bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicentre retrospective assessment of toxicity and response to immunotherapy in elderly patients with metastatic melanoma.
Authors: Pathmanathan Shivanshan , Babu Hari S , Mason Robert , Htut Saw , Otty Zulfiquer Ali , Lyle Megan , Dzienis Marcin Radoslaw
Published: June 2021

9565

Background: The incidence of melanoma increases with age, however, elderly patients remain under-represented in landmark immunotherapy trials for metastatic melanoma. This study aims to investigate the impact of age on efficacy and toxicity of immunotherapy, and complications of immunosuppression to treat toxicity. Methods: A multicentre retrospective study involving centres in Australia [Gold Coast University Hospital, Cairns Base Hospital, Townsville University Hospital] was performed to compare the efficacy and toxicity of immunotherapy in metastatic melanoma in patients ≥70 years versus patients < 70 years treated between 2015 and 2019. Data collected included: baseline demographics, PFS, OS, Grade 3 or higher (Gr3+) adverse events as per CTCAEv5, adverse events leading to discontinuation, duration of steroids used to treat toxicity and complications secondary to steroids. Comparison of survival outcomes between the groups was calculated using Kaplan Meier, Log rank test and multivariate Cox regression analysis. Fisher exact test was used to determine differences in toxicity between the two groups. Results: A total of 229 patients were included with 106 patients ≥70years and 123 patients < 70 years. Baseline demographics were similar. Dual immunotherapy (ipilimumab + nivolumab) was less commonly used in patients ≥70years [13 v 38% p < 0.001]. Although the median PFS was numerically higher amongst ≥70years [10.8 v 6.9months p = 0.99], the landmark PFS was not [3yr PFS: 31 v 39%; 4yr PFS: 22 v 39%]. The median OS was similar in patients ≥70 years v < 70years [27.5 v 28.7 months p = 0.91], with similar landmark survival [3yr OS: 46 v 49%; 4yr OS: 42 v 49%]. Age was not associated with a difference in overall survival on multivariate analysis. There was no increase in Gr3+ adverse events in patients ≥70 years [22 v 21% p = 1.00] or discontinuation rates [26 v 20% p = 0.35]. There was one death in a patient < 70years secondary to colitis. There was a significantly higher rate Gr3+ adverse events in ≥70years patients receiving dual immunotherapy [71 v 35% p = 0.029] and a similar rate of Gr3+ adverse events with PDL1 inhibitors [13 v 11% p = 0.7]. Median duration of steroids was similar in both group [15 v 17wks], as was the median duration of high dose steroids defined as greater than 10mg of prednisone [5 v 6wks]. Complications of steroids was numerically higher in the elderly population [42 v 25% p = 0.15]. The most common adverse event to immunosuppression was infection. Conclusions: Patients ≥70years received similar benefit from immunotherapy in comparison to their younger counterparts. Toxicity related to PDL1 inhibitors was similar in both groups and was higher in patients ≥70years receiving dual immunotherapy. Patients ≥70 years had a clinically significant higher rate of complications secondary to steroids.
Adjuvant anti-PD-1 ab (Toripalimab) versus high-dose IFN-a2b in resected mucosal melanoma: A phase randomized trial.
Authors: Cui Chuanliang , Lian Bin , Si Lu , Chi Zhihong , Sheng Xinan , Kong Yan , Wang Xuan , Tian Hui , Mao Lili , Bai Xue , Tang Bixia , Yan Xieqiao , Li Siming , Zhou Li , Guo Jun
Published: June 2021

9573

Background: Immunotherapies including anti PD-1 ab and high-dose IFN-a2b (HDI) have been approved for adjuvant therapies in resected cutaneous melanoma, but their roles in mucosal melanoma are still unknown. To determine the efficacies of toripalimab versus HDI as adjuvant therapy in patients (pts) with resected mucosal melanoma, this open-label, phase randomized trial was conducted. Methods: Mucosal melanoma pts who have undergone complete resections of localized with or without regional lymphatic disease were randomly (1:1) assigned to receive HDI (15x106 IU/m2/d1-5/w/ 4weeks IH, followed by 9x106 IU tiw IH) or toripalimab (3mg/kg intravenously q2w) for 52 weeks unless disease recurrence, unacceptable toxicity or consent withdrawal. Head and neck primary would receive adjuvant radiotherapy within 6-8weeks after enrollment. The primary end point was RFS in the intention-to-treat population. Data cutoff was December 10, 2020. Clinical trial information: NCT03178123. Results: From Jul 2017 to May 2019, 187 pts were screened, and 145 were randomized into HDI group (n = 72) and toripalimab group (n = 73). The median age was 58years; M:F 37.2%: 62.8%; localized disease 80.7%, regional lymphatic disease 19.3%; local excision ± CLND 37.2%, wide excision ± CLND 62.8%; head and neck primary 39.3%( 87.5% received adjuvant radiotherapy); PDL-1positive 51.0%(CPS≥1%, 22C3), PDL-1 negative 49.0%. There was no difference in baseline characteristics between two groups. At a median follow-up of 31.5 months, there were 93 RFS events (43 in HDI group vs. 50 in toripalimab group), 76 DMFS events (35 vs. 41respectively) and 65 OS events (30 vs. 35 respectively). The median RFS, DMFS and OS were shown in the table. In the HDI group, 32.6% of pts received anti PD-1 ab in the following treatment. Grade 3/4 AEs were reported in 83.3% of pts in HDI group (most decrease of leukocytes or neutrophils) and 15.1% of pts in toripalimab group (mainly increase of amylase or liver enzymes). Discontinuations of treatment due to any AE occurred in 20.8% of HDI group and 15.1% of toripalimab group. Conclusions: Both adjuvant toripalimab and HDI therapy improve RFS of mucosal melanoma. Toripalimab shows longer RFS in PDL1 (+) subgroup and better tolerance than HDI. Clinical trial information: NCT03178123. [Table: see text]
A simulation model-based clinical decision tool to guide personalized treatment based on individual characteristics: Does 21-gene recurrence score assay testing change decisions?
Authors: Jayasekera Jinani , Sparano Joseph A. , Chandler Young , Isaacs Claudine , Kurian Allison W. , Kushi Lawrence H. , O'Neill Suzanne C. , Schechter Clyde B. , Mandelblatt Jeanne S.
Published: June 2021

e12507

Background: There is a need for web-based decision tools that integrate clinicopathologic features and genomic information to guide breast cancer therapy for women with node-negative, hormone receptor positive, HER2 negative (“early-stage”) breast cancer. We developed a novel simulation model-based clinical decision tool that provides prognostic estimates of treatment outcomes based on age, tumor size, grade, and comorbidities with and without 21-gene recurrence scores (RS). Methods: We adapted an extant breast cancer simulation model developed within the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) to derive estimates for the 10-year risks of distant recurrence, breast cancer-specific mortality, other cause mortality and life-years gained with endocrine vs. chemo-endocrine therapy for individual women based on their age, tumor size, grade, and comorbidity-level with and without RS test results. The model used an empiric Bayesian analytical approach to combine information from clinical trials, registry and claims data to provide individual estimates. External validation of the model was performed by comparing model-based breast cancer mortality rates and observed rates in the Surveillance Epidemiology and End Results (SEER) registry. Results: Several exemplar profiles were selected to illustrate the clinical utility of the decision tool. For example, the absolute chemotherapy benefit for 10-year distant recurrence risk and life-years gained, without RS testing, and the outcomes if a woman got tested and had a RS 16-20 are provided below for a 40-44-year-old woman and a 65–69-year-old woman diagnosed with a small (≤2cm), intermediate grade tumor and mild comorbidities. Conclusions: Simulation modeling is useful for creating clinical decision tools to support shared decision making for early-stage breast cancer treatment.[Table: see text]
Projected long-term impact of adjuvant trastuzumab emtansine (T-DM1) on metastatic breast cancer occurrence in Turkey.
Authors: Press David J. , Özcan Gözde , Teksoy Ezgi , Tomar Akanksha , Revil Cedric , Napalkov Pavel , Williamson Mellissa
Published: June 2021

e12523

Background: Progression from early stage breast cancer (eBC) to metastatic breast cancer (mBC) constitutes a substantial disease burden in Turkey. At a population-level, investment in treatment with curative intent may contribute to long-term reductions or delays in mBC. Women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive eBC who do not achieve pathologic complete response (pCR) after neoadjuvant taxane and trastuzumab-based treatment may be indicated for adjuvant trastuzumab emtansine (T-DM1) monotherapy. For this clinical population, the KATHERINE trial (NCT01772472) demonstrated significantly higher invasive disease-free survival among women who received adjuvant T-DM1 relative to trastuzumab (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; p<0.001). Methods: We developed epidemiology models based on data from cancer registries, observational studies, clinical trials, estimated population-level T-DM1 uptake, and extrapolations, by calendar year to predict the population-level number of women who will avoid mBC in Turkey over the next 10 years (i.e., 2022 to 2031). Weighted transitional probability averages were based on invasive disease-free and overall survival curves from the KATHERINE trial. Results: Over the next 10 years in Turkey, we projected that 22,597 women will be diagnosed with HER2-positive eBC and will not achieve pCR after neoadjuvant therapy. We projected that the total number of women who will experience mBC occurrence following adjuvant T-DM1 use from 2022-2031 will decrease annually from 0 to 249 relative to projections without introduction of T-DM1, with a cumulative total of 1,219 women not experiencing mBC occurrence, corresponding to 17% of total projected mBC occurrence over the next decade. At year 10 (2031), we projected that 29% fewer women would experience mBC occurrence in Turkey (604 with TDM-1 vs. 853 with trastuzumab). Conclusions: Population-level improvements in HER2-positive eBC to mBC disease progression are expected over the next 10 years in Turkey following adjuvant T-DM1 monotherapy. Further research will elucidate treatment-related improvements in costs to society as a result of population-level improvements in disease outcomes for women diagnosed with eBC.[Table: see text]
Breast cancer after IVF: Can ovary stimulation and follicular response affect prognostic factors?
Authors: Izquierdo Maxim , Baulies Sonia , Devesa Marta , Tresserra Fransec , Ara Carmen , Rodriguez Ignacio , Fabregas Rafael , Coroleu Buenaventura , Barri Pedro S , Barri Pere
Published: June 2021

e12538

Background: The ovary stimulation and the follicular response is related with estradiol level. Study in breast cancer patients after IVF if ovarian response or number of IVF cycles affects the prognostic factors. Methods: Patients with breast cancer who underwent IVF are studied the prognostic factors (Ki67, HER2, estrogen receptor (ER), progesterone receptor (PR), oncogene p53, histologic grade) in relation to the ovary response and number of IVF cycles. Results: 73 patients with breast cancer after IVF are studied. They performed 135 cycles of IVF, 36 (49’3%) with 1 IVF and 37 (50’7%) with more than one IVF. Hyper response was present in at least one IVF in 24 (32.9%) patients and there was no hyper response in any IVF in 49 (67.1%) patients. The prognostic factors were: Ki 67> 20 in 31'91% (15/47) Ki 67 <20 in 68'08% (32/47), HER2 + 31'94% (23/72) HER2- 68'05% (49/72), p53 + 45'09% (23/51), p53-54'90% (28/51), HG II-III 56'36% (31/55), HG I 43'63% ( 24/55), RE + 87'5% (63/72), RE- 12'5% (9/72), RP + 76'38% (55/72), RP- 23'61% (17/72). None of prognostic factors varied with the ovary response (hyper response in at least one IVF cycle, normal response, normal or low response) (p=ns). The only prognostic factor that varied with the IVF number was p53 +. Patients with p53 + (23/51), 7 (30’43%) has one IVF, and 16 (69’53%) have more one IVF (p<0’05). Conclusions: In breast cancer after IVF, the ovary stimulation and the follicular response not affect Ki67, HER2, estrogen receptor, progesterone receptor, p53, and histologic grade. p53 positive is more frequent in patients with more than one IVF.
Gender disparity in breast cancer: A population-based study in the U.S. Department of Veterans Affairs.
Authors: Ajmal Zainub , Khan Abdul Moiz , Tuz Zahra Fatima , Gemoets Darren , Mehdi Syed Arzoo
Published: June 2021

e12549

Background: Over the last several decades, the mortality for breast cancer has improved, however, there remains a large gender disparity with male patients having worse overall survival. Recent studies have identified increased mortality in male breast cancer (MBC) despite adjusting for age and other clinical factors necessitating a need to evaluate both screening and treatment patterns for MBC. The survival trends in MBC have not been studied across the VA population. Methods: Male and female breast cancer cases between 2000-2018 were identified in National VA Cancer Cube Registry. A total of 1511 cases of MBC and 8081 cases of female breast cancer (FBC) were identified. IRB approval was obtained. Statistical significance was set to 0.05, with significant results noted with an asterisk (*). Results: Our data showed that the number of new MBC cases per year remained stable over the study period while the FBC cases rose by 13.6* per year. The racial distribution of Caucasian and African American (AA) patients was comparable among the two groups. For FBC, the peak incidence was between ages 50-60, while for MBC, the peak incidence was at age greater than 70 years. Males were more likely to present at a later disease stage (stage III and IV) compared to females, (26.94% vs 13.8%) *. They also had a worse performance status (ECOG 3 or higher) at presentation compared to female patients, (3.72% vs 1.32%) *. The survival characteristics and first course of treatment received are summarized in the table below. Our findings show that males have a worse 5-year survival both in early and late-stage disease and across both Caucasian and AA races. This poor survival difference remains when comparing MBC patients older than 50 years but not when comparing the younger subset in both groups. These findings suggest that the overall poor survival of MBC may be related to late detection, advanced age at presentation and subsequent increased comorbidities and poor performance status. Conclusions: Patients with MBC present at a later disease stage and have a worse overall survival when compared to FBC. This difference in survival remained when stratified by age, race and stage at presentation. These results imply the possible underutilization of screening in males as well as differences in the clinical and pathological behavior of male and female breast cancer.[Table: see text]
Impact of pre-treatment derived neutrophil-lymphocyte-ratio on outcomes in patients with triple-negative breast cancer.
Authors: Sharma Rakesh Kumar , Gogia Ajay , Gupta Ritu , Deo SVS , Sharma Dayanand , Mathur Sandeep , Sagiraju Hari Krishna Raju
Published: June 2021

e12556

Background: There is an ambiguity of data regarding the predictive and prognostic significance of pre-treatment-derived neutrophil-lymphocyte-ratio (DNLR) to attain pathologic complete response (pCR) after neo-adjuvant chemotherapy (NACT) and survival in patients with triple-negative breast cancer (TNBC). Methods: In this ambispective study, conducted at Dr. B.R.A., I.R.C.H., AIIMS, New Delhi, 328 patients of TNBC registered from a period of May 2013 to June 2020, who received treatment with curative intent were included. Patients with oligometastatic TNBC who received NACT with curative intent were also included in the analysis. Survival analysis to evaluate the correlation of pre-treatment DNLR with relapse-free survival (RFS) and overall survival (OS) was done. Logistic regression analysis was done to evaluate the association of DNLR with pCR among the subset of the sample who completed NACT and underwent surgery. Results: The median age of our cohort was 45 (18-74) years. Study cohort comprised of 165 (50.3%) pre-menopausal, 150 (45.7%) post-menopausal and 12 (3.7%) peri-menopausal patients respectively. Stage distribution as per AJCC 7th edition was stage-I 8 (2.4%), stage-II 127 (38.7%), stage-III 171(52.1%), and stage-IV 22 (6.7%) patients respectively. The median duration of symptoms was 3 (0.25-36) months. One seventy-three (52.7%) patients received NACT and underwent surgery, out of which 52 (30.1%) patients achieved pCR. Median DNLR in the overall population was 1.7 (0.4-10.1) and the median derived lymphocyte count of 2290 (370-11700) with < 5%(n = 14) having baseline lymphopenia( < 1000). Based on the maximum sensitivity and specificity, a DNLR cut-off point of 1.77 in the overall population and 1.88 among those patients who underwent surgery following NACT were used to categorize low and high DNLR. Median RFS was 73.5 months in our sample, whereas median OS was not reached. The 3-year RFS and OS rates were 65.8% (59.0-71.8) and 85.1% (79.5-89.2%) respectively. High DNLR( > 1.77) was not associated with RFS [HR (95%CI): 1.36 (0.90-2.06)] and OS [HR (95% CI): 0.97 (0.52-1.81)]. In a subset analysis of patients (173) undergoing surgery following NACT, high DNLR ( > 1.88) was not found to be associated with pCR [OR (95% CI): 0.81 (0.42-1.57)]. Conclusions: Pre-treatment DNLR is an easily available inflammatory marker. Indian patients of TNBC usually have raised baseline lymphocyte count, hence, pre-treatment DNLR may not be a reliable predictor of pCR and survival outcomes in these patients. Association of DNLR at various treatment and post-treatment time points with survival outcomes needs further exploration.
Spatiotemporal loco-regional recurrence patterns after breast-conserving surgery.
Authors: Qu Feilin , Mao Rui , Liu Zhebin , Lin Caijin , Li Junjie , Shao Zhiming
Published: June 2021

e12580

Background: Loco-regional recurrence (LRR) following breast-conserving surgery (BCS) represents a heterogeneous class of disease that has significant variation in its biological behavior and prognosis. Herein we report for the first time the spatiotemporal patterns of LRR post-lumpectomy in a Chinese population-based cohort. Methods: This retrospective study analyzed the single institutional patient-level data of breast cancer patients who underwent BCS between January 2006 and December 2016 at Shanghai Cancer Hospital of Fudan University. The enrolled patients were followed up regularly after initial surgery. Multivariate Cox regression models were performed to identify independent risk factors for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype. Results: 4,325 patients were included, with a median follow-up of 66 months. A total of 120 (2.8%) LRRs were recorded as the first site of failure. Age at onset, pathologic stage, and molecular subtype were identified as predictors of loco-regional relapse. The major type of LRR was ipsilateral breast tumour recurrence (IBTR), which mainly (83.6%) occurred ≤5y post surgery. ARR curves showed that relapse peaked in the first 2.5 years in the overall population. Patients with regional nodal recurrence (RNR), shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2+ positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery. Conclusions: Currently, the LRR rate is generally low. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.
Anlotinib plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: A prospective, single-arm, single-center, phase II clinical study.
Authors: Chen Xi , Zhang Shuqun , Li Xuexin , Zhang Yinbin , Li Youhuai , Kang Huafeng , Haitao Guan , She Qing , Ma Xiaobin , Diao Yan , Liu Di , Min Weili , Liu Mengjie , Wu Fei , Feng Cong
Published: June 2021

e12585

Background: Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Combining anti-angiogenesis with chemotherapy yielded increased response rates in patients with early-stage triple-negative breast cancer (TNBC). This phase II study aims to evaluate the efficacy and safety of adding anlotinib to standard neoadjuvant chemotherapy in primary TNBC. Methods: Patients aged 18 years or older with previously untreated stage ⅡB-IIIA histologically documented TNBC were assigned to receive chemotherapy plus oral Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 8 cycles). Chemotherapy comprised of epirubicin at 90 mg/m2 and cyclophosphamide at 600 mg/m2 followed by docetaxel at 100 mg/m2, (21 days per cycle; both total 4 cycles), which was then followed by surgery. The primary endpoint was pathologic complete response (pCR) (no invasive carcinoma in breast or axilla). Stratification was based on the clinical breast cancer stage. This study is registered on Chinese Clinical Trials.gov (ChiCTR2000038174), and still ongoing. Results: Between July 2019 to June 2020, 18 patients (female) with pathological stage ⅡB (83.3%), and IIIA (16.7%) were enrolled with a median age of 46 years (range: 32-72). Overall pCR rate was 44.4% (8/18, CI 95%: 24.6%-66.3%). The pCR rate of pathological stage IIB patients was 46.7%(CI 95%: 26.7%-69.9%), which is tend to be better than the pCR rate of 33.3%(CI 95%: 6.2%-79.2%) for patients with pathological stage IIIA. There are 21 kind of AEs were observed, all including 56 times grade 1 AEs and 34 times grade 2 AEs, no grade 3 or higher AE was observed. The most common AEs included hand-foot syndrome(55.6% in total with 33.3% grade 2 and 22.2% grade 1), oral mucositis(50.00% in total with 33.3% grade 2 and 16.67% grade 1), fatigue(61.1%, all grade 1), hoarse voice(33.3%, all grade 1), nasal bleeding(27.8%, all grade 1), hypertension(22.2% with 5.6% grade 2) and diarrhea(22.2% with 5.6% grade 2). Neither unexpected safety signals nor treatment-related death occurred. Conclusions: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and promising antitumor activity for patients with high-risk, early-stage TNBC. Clinical trial information: ChiCTR2000038174.
Targeted breast surgery: Non-direct approach.
Authors: Kern Peter , Kessel Alina , Hoffmann Oliver , Bittner Ann-Kathrin , Kimmig Rainer
Published: June 2021

e12602

Background: Breast conserving surgery is the standard in T1-T3 primary breast cancer. The cosmetic result is very much depending upon the surgeon ́s experience, the tumor-size/breast ratio and the technique applied. We have proposed a nomogram earlier (1) which has been cited earlier by the American Society of Breast Surgeons Consensus Conference as a concept for avoidance of re-excisions and achievement of a favorable aesthetic result. Our nomogram proposed 5 simple oncoplastic techniques to handle the vast majority of breast cancer cases, with high rates of free margins. However, these techniques all used direct access to the mammary gland through the skin above the tumor, leaving permanent scars in the visible skin of the breast. To avoid this, we now have chosen a more natural access to the mammary gland along natural transitions and Langerhans´s skin lines in this prospective open-label study. Methods: We conducted a prospective open-arm study including all primary invasive and non-invasive breast cancer cases of tumor stages AJCC 0-III A (Version 8.0). Non-palbable tumors and those undergoing neoadjuvant chemotherapy had to be marked by a wire and clipped before. Intraoperative ultrasound was applied before skin incision and after removal of the tumor including ultrasound of the specimen to confirm clear margins). Resection was performed as a segmentectomy and SLN biopsy and axillary clearance was done according to national guidelines. Access to the tumor was chosen in a non-direct approach according to the proximity of the tumor to one of the following natural transitions: 1. areola 2. axillary line 3. inframammary fold. Results: 84 patients with breast conserving targeted breast surgery with a "non-direct to the tumor approach" have been enrolled so far. 76 patients had primary surgery with stage distribution as follows: Tis (1), T1a (3), T1b (8), T1c (30), T2 (30), T3 (4) and T4b(1). 8 patients had neoadjuvant chemotherapy with stage distribution as follows: ypT0 (3), ypT1a (2), ypT1c (1) and ypT2 (2). Histopathology was predominantly invasive-ductal breast cancer (70), followed by invasive-lobular (6), ductulo-lobular (5), invasive- ductal and pure DCIS (1), invasive-ductal and mucinous (1) and mucinous only (1). After first surgery according to our nomogram 77 patients had a tumor resection with free margins and 7 with involved margins, thus 91,6 % tumors were resected with free margins at first surgery. The remaining 8,4 % of cases were margin-free after second surgery. Conclusions: Scars were not visible on the surface of the breast outside of natural transitions and rate of free margins was high with targeted breast surgery at a rate of 91,6 % without any cosmetic impairment due to the remote natural access to the mammary gland. Patient-reported outcome in detail has been evaluated by validated questionnaires and demonstrated a high satisfaction with scar pattern, volume and symmetry.
Similar decrease of proliferation employing Ki-67 after brief neoadjuvant hormonal treatment on invasive ductal carcinoma versus invasive lobular carcinoma.
Authors: Majer Martin , Little Elizabeth Fauchier , Jones Sarah , Dong Jasmine , Bezdickova Karolina , Hutton David , Tomanova Lucie , Promlap John , Promlap Tien , Schneringer Greg , DeMartini Steve , Russell Michael , Joyner April , Schmidt Susan , Nagubandi Ravi , Skau Randell , Swars Monica , Powell Megan , Ordorica Edward J.
Published: June 2021

e12606

Background: Invasive lobular carcinoma (ILC) differs from the more prevalent invasive ductal carcinoma (IDC) in histology, molecular underpinning, and biological responsiveness to cytotoxics. Patients diagnosed with IDC or ILC were evaluated in the clinical setting to determine if they differ in responsiveness to neoadjuvant hormone treatment. Methods: This is a retrospective observational study of an underserved, low income, rural population in Oroville, California. The data for this study was collected over ten years (2011-2021) from 58 estrogen receptor positive (ER+) breast cancer patients. The majority of these patients (48/58) were diagnosed with IDC with ages ranging from 35 to 91 (mean age is 66) and the remaining 10 were diagnosed with ILC with ages ranging from 58 to 85 (mean age is 64). Patients were given neoadjuvant hormone treatment starting after their initial biopsy confirming ER+ status until scheduled surgical removal by lumpectomy or mastectomy. Ki-67 was measured prior to treatment and then measured again after a minimum of 14 days on hormone therapy. The initial Ki-67 range for patients with IDC was 2%-75% (median of 15%). Ki-67 initial range for patients with ILC was 2%-30% (median of 11%). Positive response to treatment was set at > 50% reduction in Ki-67, with no response set at < 50% reduction in Ki-67. We compared the response rates of ILC and IDC patients using a chi-square test. Results: Chi-square analysis found no statistically significant difference between IDC and ILC response to hormone therapy. 34/48 (71%) patients with IDC responded to treatment, and 8/10 (80%) of ILC patients showed response. Incidentally, we noticed a higher prevalence of ILC in our community compared to expected numbers. Conclusions: When evaluating hormone therapy responsiveness in the neoadjuvant setting, there is no observable statistical difference in response rates between IDC and ILC. Neoadjuvant hormone testing employing Ki-67 response identifies subgroups of patients who benefit from the addition of new biologics (-ciclibs, mTOR inhibitors) in addition to hormone treatment. Our experience supports testing in this way to further individualize the care of patients unable to participate in clinical trials.
Change in HER2 status after neoadjuvant chemotherapy (NAC) with trastuzumab and pertuzumab (HP) in patients with HER2-positive early-stage breast cancer.
Authors: Ferraro Emanuela , Razavi Pedram , Chandarlapaty Sarat , Modi Shanu , Wen Hannah Yong , Brogi Edi , Norton Larry , Robson Mark E. , Dang Chau T.
Published: June 2021

e12614

Background: Combination of HP with NAC in the neoadjuvant setting leads to an high rate of pathological complete response (pCR) in patients with stage II-III HER2+ breast cancer (BC). The rate of change in HER2-status after NAC reported in literature is between 10-30%, although NAC comprises a various regimens, and the clinical significance of this phenomenon is unclear. Methods: We extracted data on patients with HER2+ BC treated with NAC and HP between September 1, 2013 to November 1, 2019. Only patients with internally verified HER2 status at our center were enrolled. The rate of pCR (ypT0/is ypN0) and the change in HER2 status on residual disease from baseline were evaluated. We used standard definition of HER2 status based on ASCO/CAP guidelines 2018. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+, FISH non-amplified. Results: Overall, 130 pts were identified. All patients received dose-dense AC-THP, except for 13 patients who received TCHP or other HP-based regimens. The pCR was achieved in 77/130 (59%) of patients and 53/130 (41%) had residual disease. Among 53 patients with residual disease, HER2 status was analyzed in 25 patients and was pending on the remaining patients. In the 25 analyzed patients, 13 had HER2-loss in residual disease. In 4/13 patients, HER2 expression was lost (IHC 0); in 9/13 patients, HER2-low profile was found (IHC 1+ in 6 patients, and IHC 2+, FISH non-amplified in 3). Details on HER2 status change are described in the table below. Conversely, 12/25 had concordant HER2 status after NAC. Conclusions: At single center, the change in HER2 status after NAC with HP appeared frequent. Pathological review of additional cases is ongoing. The clinical significance is still unclear but may open the possibility to investigate tailored approach in post-neoadjuvant setting based on the biological profile of residual disease. [Table: see text]
Paclitaxel versus docetaxel-based neoadjuvant chemotherapy and risk of lymphedema in breast cancer patients.
Authors: Zhu Yirong , Refaat Abdelrhman Tamer , Ho Yvonne D. , Thomas Tarita , Small William , Godellas Constantine , Vaince Faaiza , Mai Hanh P.
Published: June 2021

e12620

Background: Neoadjuvant chemotherapy (NAC) is commonly utilized in women with locally advanced breast cancer, usually followed by surgery and radiation therapy (RT). Many studies aimed to address the risk factors contributing to a higher incidence of lymphedema in patients with breast cancer. Our group previously reported the extent of surgery increases the risk of lymphedema. Adjuvant chemotherapy with taxane-based regimens are associated with an increased risk of lymphedema likely due an increase in interstitial extracellular fluid volume therefore resulting in fluid retention. This study aims to directly compare and characterize the risk of lymphedema in patients receiving paclitaxel versus docetaxel-based NAC. Methods: This is a retrospective study approved by our institutional review board. The study included women with breast cancer treated consecutively at our institution with taxane-based NAC followed by surgery and RT from 2006 to 2018. Patients and tumor characteristics including age, race, body mass index (BMI), clinical stage, hormone receptor, HER2 status, type of surgery, RT techniques, and type of NAC (Paclitaxel versus Docetaxel), and its association to risk of lymphedema were analyzed using univariable and multivariable binary logic regression tests. Lymphedema was assessed before RT and at follow up visits, and was identified by >2.0-cm increase in arm circumference, or >10% increase in limb volume, or new self-reported lymphedema symptoms. Results: A total of 263 patients treated with either paclitaxel or docetaxel-based NAC were identified and analyzed. At a median follow up of 28.4 months (range 3.5-158.7 months). 26.2% (69/263) of patients developed lymphedema. On a multivariable analysis, patients who underwent axillary lymph node dissection (ALND) had a significantly higher rate of lymphedema (42.6%) compared to those who had only a sentinel lymph node biopsy (SLNB, 10.5%, p<0.05). Regardless of the type of surgery, there was no significant difference in rates of lymphedema between patients who received paclitaxel versus docetaxel-based NAC (28.7% vs 21.3%). However, among high-risk patients who underwent mastectomy with ALND, NAC with Paclitaxel was associated with a significantly higher rate of lymphedema compared to docetaxel (56.8% vs 22.7%, RR 2.50, p<0.05). Conclusions: This represents one of the largest studies examining the impact of taxane-based NAC on the risk of lymphedema in women with breast cancer. In this study, paclitaxel-based NAC was associated with a significantly higher risk of lymphedema in women who underwent mastectomy and ALND compared to docetaxel based chemotherapy. A larger, balanced, prospective study is warranted to verify this previously unidentified lymphedema risk from paclitaxel and guide individualized NAC decision.
Baseline neutrophil-to-lymphocyte ratio and absolute lymphocyte count in patients with HER2-negative breast cancer treated with eribulin may predict overall survival.
Authors: Maeda Shigeto , Anan Keisei , Koga Kenichiro , Kuba Sayaka , Yano Hiroshi , Kai Yuichiro , Nishimura Reiki , Toh Uhi , Yamaguchi Miki , Mashino Kohjiro , Mitsuyama Shoshu , Tamura Kazuo , Tanaka Toshihiro , Iwase Hirotaka
Published: June 2021

e13005

Background: In Japan, eribulin has been approved for inoperative or recurrent breast cancer, following treatment with an anthracyclines and a taxanes. We reported the efficacy and safety of eribulin as a first-line to third-line treatment in patients with advanced/metastatic breast cancer (MBC) previously treated with anthracylinsanthracyclines and taxanes (Breast 2017). Briefly, the main inclusion criteria were as follows: no history of eribulin administration; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2,; human epidermal growth factor receptor 2 (HER2)-negative,; 20–75 years; ≥4 weeks from the last dose of chemotherapy, or ≥2 weeks from the last dosing of endocrine or radiation therapy; measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1; sufficient organ function; life expectancy of ≥3 months; and no significant abnormalities on electrocardiogram. Patients in this clinical trial were enrolled between December 1, 2011, and November 30, 2013. Eribulin was administered intravenously at a dose of 1.4 mg/m2 during a 2-5 min infusion on days 1 and 8 every 3 weeks. In contrast, baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) were reported to predict progression-free survival (PFS) or overall survival (OS). However, these reports were mainly retrospective analysis. Therefore, retrospective evaluation of NLR/ALC in a prospective clinical trial is important to understand the association between NLR/ALC and OS/PFS. Methods: Of 47 prospectively enrolled patients in a previous trial, 45 patients were retrospectively evaluated for baseline NLR/ACL and at the time of 3 cycles of eribulin. The association between NLR/ALC and OS/PFS was also were analyzed for association with OS/PFS. The Kaplan-Meier method was used to estimate the OS/PFS distribution. The cut-off values for baseline NLR and ALC were set at 3 and 1500 /ul, respectively. Results: The median OS of patients with a baseline NLR < 3 was significantly longer than that of patients with a baseline NLR ≥ ≧3 (769 days vs. 409 days; log-rank test p = 0.0333). The median OS of patients with a baseline ALC ≥ ≧1500 was also significantly longer than that of patients with a baseline ALC < 1500 (964 days vs.vs 427 days; log-rank test p = 0.0425). Association between baseline NLR/ALC and PFS were not seen, and also association between at the time of 3 cycles of NLR/ALC and OS/PFS were not seen neither. Conclusions: Baseline NLR and ALC in the patients with HER2- negative breast cancer who plan to treat eribulin may predict overall survival. Clinical trial information: UMIN000007121.
Analysis of circulating tumor DNA identifies homologous recombination repair molecular features of Chinese breast cancer.
Authors: Li Mingwei , Yang Tongtong , Wang Huina , Lou Feng , Cao Shanbo
Published: June 2021

e13006

Background: Breast cancer (BC) is the most common cancer in women world-wide. Assessments of genomic variants in circulating tumor DNA (ctDNA) have generated great enthusiasm for their potential application as clinically actionable biomarkers in the management of BC. Alterations in homologous recombination repair (HRR), are a determinant of sensitivity to platinum chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPi) in BC. However, as far as we known, most of HRR genes, except BRCA1/2, have not yet been fully understood to date. In this study, we aimed to elucidate the comprehensive HRR genetic alteration profile of breast tumors among Chinese patients by ctDNA analysis. Methods: Plasma ctDNA from 259 patients with BC were deeply sequenced via next-generation sequencing (NGS) techniques using AcornMed Biotechnology for 808 genes panel. Molecular profiles were reviewed to identify somatic and germline pathogenic mutations in the 14 HRR genes ( ATM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, CDK12, and BARD1) . Results: At our institution, 259 patients underwent NGS analysis of BC specimens. The median age was 46 (range from 31 to 79). Based on the analysis of the genetic alteration profile from our cohort, at least one of the HRR genes was observed from 29.34% of the tumor samples, with BRCA1 (8.11%), BRCA2 (5.79%), RAD51C (5.02%), CDK12 (4.63%), CHEK2 (1.93%), ATM (1.16%), and BARD1 (1.16%) as the most commonly altered genes. As compared with MSKCC dataset (Table), genetic alterations detected from our cohort affected genes involved in HRR (29.34% vs. 14.03%, P＜0.0001) pathways, with statistically different genetic alteration rates. Moreover, BRCA1/2, RAD51C, CDK12 and CHEK2 mutations exhibited higher mutation rates, whereas ATM, BRIP1 and PALB2 mutations presented a lower mutation rate in Chinese patients with breast cancer (P＜0.05). Conclusions: CtDNA can characterize the mutational feature of HRR in BC. our study contributes to the understanding of the HRR pathways and specific genetic alterations harbored by Chinese patients with BC that could potentially be developed as markers of treatment response to targeted therapeutics. Ref: Razavi P, Chang MT, Xu GT, et al. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell. 2018 Sep 10;34(3):427-438.e6. doi: 10.1016/j.ccell.2018.08.008.[Table: see text]
TDM-1 efficacy in trastuzumab-pertuzumab pre-treated HER2 positive metastatic breast cancer patients: A meta-analysis.
Authors: Omarini Claudia , Piacentini Federico , Sperduti Isabella , Cerma Krisida , Barbolini Monica , Canino Fabio , Nasso Cecilia , Dominici Massimo , Moscetti Luca
Published: June 2021

e13010

Background: Based on the results reported in Emilia trial population, current guidelines consider TDM-1 the standard second-line therapy for HER2 positive metastatic breast cancer (MBC) patients. Despite that, there are no prospective studies supporting the efficacy of TDM-1 following trastuzumab (T) + pertuzumab (P) and taxane first-line treatment. Currently, only real-world data have investigated this sequence with controversial results Methods: We performed a meta-analysis of the available real world data to determine the efficacy of TDM-1 after first-line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the phase III Emilia trial (T pre-treated population). Results: Seven studies were eligible, in three of them data were from sub-group population analysis. The meta-analysis showed a combined 1-years PFS risk difference for TDM-1 efficacy after TP in second or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p=0.07) , with low heterogeneity among studies (I2 < 0.0001, p =0.836). Considering the four studies on TDM-1 in second-line setting, 1-years PFS risk was -0.034 (95% CI -0.207 – 0,139; p=0.701) (I2 < 0.0001, p =0.91). Conclusions: Results from the meta-analysis show that the efficacy of TDM-1 after TP double-block seems to be similar to the previously reported in Emilia trial. In the second line setting, available data are not mature enough to confirm TDM-1 efficacy in TP pre-treated population. Currently, TP pretreated patients should receive TDM-1 as indicated in the guidelines.
Pre-clinical development of an anti-cancer drug ENZ302, a promising candidate for multiple cancer therapeutics.
Authors: Chakraborty Arindam , Banerjee Abir , Gadgil Himanshu
Published: June 2021

e13053

Background: Vernonia cinerea extract has been known to be used for various haematological disorders including cancer. In the current study, using state-of-the-art extraction and bioanalytical tools we have identified an active compound having anti-tumor properties from the same plant Vernonia cinerea. The crude extract of Vernonia cinerea as well as the active molecule obtained through the chemical route (ENZ302) showed anti-tumor activity against various cancer models including CML, AML, ALL, HER2+ breast cancer, colon cancer, etc. Methods: Various methods including RP-HPLC, XRD, NMR, IR, cell based assay and LC-MS were used to elucidate the molecular structure of ENZ302. MTD, DRF, PK, and Xenograft study etc were carried out in murine model during the preclinical development of ENZ302. Results: ENZ302 resulted significant cytotoxic effect within 8 hrs of treatment in TNBC (Triple Negative Breast Cancer) model, MDA-MB-468 cells when compared with a known inhibitor Lapatinib. However, ENZ302 treatment in primary cells demonstrates no anti-proliferation activity, indicating the specificity of it’s mode of action. Interestingly, a dose-dependent decrease in tumor volumes was observed for ENZ302 in a xenograft model of TNBC while administered orally. ENZ302 did not cause any adverse changes even at 2gm/Kg dose, indicating the safety of the compound. Although a single-dose PK study showed that ENZ302 has a half-life of ̃40 mins, however, in vitro metabolism of the compound in mouse, rat, dog, and human hepatocytes/microsomes showed the molecule is stable in hepatocyte with very low clearance in microsomes (half-life > 30 min), indicating most of the clearance occurring through the kidney. Conclusions: Our preliminary data suggest that ENZ302 is a specific tyrosine kinase (e.g. Src) inhibitor and a promising therapeutic agent against several cancers. A comprehensive proteomic analysis is ongoing to understand the mechanism of action of ENZ302 that makes it effective against several cancers. The discovery of ENZ302 holds ample opportunities to develop a safe and efficacious treatment regimen against several cancers including TNBC.
The common gamma-chain cytokines IL-2, IL-7 and IL-15 impact on proliferation of lymphocytes in vitro in breast cancer patients.
Authors: Timofeeva Sofia V. , Sitkovskaya Anastasia O. , Zlatnik Elena Yu. , Filippova Svetlana Yu. , Shamova Tatiana V. , Mezhevova Irina V. , Novikova Inna A. , Vashchenko Larisa N. , Kechedzhieva Emma E. , Dashkova Irina R. , Ausheva Tatiana V. , Andreyko Elena A. , Saforyan Natalya S. , Kit Oleg I.
Published: June 2021

e13060

Background: Monotherapy with low doses of cytokines does not provide significant therapeutic results, while treatment with high doses leads to a number of side effects, for example, cytokine release syndrome, etc. Therefore, it is necessary to study the effect of cytokines on immune cells which are involved in the regulation of pro- and antitumor immune response. Thus, the aim of this study was to analyze the dynamics in the proliferation of the total fraction of lymphocytes after expansion and exposure to γc-cytokines: IL-2, IL-7 and IL-15 and their combinations in vitro in patients with diagnosed breast cancer. Methods: The study included 10 patients with locally advanced stage I-III breast cancer. Peripheral blood mononuclear cells (PBMC, ficoll-hypaque) were used as material. After density separation the cells were cultured at a dose of 500 thousand cells / ml in 6-well plates (Biofil, China) in RPMI 1640 (Gibco, USA) supplemented with 10% FBS (HyClone, USA) at 37° C, 5% CO2. Expansion of lymphocytes was performed by kit with anti-biotin magnetic particles MACSiBead to CD2, CD3 and CD28 (Miltenyi Biotec, Germany), according to the manufacturer's protocol. Stimulation of lymphocyte proliferation was performed on days 4, 8 and 12 by introducing recombinant cytokines - IL-2, IL-7, IL-15 (Miltenyi Biotec, Germany) and their combinations. Cytokines were introduced at a concentration of 40 ng / ml each in the following variants: IL-2; IL-2 / IL-15; IL-2 / IL-15 / IL-7; IL-15; IL-15 / IL-7. Plates with cell suspension were cultured at 37 ° C, 5% CO2 for 15 days. Results: The data obtained on the 11th day of incubation demonstrated statistically significant differences in cell viability in samples with the addition of interleukin IL-7 / IL-15 combination (778%) compared to control samples by 1.5 times (p < 0.05). The proportion of lymphocytes in samples with the addition of only IL-15 (702%) and IL-7 / IL-15 (756%) combination was 1.47 and 1.6 times higher, respectively, compared with the control (p < 0.05) at the 12th day of co-cultivation. Conclusions: Stimulation of lymphocyte proliferation by the IL-7 / IL-15 combination results in a high frequency of viable cell production. Despite the only culture stage, the results of the study may be important for optimizing the use of γc-cytokines in the treatment of patients with breast cancer.