Background: Nucleosomes are composed of DNA wound around histone proteins and represent the basic structural unit of chromatin in the nucleus. When cells die, nucleosomes get out of the cell and end eventually in the circulation. Plasma nucleosomes might serve as a non-specific biomarker of cell death, which might be of particular interest for non-invasive tumor monitoring. The aim of this study was to assess the prognostic value of circulating nucleosomes in primary breast cancer. Methods: This study included 92 primary breast cancer patients treated with surgery from March 2012 to February 2015, for whom plasma isolated on the day before surgery was available in the biobank. Plasma nucleosomes were detected using Cell Death Detection ELISA kit with anti-histone and anti-DNA antibodies. Results: Circulating nucleosomes were associated with the systemic inflammatory index (0.17 vs. 0.27, P = 0.02) and with aldehyde-dehydrogenase expression (0.22 vs. 0.15, P = 0.03). Patients with lower than mean nucleosomes had significantly better disease-free survival (HR = 0.46, P = 0.05). The prognostic value was most pronounced in lymph node positive disease with high proliferation rate and in patients with detectable circulating tumor cells with epithelial-to-mesenchymal transition, but negative for epithelial circulating tumor cells. In a multivariate analysis, nucleosomes, hormone receptor status, HER2 status, lymph node involvement and tumor grade were independent predictors of disease-free survival. Conclusions: Our data suggest prognostic value of plasma nucleosomes in primary breast cancer and their association with metastatic ability and stem-cell ness characteristics. Their quantification could be added to the established prognostic markers.
Immunological changes with perception of cold in breast cancer (BC) patients.
Authors: Gandhi Shipra , Sarma Maithreyi , Attwood Kristopher , Ambrosone Christine B. , Repasky Elizabeth A. , Hong Chi-Chen
Published: May 2020

e12559

Background: Tumor-bearing mice “feel colder” than non-tumor bearing mice and prefer to be at thermoneutral temperatures. Cold stress results in immunosuppressive tumor microenvironment [decrease in CD8+T-cells, increase in myeloid derived suppressor cells and T-regulatory cells]. Cytokines play a significant role in modulating these immune cells. Breast cancer (BC) patients frequently report feeling excessively cold under ambient temperature. We examined the association between cytokine levels and thermal discomfort symptoms in BC patients in the Women’s Health After Breast Cancer (ABC) Study treated at Roswell Park Comprehensive Cancer Center. Methods: 424 stage I-III BC patients were identified. Standard demographics, body mass index (BMI), race, grade, histological subtype, tumor size, stage, nodal status, treatment received, and menopausal status were recorded. Peripheral blood was prospectively collected at diagnosis and one year post diagnosis and analyzed for a panel of 27 cytokines. Patients completed a questionnaire reporting symptom of “feeling cold when others are fine” using a Likert scale one year post BC diagnosis. Relationships between cytokines levels as tertiles and symptoms of “feeling cold” were evaluated using logistic regression. Change in cytokine levels from the time of BC diagnosis to one year post were also evaluated [ > 20% decrease, no change (-20 to +20%), and > 20% increase]. Results: Overall, 195/424 (46%) patients reported “feeling cold”. There were no differences in patient and tumor characteristics between patients who reported “feeling cold” vs “not cold.” Interestingly, 53.4% patients on chemotherapy reported “feeling cold” (p < 0.05). At baseline, higher IL-17E and IL-6 were associated with decreased perception of feeling cold (p < 0.05, p < 0.01). At one year post diagnosis, higher TNF-β was associated with decreased perception of feeling cold (p < 0.05). Changes in IL-22 and IL-33 were associated with increased perception of feeling cold (p < 0.05, p < 0.05). Multivariate model adjusted for age, race, BMI, histological subtype, stage, grade, treatment and menopausal status showed a trend towards decreased cold perception with higher IL-6 but was not statistically significant. Conclusions: We observe significant differences in pro-tumorigenic IL-6 and anti-tumorigenic IL-17E & TNF-β cytokines in BC patients reporting thermal discomfort. This suggests avenues for using thermal therapies to modulate inflammatory cytokine production in breast cancer.
Prognostic value of tumor: Infiltrating lymphocytes and androgen receptors correlation in triple negative breast cancer.
Authors: Tecic Vuger Ana , Separovic Robert , Vazdar Ljubica , Pavlovic Mirjana , Sitic Sanda , Tecic Vuger Ana , Sarcevic Bozena , Vrbanec Damir
Published: May 2020

e12571

Background: Little is known about correlation of tumor infiltrating lymphocytes (TIL) and androgen receptors (AR) and their joint effect on early triple-negative breast cancer (TNBC) prognosis. Analyzes to date evaluated mostly stromal TIL (sTIL) and intratumoral (iTIL), but not separately in central tumor (CT) and invasive margin (IM). Methods: We retrospectively analyzed consecutive sample of 152 early TNBC patients treated at our institution 2009-2012. TIL and AR were assessed using standard FFPE samples, TIL according to International Working Group for Evaluation of TIL recommendation, sTIL and iTIL in CT and IM, and AR by immunohistochemistry. Results: Median age was 58, 84% NOS, median T 2.2cm, 41% N+, 22%, 59% and 19% in stage I, II and III, respectively. Radical mastectomy was performed in 39%, adjuvant chemotherapy in 88% and radiotherapy in 74% of patients. Positive AR defined as ≥1% nuclear-stained cells, were expressed in 31%, and AR≥10% in 26% of patients. Median TIL content was: sTIL 19%, iTIL 5%, TIL in CT 5%, at IM 18%, sTIL in CT (CTs) 5%, iTIL in CT (CTi) 1%, sTIL at IM (IMs) 30%, and iTIL at IM (IMi) 5%. Prevalence of intermediate or high TIL content, defined as ≥10% was: CTs in 48%, CTi in 23%, IMs in 86%, and IMi in 47% of cases. In bivariable analysis all TIL indicators were significantly associated with longer OS, while AR was not. After adjustment for potential confounders using Cox proportional hazard regression, significant predictors of OS were sTIL (p0.007), IM TIL (p0.002), IMs (p0.001), and IMi (p0.030). In all cases higher TIL content was associated with longer OS. Although AR was not significant predictor of OS, it's interactions with TIL IMs and IMi was. There was no significant difference in OS between patients with high IMs and low IMs and AR0, but those with high IMs and AR≥1 had HR0.22 (p0.045) for death compared to patients with low IMs and AR0. Also, no difference for high IMi and low IMi and AR0, but patients with high IMi and AR≥1 had HR0.10 (p0.028) for death compared to patients with low IMi and AR0. Conclusions: Section analysis reveals frequent intermediate to high density and statistically significant prognostic impact of TIL on IM. That directs question towards role of different tumor compartments. Furthermore, combination of high expression of IMs and IMi with AR≥1 appears to be associated with longer OS than in patients with high IMs and IMi but with AR0. The correlations between AR and all TIL studied are extremely small, indicating their independence, but if so, their interaction in impact on OS is particularly interesting.
4D radiomic biomarker of functional tumor heterogeneity to predict breast cancer recurrence in pretreatment dynamic FDG-PET.
Authors: Chitalia Rhea , Viswanath Varsha , Pantel Austin R. , Peterson Lanell , Cohen Eric , Muzi Mark , Karp Joel , Mankoff David A. , Kontos Despina
Published: May 2020

e12573

Background: Breast cancer heterogeneity is thought to be associated with adverse outcomes. Dynamic molecular imaging modalities, including PET, permit 4-D sampling of tumor biologic properties and can therefore capture functional heterogeneity revealed by the temporal dimension of the dynamic tracer uptake. With the goal of improved non-invasive characterization of in vivo tumor biology, we have developed and tested a novel radiomic biomarker that characterizes 4-D functional tumor heterogeneity (FTH). We hypothesize subclonal populations are spatially contiguous regions of shared physiologic behavior that drive breast cancer heterogeneity and can be quantified. We describe an initial application of this approach to FDG PET imaging of breast cancer. Methods: We retrospectively analyzed data from a study of 50 patients with locally advanced breast cancer. Patients underwent 60-minute dynamic FDG PET over the chest prior to neoadjuvant chemotherapy and breast surgery and were followed for disease recurrence (DFS). A 3-D region bounding each tumor was identified by a radiologist and a novel Markov Random Field based 4-D segmentation paradigm segmented each tumor into three spatially constrained sub-regions with distinct time activity curve dynamics. From each tumor, an FTH imaging signature was extracted characterizing cluster compactness and separation. FTH imaging signatures were z-score normalized across all patients. Time-to-event analysis was used to assess the prognostic value of the FTH imaging signatures in predicting DFS. Discriminatory capacity compared to a baseline model of established prognostic factors (age, hormone receptor status, baseline tumor size) and standard PET uptake and kinetics markers (SUV, K1, and Ki) shown to be predictive of DFS (Dunnwald, J Clin Oncol 26:4449, 2008) was evaluated using the c-statistic and the log-likelihood statistical test. Results: 17 of 50 women (34%) had recurrence events. Adding FTH imaging signatures to the baseline model of age, baseline tumor size, and hormone receptor status improved a cross validated c-statistic from 0.51 to 0.74 (p < 0.05), and demonstrated higher discriminatory capacity over a model of age, tumor size, hormone receptor status, and standard PET measures (c-statistic = 0.59). Conclusions: Imaging biomarkers of 4-D metabolic tumor heterogeneity may add prognostic value in predicting recurrence-free survival in breast cancer and merit further study.
Axillary management after neoadjuvant chemotherapy in breast cancer: A survey by Brazilian Society of Mastology.
Authors: Frasson Antonio Luiz , Lichtenfels Martina , Resende Heloisa Magda , Barbosa Fernanda , Miranda Isabela , Borba Alessandra , Falcone ANA Beatriz
Published: May 2020

e12609

Background: Several trials have been investigating the accuracy of sentinel lymph node biopsy (SLNB) in clinically node-positive breast cancer patients undergoing neoadjuvant chemotherapy (NAC). A survey of breast surgeons was performed to assess the current management of axilla after NAC in Brazilian clinical practice. Methods: Brazilian Society of Breast Surgeons members were invited by email to complete an anonymous online survey. From 2000 eligible members, 426 (21.3%) members responded the survey. Results were summarized as proportions based on the number of responses to each question. Results: The majority of responders, 43.4%, indicated performing routine axillary staging by physician exam, ultrasound and PAAF (if necessary) in patients who are to undergo neoadjuvant chemotherapy. Approximately 43% of responders perform SLNB instead of ALND in patients with N1 axillary involvement before neoadjuvant chemotherapy, however many breast surgeons also indicated SLNB for N2 (27.7%) and N3 (18.8%) patients. Axillary complete pathologic response (ypN0) is necessary to omit ALND for 42.8% of responders and 19.5% do not perform ALND in patients getting ypN1is+ (isolated tumoral cells). Considering the option with patients getting ypN1is+ (isolated tumoral cells) and ypN1mic (micrometastases), 24.5% reported not performing ALND after SLND. Fifty-eight participants, 13.8%, accepted only SLNB in patients getting ypN1is+ (isolated tumoral cells), ypN1mic (micrometastases) and ypN1. The molecular profiling of breast tumor is considered when choosing axillary management after neoadjuvant chemotherapy for 26.3% of responders and for 73.7% the molecular profiling is not influencing the decision. Conclusions: Our survey highlighted the trend toward de-escalation of axillary surgery in patients undergoing neoadjuvant treatment and a high heterogeneity in axillary management after chemotherapy in Brazilian practice.
Giant tumors of the breast in adolescents and types of reconstruction during thelarche.
Authors: Kern Peter
Published: May 2020

e12614

Background: Tumors like cystosarcoma phylloides may exhibit malignant potential and occur already in young adolescents in their thelarche. Adolescents often do not report the growth of a tumor in the breast due to lack of knowledge or shame. The necessity for surgical intervention interferes with the normal development of the breast, however must be performed due to the deformation of the growing breast and the malignant potential of cystosarcoma phylloides. Methods: We report on two young girls, 13 years of age, who presented with giant cystosarcoma phylloides and fibroadenomas, with tumor diameters of 9 and 13 cm in their thelarche with extension to whole volume of the breast. Results: Both tumors were removed via an axillary access to the breast to avoid scars in the developing breast and removed with free margins at first surgical intervention. Autologous reconstruction by lateral thoracic wall advancement mammaplasty in one patient and implant based reconstruction as a temporary spacer have been used for reconstruction. The young patients showed a high degree of satisfaction in validated Breast QoL questionnaires. Conclusions: Surgical intervention in giant cystosarcoma phyllodes of the breast in adolescents require careful planning of surgery and avoid unnecessary scars in the developing breast. Axillary approach for surgical removal of the tumor and replacement by thoracic wall advancement mammoplasty or temporary implant-based reconstruction may both be safely applied in thelarche.
Gene expression profiling involved in response to neoadjuvant therapy in breast cancer.
Authors: Bofill Salvador , Garrigos Carmen , Benavent Marta , Gonzalez Rosario , Montaño Alvaro , Falcon Gonzalez Alejandro
Published: May 2020

e12618

Background: Neoadjuvant systemic therapy for breast cancer is used increasingly but, there is a group of patients which do not benefit from this therapy. With these premises, we stablished that our main objective was to identify differential expression genes patterns in patients (pts) with the ER/PR- Her2+, ER/PR+ Her2+ and triple negative (TN) subtypes breast cancers according to response to neoadjuvant therapy. Methods: RNA from formalin fixed paraffin embedded tumor samples from 54 pts with breast cancer that had received neoadjuvant therapy was extracted with mirVana miRNA isolation kit (Ambion). Patients with TN subtype received neoadjuvant chemotherapy based on anthracyclines and taxanes and patients with the Her2+ subtype received treatment with taxanos-trastuzumab and anthracyclines. The RNA expression levels were identified by ClariomD Asssay (ThermoFisher). Results were analyzed with Transcriptome Analysis Console and with in-house scripts in R (version 3.5.1). Data were corrected and normalized using Robust Multichip Average method from the oligo package. Expression was summarized at gene level using the corresponding annotation for ClariomD array BrainArray. Expression analyses were performed with limma package. A fold change ≥ 2 and p < 0.05 was considered statistically significant. We defined to groups: R (response, RCB 0) and NR (not response, RCB III) pts. Results: The median age of the pts was 52 years and 58% were menopausal and 42% pre-menopausal. Tumor stage were T1 9%, T2 50%, T3 30%, T4 11% and lymph node involvement were N0 31%, N1 41%, N2 24%, N3 4%. We obtained twelve genes differentially expressed in R vs NR groups. Respect to TN, two genes (AC053503.12, C9orf153) were differentially expressed between R (n = 11) and NR (n = 11). In ER/PR+ Her2+ subgroup, NBPF4 showed a differential expression in R (n = 8) vs NR (n = 7). In pts with ER/PR- Her2+, nine genes (DHRS2, SLCO1B3, UGT2B15, RGS2, SULT1E1, MED23, FKBP5, MIEN1, HER2) were differentially expressed in R (n = 10) vs NR (n = 7). We have started a validation in an independent cohort of pts in ER/PR+ Her2+ subgroup, confirming the results previously obtained. Conclusions: We found twelve genes differentially expressed in the different molecular subtypes of breast cancer involved in the response to neoadjuvant therapy. Several of these genes, especially UGT2B15, SULT1E1, FKBP5, MIEN1 and HER2 have been reported as key genes in tumoral processes, such as cell proliferation, invasion and drug resistant pathways, suggesting that its could be good biomarkers of response to neoadjuvant therapy in breast cancer.
Impact of sequence order of anthracyclines and taxanes in neoadjuvant chemotherapy for breast cancer: Results from a prospective institutional database.
Authors: Tesch Megan , LeVasseur Nathalie , Simmons Christine E. , Chia Stephen K. L.
Published: May 2020

e12619

Background: There has been growing interest in the optimal sequencing of anthracyclines and taxanes in neoadjuvant chemotherapy (NACT) for breast cancer. However, data comparing efficacy of administering taxanes prior to anthracyclines as opposed to the opposite sequence remains limited and inconsistent. The objective of our study was to assess the impact of sequence order on pathologic and clinical outcomes in a real-world setting. Methods: A prospective institutional database was analyzed to identify all HER2-negative breast cancer patients treated with NACT from 2012 to 2019. Rates of pathologic complete response (pCR), down-staging, and breast-conserving surgery were compared between patients who received anthracyclines followed by taxanes (AC-T) to those who received taxanes followed by anthracyclines (T-AC). Chi-square and independent sample non-parametric tests were used to test for associations between variables and outcomes. Results: Of the 270 patients who met eligibility criteria, 175 (65%) received AC-T and 95 (35%) received T-AC. Median age was 55 (IQR 24-86). Overall, 83% of patients had stage IIB or greater tumors, 40% had grade 3 histology, and 36% had triple-negative disease. Characteristics were balanced between the AC-T and T-AC groups (all p < 0.05). Median duration of treatment with NACT was 102 days (IQR 29-203). Rates of pCR (19% vs 21%, p = 0.750), down-staging (68% vs 61%, p = 0.188), and conversion to breast-conserving surgery (26% vs 20%, p = 0.314) were similar for AC-T vs T-AC, respectively. pCR was higher in triple-negative compared to hormone-positive cases (33% vs 13%, p < 0.001). Conclusions: In this small population-based cohort, sequence order of anthracyclines and taxanes did not demonstrate statistically significant differences in evaluated outcomes from NACT for breast cancer. This supports the current variation in prescribing practice and highlights the need for further studies in this area.
The long-lasting anti-tumor activity of cisplatin affecting the sustainable systemic immune alteration may improve distant-disease free survival of triple-negative breast cancer in patients with a substantial residual tumor following preoperative chemotherapy: A retrospective analysis with translational research.
Authors: Yamaguchi Ayane , Kawaguchi Kosuke , Ishiguro Hiroshi , Kataoka Tatsuki R , Torii Masae , He Chenfeng , Kawaguchi-Sakita Nobuko , Kawashima Masahiro , Takada Masahiro , Suzuki Eiji , Toi Masakazu
Published: May 2020

e12631

Background: Residual disease after preoperative chemotherapy is known to be a poor prognostic factor in triple-negative breast cancer (TNBC). Perioperative use of cisplatin (CDDP) is a well-known, standard treatment for most tumors except breast cancer. In this study, we explore the long-lasting anti-tumor activity of CDDP for TNBC patients. Methods: This research was based on consecutive study of seventy-nine previously untreated stage I–III TNBC patients treated with or without CDDP-based preoperative chemotherapy from 2007 to 2018 at the Kyoto University Hospital. We calculated the residual cancer burden (RCB) using the RCB calculator. All patients were sorted according to their RCB class: the pathological complete response (pCR), and RCB class I (minimal), II (moderate) or III (extensive). Distant disease-free survival (DDFS) was analyzed using the Kaplan-Meier method. Using mass spectrometry, we measured platinum concentrations in serum and normal breast tissue removed during surgery from patients treated with any platinum agents. We examined multiplex cytokine assays from serum sequentially, comparing CDDP and non-CDDP groups. Results: Forty-seven cases were treated with CDDP, and thirty-two did not have CDDP. The pCR rate was 53.2% for the CDDP group and 21.9% without CDDP. Patients with pCR and RCB class I were all distant disease-free. There was no significant difference between each RCB class using CDDP. However, patients belonging to RCB classes II and III with CDDP showed a better prognosis than the same RCB classes without CDDP (hazard ratio = 0.12). Platinum concentrations in serum were correlated with the time from the last dose of platinum agents, but platinum was even detected in serum two years after CDDP. No significant difference was found in the platinum concentrations of serum or normal breast tissue in the pCR and non-pCR groups. We also found that there were significant cytokine expression alteration related to T-cell infiltration only in the CDDP group one year after operation. It is suggested that CDDP may even affect the systemic immune alteration one year after operation. Conclusions: Our data shows that CDDP- based chemotherapy improves DDFS in patients with a substantial residual tumor. CDDP seems to sustain anti-tumor activity for a number of years and interaction with the systemic immune alteration.
Pathological complete response rates in HER2 amplified breast cancers based on levels of HER2 amplification.
Authors: Patel Ina , Hashimie Yasmeen , Hall James , Bhat Ashwini
Published: May 2020

e12632

Background: Untreated HER2 (Human Epidermal Growth Factor) amplified breast cancer has poorer prognosis, compared to those with HER2 negative status with shorter time to relapse and increased incidence of metastases and higher mortality. Both Trastuzumab and Pertuzumab (humanized monoclonal antibodies against HER2) have shown to improve PCR (Pathological Complete Response) rates when used in the neoadjuvant setting. However, whether the quantitative level of HER2 amplification affects PCR rates or disease-free survival/overall survival has not been well studied. If the level of HER2 amplification correlates with PCR rates, this could be a tool for clinicians to use as a predictive marker for response to therapy. Methods: This is a retrospective chart review of community oncology clinic patients with HER2 amplified breast cancer Stage I-III to evaluate the rates of PCR after HER2 targeted neo-adjuvant therapy categorized by HER2 CISH (Chromogenic in situ hybridization) amplification and stratified based on levels of amplification of < 3, 3 to 5, or > 5. Pathology reports were reviewed for report of PCR. Inclusion criteria was women age 19 to 90, HER2 positive biopsy proven breast cancer, Stage I-III, patients treated with neoadjuvant chemotherapy, adequate renal function, and left ventricular ejection fraction within normal range. Exclusion criteria was pregnancy, metastatic disease, history of other malignancies, and impaired renal or cardiac function. Results: The data consisted of 36 unique patients, 25% of whom had a HER2 below 3, 22.2% had a HER2 between 3 and 5, and 52.8% had a HER2 value > 5. There was found to be a statistically significant association between the level of HER2 amplification and PCR rates with increased amplification of HER2 relates with increased PCR rates (p value < 0.0176). Both three-year disease-free survival and three-year overall response rates were not statistically significantly associated with HER2 category (p value -0.2691 and 0.4692 respectively). Conclusions: The information from this study may introduce a future systematic approach to further risk stratify patients based upon their quantitative HER2 amplification level to help predict response to therapy. We have noted that a level of HER2 amplification > 5 led to significant association with PCR compared to < 3 and 3-5 values.