bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meta-analysis of randomized phase II-III trials evaluating triplet combinations of immunotherapy and targeted therapy for BRAF V600-mutant unresectable or metastatic melanoma.
Authors: Ferrucci Pier Francesco , Gaeta Aurora , Cocorocchio Emilia , D'Ecclesiis Oriana , Gandini Sara 
Published: June 2022

9541 Background: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF -V600 metastatic melanoma (B-mut MM) patients. However, still more than 50% of those patients do not respond or relapse to these current strategies. Preclinical and translational data suggest that ICI plus TT may improve treatment outcomes in patients with B-mut MM, but with conflicting results in the clinical setting. Methods: We performed a systematic review and meta-analysis of randomized phase II-III studies published until January 2022 comparing first-line ICI+TT vs TT alone in B-mut MM. We obtained summary estimates through random-effects models. Overall survival (OS) and progression-free survival (PFS) were the main outcomes retrieved but we look also at difference in responses and adverse events. Results: We summarized data from 3 independent trials and we showed a significant advantage in terms of PFS and OS for the experimental arms in B-mut MM patients treated with ICI+TT rather than TT alone. The summary estimate indicates a significant 23% decrease in risk of progression (SHR = 0.77, 95%CI: 0.66-0.89, with no between-study heterogeneity I2= 0%) and a significant 21% reduction in risk of death (SHR = 0.79, 95%CI: 0.66-0.96, with no heterogeneity I2= 0%). However, no difference was shown (p-value = 0.56) between arms in terms of summary Objective Response Rate (ORR) estimates (Summary ORR doublet = 65.4% [61.5%; 69.2%] and Summary ORR triplet = 67% [63%; 70.9%], respectively). From the subgroup analysis on PFS risk estimates, no significant differences were observed in summary HRs by age ( < 65 vs ≥65 years, p-value = 0.11), sex (female vs male, p-value = 0.58), ECOG PS (0 vs 1, p-value = 0.36), LDH levels (lower vs upper, p-value = 0.59) and PDL1 status (positive vs negative, p-value = 0.89). Significant differences were found in frequencies of grade 3 or more adverse events with higher number of events occurring in B-mut MM vs TT alone (Summary Odd Ratio = 2.01, 95%CI: 1.16-3.47, I2= 74%), whereas no significant differences were found in terms of any adverse event between arms (SOR = 1.83, 95%CI: 0.70-4.78, I2= 0%). Conclusions: This study supports and extend the discussion on first-line available combinations to be offered to B-mut MM patients. Combining ICI with TT demonstrated an effective advantage on both PFS and OS, although augmenting toxicities. Further biomarker-driven investigation may identify patient subpopulations who could benefit from ICI+TT combinations in order to expand their window of therapeutic opportunities.
Management of checkpoint inhibitor toxicity and survival in patients with advanced melanoma.
Authors: van Not Olivier Jules , Verheijden Rik Jasper , van den Eertwegh Alfonsus Johannes Maria , Haanen John B. A. G. , Blank Christian U. , Aarts Maureen J.B. , Van Den Berkmortel Franchette , de Groot Jan Willem , Hospers Geke , Kapiteijn Ellen , de Meza Melissa Melanie , Piersma Djura , Van Rijn Rozemarijn , Stevense - den Boer Marion , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Boers-Sonderen Marye J. , Blokx Willeke , Wouters Michel W.J.M. , Suijkerbuijk Karijn 
Published: June 2022

9546 Background: Management of checkpoint-inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of immunosuppressive treatment with anti-TNF on checkpoint-inhibitor efficacy. Methods: Advanced melanoma patients experiencing grade ≥3 irAEs after treatment with first-line ipilimumab-nivolumab between 2015 and 2021 were included from the Dutch Melanoma Treatment Registry. Progression-free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS) were analyzed according to toxicity management regimen. A cox proportional hazards model was used to account for the confounders age, sex, performance status, lactate dehydrogenase, site of metastases and type of irAE. Results: Out of 771 ipilimumab-nivolumab treated patients, 350 were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids only and 115 received steroids with second-line immunosuppressants consisting of anti-TNF, mycophenolic acid, tacrolimus and other immunosuppressants. Median PFS was significantly longer for patients treated with steroids (11.3 months) than for patients treated with steroids and second-line immunosuppressants (5.4 months; HR 1.43; 95%CI 1.07-1.90; p = 0.01). Median OS was also significantly longer for the steroids group (46.1 months) than for the steroids and second-line immunosuppressants group (22.5 months; HR 1.64; 95%CI 1.16-2.32; p = 0.005). Results for MSS were similar (not reached versus 28.8 months; HR 1.70; 95%CI 1.16-2.49; p = 0.006). Median PFS, OS and MSS are shown in Table 1. After adjustment for potential confounders, patients treated with steroids + second-line immunosuppressants showed a non-significant trend towards a higher risk of progression (HRadj 1.40; 95%CI 1.00-1.97; p = 0.05), a higher risk of death (HRadj 1.54; 95%CI 1.03-2.30; p = 0.04) and of melanoma-specific death (HRadj 1.62; 95%CI 1.04-2.51; p = 0.032) compared to the steroids group. Conclusions: Second-line immunosuppression for irAEs is associated with impaired PFS, OS, and MSS in advanced melanoma patients treated with first-line ipilimumab-nivolumab, irrespective of being anti-TNF or other second-line immunosuppressants. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in melanoma but also in other tumor types. [Table: see text]
Prophylactic lymphaticovenous bypass performed during complete lymphadenectomy is oncologically safe.
Authors: Cakmakoglu Cagri , Gastman Brian , Xia Thomas , Kwiecien Gregorz 
Published: June 2022

9557 Background: Lymphaticovenous anastomosis (LVA) is a physiologic surgery indicated for secondary lymphedema of the extremities, particularly for disease refractory to conservative management. Immediate lymphatic reconstruction (ILR) is prophylactic LVA concurrently performed with CLND. After the transected lymphatics are mapped through a dye injection, they are anastomosed to a nearby venous outflow tract. Though prophylactic LVA is increasingly being performed, its risk on cancer recurrence and distant metastasis is currently unknown. The purpose of this study was to compare the distant-metastasis free survival (DMFS) and relapse-free survival (RFS) times in melanoma patients who underwent prophylactic LVA during CLND versus those who underwent conventional CLND for grossly metastatic disease. Our study is the first prospective evaluation of the impact of prophylactic LVA on DMFS in patients undergoing CLND. Methods: This was a prospective study of patients with cutaneous melanoma who underwent CLND with concurrent LVA (LVA group) or CLND alone (comparison group) between 2012 and 2021. Patients were excluded if they had non-melanoma skin cancers, stage IV cancers before CLND, microscopic lymphatic disease only or follow-up time of less than 12 months who did not die from melanoma-related causes. The comparison group consisted of all consecutive patients that underwent CLND alone and met inclusion criteria. To reduce surgical technique variability, all cases were performed by a single, high-volume surgeon at a tertiary care center. Results: A total of 46 melanoma patients underwent prophylactic LVA during this time period. Twenty-three of these patients met all inclusion criteria and were included in the LVA group. Twenty-two consecutive patients that underwent CLND alone were included in the comparison group. All patients underwent either axillary or inguinal CLND. Average number of lymph nodes removed during CLND were 18.20 ± 9.61 and 17.04 ± 9.97 for the LVA and comparison groups, respectively (p = 0.69). Size of largest metastatic tumor in lymph nodes was 45.91 ± 35.03 mm and 44.54 ± 23.32 mm, respectively (p = 0.99). Average time to first recurrence diagnoses was 6.75 ± 3.54 months vs 8.28 ± 5.66 months. For distant metastases only, the average time to first recurrence diagnoses was 6.16 ± 3.79 months and 9.39 ± 6.19 months, respectively (p = 0.25). There was no significant difference in recurrence type between the two groups (p = 0.66). There were no differences in DMFS and RFS times between the LVA and comparison groups. Conclusions: Prophylactic LVA performed for grossly metastatic melanoma does not negatively impact DMFS nor RFS. Considering the extremely aggressive nature of melanoma, our finding is potentially applicable to other cancers that are amenable to CLND and LVA.
A real-world experience of TCH (docetaxel/carboplatin/trastuzumab) regimen in early, locally advanced and oligometastatic HER2 positive breast cancer from tertiary care center in North India.
Authors: Gupta Anshul , Gogia Ajay , Sagiraju Hari Krishna Raju , Deo S.V.S. , Gupta Ritu , Mathur Sandeep , Sharma Dayanand 
Published: June 2022

e12505 Background: In HER2 positive breast cancer, TCH is a safe and efficacious anthracycline free regimen used as both adjuvant and neoadjuvant modality. Three is scarcity of data regarding its long term safety and efficacy from India. Methods: This retrospective study comprised of 210HER2 positive breast cancer female patients treated with TCH [docetaxel (75mg/m2), carboplatin (AUC=6) and trastuzumab (8mg/kg loading followed by 6mg/kg) q 21 days with GSF prophylaxis] protocol for 6 cycles at our centre between Jan 2014 and Dec 2021. All eligible patients received maintenance trastuzumab, hormonal therapy and radiotherapy as per institutional protocol. The information regarding baseline clinico-demographic characteristics, treatment details, outcomes and toxicities were collected and evaluated. Results: The median age was 49 years (23-72), 113 (53.8%) were post-menopausal and 100 (47.6%) were Estrogen receptor/Progesterone receptor positive. Sixty-eight (32.4%) patients were stage I and II, 112 (53.3%) stage III and 30 (14.3%) were oligometastatic. TCH regimen was given as neoadjuvant chemotherapy (NACT) in 130 (61.9%) patients and as adjuvant chemotherapy in 80 (38.1%) patients. Of the patients receiving NACT, 114 (87.6%) patients underwent surgery. Twenty-two (19.3%) patients underwent breast conservation surgery and 92 (80.7%) underwent modified radical mastectomy. Over the study period, 62 (29.5%) patients had progression of the disease and 22 (10.5%) patients died. With a median follow up of 31.9 months, 3-year disease free survival (DFS) was 63.5% and overall survival (OS) was 90.8%. Median DFS was 31 months in patients with node positive disease and was not reached in patients with node positive disease. Of the patients who received NACT, pathologic complete response (pCR) was recorded in 42 (36.8%) patients. Three-year DFS was 59.1% in patients who achieved pCR and 44.8% in those who did not achieve pCR. Any grade 3/4 toxicity was seen in 26.7% patients which caused dose modification in 13.9% patients. The most common grade 3/4 hematological toxicity was anemia (15.1%) and thrombocytopenia (10.4%), while non-hematological toxicity was diarrhea (11.6%). Febrile neutropenia was seen in 4 (1.9%) patients. Four patients (1.9%) had reversible decrease in cardiac left ventricular ejection fraction. Conclusions: Anthracycline free TCH regimen is an effective and safe regimen for use in curative (adjuvant and neoadjuvant) setting for HER2 positive breast cancer in Indian women with outcomes comparable to the anthracycline based regimens reported in literature.
Are we overtreating stage I triple negative breast cancer in Ontario? A population-based study using the ICES database.
Authors: Shum Kathryn , Hussein Abdulkadir , Hamm Caroline M. 
Published: June 2022

e12511 Background: Triple-negative breast cancer (TNBC) has been associated with poorer long-term outcomes compared to other breast cancer subtypes. Due to the lack of targeted therapies, the use of adjuvant chemotherapy is the mainstay of treatment, and its efficacy has demonstrated to be correlated with tumor size. Currently, different national guidelines exist regarding chemotherapy in early stage I TNBC. This study aims to examine the outcomes of the use of adjuvant chemotherapy in stage I TNBC stratified by tumor size and treated in Ontario, using the ICES database. Methods: Records of stage I TNBC patients diagnosed in 2012 to 2014 were collected from the ICES database and analysed. Kaplan-Meier curves and log-rank tests were used to compared differences in overall survival (OS) between groups. Stage I TNBC cancer patients were analyzed by tumor size: T1a (< 0.5 cm), T1b (> 0.5 cm and < 1.0 cm) and T1c (>1.0 cm and < 2.0 cm). A Cox proportional hazard model was used to determine significance of variables. Results: Of the 610 stage I TNBC patients, 183 had tumor sizes ≤ 1cm, representing stages T1aN0M0 and T1bN0M0, and 427 had tumor sizes > 1cm to 2cm, representing stage T1cN0M0. Patients with tumor sizes ≤ 1cm who received adjuvant chemotherapy did not have a significant difference in OS compared to those who did not receive adjuvant chemotherapy (p = 0.41, hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.021-2.5). However, patients with tumor sizes > 1cm to 2cm who received adjuvant chemotherapy demonstrated a significantly better OS compared to those without (p = 0.023, HR = 0.40, 95% CI 0.16-0.86). Conclusions: Patients with TNBC stage T1cN0M0 should receive adjuvant chemotherapy for better OS. For stages T1aN0M0 and T1bN0M0, patients may be overtreated and avoidance of adjuvant chemotherapy can be considered at this time. Prospective studies should investigate the efficacy of adjuvant chemotherapy in TNBC patients with stage T1aN0M0 and T1bN0M0.
Melatonin effect on sleep disorders in breast cancer patients receiving adjuvant chemotherapy.
Authors: Shahrasbi Abdolali , Einei Nasrin , Esfandbod Mohsen , Derakhshan Kamran 
Published: June 2022

e12512 Background: Sleep disturbances in breast cancer patients who have received chemotherapy are among the most common causes of decreased quality of life during breast cancer treatment. Melatonin is an endogenous hormone and its secretion level is directly related to sleep quality. Melatonin supplements may help with certain conditions, such as delayed sleep-wake phase disorder. In this study, we investigated the effect of melatonin pills in treating sleep disorders in patients diagnosed with invasive breast cancer and who were received adjuvant chemotherapy. Methods: In this randomized clinical trial (before and after), 25 breast cancer patients aged 40 to 60 years who were under adjuvant chemotherapy drugs and had sleep disorders Pittsburg sleep quality index (PSQI) < 5, were enrolled. All the patients were interviewed by a psychiatrist and learned about the Pittsburg questionnaire and filled it out personally. They were evaluated in three phases before starting chemotherapy, one month and three months later. Melatonin was administered orally at a dose of 6mg per night. Then, the effects of melatonin on sleep disorders were determined by the questionnaire and compared by analysis of variance (ANOVA tool) and required statistical analysis. Results: In our study, all cases were women with a mean age of 48.4 ± 6.3 years. In general, all the different domains of sleep components except the “sleeping pills” section were significantly improved during the study period. Over the first 30-days, total score, sleep quality, sleep duration, sleep delay, and daily performance improved considerably. By the end of day 90, sleep efficiency and sleep disorders also became better (table). Conclusions: Melatonin well affects the sleep condition of breast cancer patients who received adjuvant chemotherapy, and this effect persists with the continuation of the treatment plan.[Table: see text]
Automated H&E whole slide image surrogate Ki67 index prediction and prognostic value across breast cancer subtypes.
Authors: Mukhopadhyay Satabhisa , Dasgupta Tathagata , Berwick Angelene , Walsh Elizabeth , Hanby Andrew , Millican-Slater Rebecca , Cummings Michele , Orsi Nicolas M. 
Published: June 2022

e12518 Background: Despite its purported prognostic significance in breast cancer, Ki67 index assessment remains poorly standardized and features high discordance rates amongst pathologists. Moreover, its clinical utility is presently confined to low stage, ER+/HER2- tumors in determining the advisability of adjuvant chemotherapy. Unfortunately, established cut-offs limit its utility to tumors with either high or low Ki67 index extremes. While Ki67 is a marker of actively dividing cells, it fails to capture the detail of cell cycle phase and dynamics which could be informative in terms of prognosis and tumor sensitivity to specific therapies (e.g. CDK4/6 inhibitors). This study therefore developed two novel indices as surrogates of (i) Ki67 index and (ii) quiescent cell population load (QPL). Methods: Breast cancer (comprising evenly distributed hormone receptor/HER2 status cases) H&E slides ( n = 79 cases/108 slides) were digitized on an Aperio DT3 scanner, and used to extract surrogate Ki67 and QPL indices. Sections were also stained for Ki67 by immunohistochemistry (IHC) using a clinically validated assay and digitized. Whole slide image (WSI) tumor Ki67 counts were performed on QuPath and used to validate the surrogate Ki67 index (Cohen’s kappa score). Indices (i) and (ii) were related to progression free survival (PFS). Survival analyses were performed using Kaplan-Meier (KM; with median cut-off) and Cox Proportional Hazards (as a continuous variable) models. Results: The surrogate Ki67 index showed good concordance with IHC scores (kappa = 0.76; 95%CI 0.61-0.91; P< 0.00001). However, this surrogate index performed better as a prognostic indicator of PFS compared to conventional Ki67 IHC (KM P = 0.048; HR = 1.35, P = 0.015 vs. KM P = 0.70; HR = 1.23, P = 0.08). Prognostically, the QPL index outperformed both Ki67 indices (KM P = 0.03; HR = 3.22, P = 0.001). Conclusions: We have developed two novel surrogate indices of Ki67 and QPL that can be readily automated to analyze H&E breast cancer WSIs. Our results show that both outperformed conventional Ki67 IHC evaluation in terms of prognostication, applied across molecular subtypes, improved informativeness of mid-range Ki67 index calls, and could potentially have predictive merit in selecting patients for cell cycle targeted therapies such as CDK4/6 inhibitors.
Effectiveness of chemotherapy on prognosis of elderly breast cancer: A retrospective cohort study based on SEER database.
Authors: Wu Yunhao , Qi Yana , Yang Jiqiao , Yang Ruoning , Chen Ruixian , Huang Ya , Liu Weijing , Zhao Xin , He Tao , Lu Shan , Fu Zhoukai , Wang Zhu , Li Qintong , Sun Xin , Chen Jie 
Published: June 2022

e12525 Background: The estimated population of breast cancer older than 70 years is over 80,000 new onset cases in 2019 and keep increasing. Currently, the proportion of standard chemotherapy for elderly patients was much lower than that for young patients, due to shorter life expectancy, more comorbidities, and concerns over increased toxicities and reduced tolerance. Till now, few evidences from clinical trials could support the use of chemotherapy for elderly patients, as also indicated by current guidelines for adjuvant chemotherapy. The effectiveness of chemotherapy for elderly breast cancer remains to be further verified. Methods: We identified 75,525 female breast cancer patients aged 70 years and older in the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2010, to December 31, 2016, and excluded those patients with secondary, metastatic, or bilateral breast cancer, not confirmed by pathology, lacking of key information, dead or loss to follow-up in 6 months after diagnosis. Propensity score matching (PSM) (PSM ratio: 1:1, caliper: 0.2* standard deviation of propensity score) was applied to construct balanced cohorts with or without chemotherapy based on demographic and pathophysiological characteristics. Kaplan-Meier analysis, multivariable Cox proportional model, and subgroup analysis were performed to evaluate the effectiveness of chemotherapy on overall survival (OS) and breast cancer-specific survival (BCSS). Results: A total of 33,177 eligible patients were included, of them, 5273 (15.89%) received chemotherapy. Through PSM, 8360 patients were successfully matched and almost reached balances between groups. In matched dataset, patients receiving chemotherapy exhibited a better prognosis on OS and BCSS (the 5-year survival rate, OS: 0.80 [0.78-0.82] with chemotherapy vs. 0.71[0.69-0.73] control; BCSS: 0.88 [0.87-0.89] with chemotherapy vs. 0.85 [0.84-0.86]; both log-rank test, P < 0.001); in multivariable Cox analysis, chemotherapy was associated with a 35% and 21% risk reduction on OS (HR [95%CI]: 0.65[0.59-0.72]) and BCSS (0.79[0.69-0.91]), respectively. Furthermore, subgroups with HER-2 positive, or more lymph nodes involved, were inclined to benefit more from chemotherapy. Conclusions: Our study provided additional evidences that chemotherapy may improve the prognosis of elderly breast cancer, especially for those subpopulations benefit more from chemotherapy treatment.
Describing U.S. real-world patients (pts) with hormone receptor-positive early breast cancer (HR+ EBC) by risk status.
Authors: Downer Mary K. , Yakubu Amin , Pérez-Moreno Pablo Diego , Steenrod Anna , Badovinac Crnjevic Tanja , Machackova Zuzana 
Published: June 2022

e12548 Background: Despite high endocrine therapy (ET) efficacy in HR+ EBC, there is an unmet need to improve outcomes across risk statuses. We describe HR+ EBC demographic and tumor characteristics, treatment, and outcomes by risk status, to inform trial design, outcomes, and care. Methods: Pts from the de-identified, nationwide US, Flatiron Health electronic health record-derived database had HR+ EBC diagnosed from January 1, 2011 to November 30, 2020. We grouped pts into EBC with clinically relevant, high risk (stage T4 or ≥N2; or N1 with ≥1 of ≥T3, grade 3, Ki67 ≥20%, Oncotype DX ≥26), medium risk (N1, not high risk; or N0 with ≥1 of grade 3, Ki67 ≥20%, Oncotype DX ≥26), or low risk (N0, not medium risk) of recurrence. Chi-square and Kruskal–Wallis tests compared characteristics and treatments; Kaplan–Meier methods estimated event-free/overall survival (EFS/OS). Results: Of 7924 pts, 3908 (49.3%), 2477 (31.3%), and 1213 (15.3%) were classified as low-, medium-, and high-risk EBC, respectively (326 missing). Pts with medium-/high-risk EBC vs low-risk were less likely to be non-Hispanic white (p < 0.001), more likely to receive BRCA, MammaPrint, or next-generation sequencing testing (p < 0.001), be slightly younger (p < 0.001), pre-menopausal at diagnosis (p < 0.001), diagnosed in earlier calendar years (p = 0.01), and have invasive lobular carcinoma (p < 0.001). Pts with high-risk EBC were more likely to receive neoadjuvant chemotherapy (NACT) ± ACT vs lower risk. High-risk EBC had significantly lower 3-year EFS/OS vs medium-/low-risk (EFS 0.85 [95% CI = 0.82, 0.87] vs 0.95 [0.94, 0.96]/0.98 [0.98, 0.99], p < 0.0001; OS 0.9 [0.88, 0.92] vs 0.97 [0.96, 0.97]/0.97 [0.96, 0.97], p < 0.0001). Conclusions: Real-world differences in US characteristics, treatments, and outcomes by risk status exist in HR+ EBC. As expected, pts with higher risk EBC were more likely to receive NACT ± ACT. Despite missing risk factors and limited follow-up, and potential misclassification of risk status/treatment and overestimation of time-to-events, US treatment patterns are guideline-aligned. Inferior outcomes in high-risk HR+ EBC show a continued need for improved treatments.[Table: see text]