bluuebunny/crossref_metadata_2025 huggingface dataset:
Latent atherosclerosis as a risk factor in chemotherapy-induced cardiomyopathy.
Authors: Paulenka Yuliya , Cotto Maritza , Rickette Christine , Hunter Krystal
Published: June 2021

e12525

Background: Anthracyclines and monoclonal antibodies targeting HER2/neu receptors are widely used antineoplastic agents in breast cancer treatment. Both therapies have been known to cause cardiovascular adverse effects, notably chemotherapy-induced congestive heart failure, especially if used in combination. Multiple factors have been postulated to increase the risk of doxorubicin and trastuzumab-associated cardiotoxicity, including a pre-existing coronary artery disease, but the role of latent atherosclerosis has not been widely studied. Methods: We retrospectively reviewed health records of female breast cancer patients at our institution treated with doxorubicin or trastuzumab between 2012 and 2017. Using echocardiography, we identified patients with underlying atherosclerotic lesions at the start of the treatment and those who subsequently developed cardiotoxicity. Chemotherapy-induced cardiomyopathy was defined as a drop in the ejection fraction (EF) to < 50% from the normal EF of > 53% pre-therapy. We used a χ2 test to search for the relationship between atherosclerosis and subsequent cardiotoxicity. Results: A total of 518 patient records were reviewed. Of 518 patients with breast cancer, 93 (18%) received doxorubicin or trastuzumab-based chemotherapy. The median age for breast cancer diagnosis was 58. Sixty-one patients (66%) were identified to have atherosclerosis on echocardiography at the time of the first chemotherapy cycle. The most common location for atherosclerotic lesions was in the aortic arch and proximal upper abdominal aorta. Of 61 patients with atherosclerosis, ten (16.4%) subsequently developed chemotherapy-induced cardiomyopathy (p = 0.77). A post hoc analysis was performed to compare the two cohorts aged 40 to 50 (p = 0.49) and 51 to 75 (p = 1.00) as they represented the majority of breast cancer cases. Conclusions: The role of atherosclerosis in doxorubicin and trastuzumab-induced toxicity remains unclear. We did not observe any statistical correlation between atherosclerosis at the start of chemotherapy and increased rates of cardiac injury. A younger population may be more susceptible to cardiotoxicity, but further research is needed as the study has limitations. Although we identified patients with latent atherosclerosis, additional evaluation via carotid artery intima-media thickness measurements would yield more precision. Other methods such as the use of computed tomography and coronary artery calcium scores would also allow for assessing atherosclerotic plaque burden. Still, not all patients were subjected to these techniques. Furthermore, the study was challenged by the small sample size and its retrospective nature. Larger prospective studies are essential to explore this area further. Identifying the means of reducing cardiovascular complications remains a priority as heart disease is currently the leading cause of death among breast cancer survivors.
Integrated immune-related gene signature to predict clinical outcome for patients with luminal B breast cancer.
Authors: Kuang Xiaying , Cai Du , Lin Ying , Gao Feng
Published: June 2021

e12526

Background: Luminal B breast cancer is always routinely treated with chemotherapy and endocrine therapy but heterogeneous with respect to sensitivity to treatment, identification of patients who may most benefit remains a matter of controversy. Immune-related genes (IRGs) was found to be associated with the prognosis of breast cancer. The aim of this study is to evaluate the impact of IRGs in predicting the outcome of luminal B breast cancer patients. Methods: According to the Metabric microarray dataset also as a training cohort, 488 luminal B breast cancer patients were selected for generation of immune-related gene signature (IRGS). Another independent dataset (n=250) of patients with complete prognostic information was analyzed as a validation cohort. Prognostic analysis was assessed to test the predictive value of IRGS. Results: A model of prognostic IRGS containing 12 immune-related genes was developed. In both training and validation cohorts, IRGS significantly stratified luminal B breast cancer patients into immune low- and high-risk groups in terms of disease free survival (DFS, HR=4.95, 95% CI=3.22-7.62, P<0.001 in training cohort, HR=2.47, 95% CI=1.29-4.75, P<0.001 in validation cohort). Multivariate analysis revealed IRGS as an independent prognostic factor (HR=4.96, 95% CI=3.00-8.18, P<0.001 in training cohort, HR=2.56, 95% CI=1.28-5.09, P=0.007 in validation cohort). Furthermore, those 12 genes mostly related with response to chemical, and the expression levels of them were completely opposite in patients of immune low- and high-risk groups. Conclusions: The proposed IRGS is a satisfactory prognostic model for estimating DFS of luminal B breast cancer patients. Further studies are needed to assess the clinical effectiveness of this system in predicting prognosis and treatment options for luminal B breast cancer patients. This work was supported by National Natural Science Foundation of China (No. 81602520), Natural Science Foundation of Guangdong Province (No. 2017A030313596).
Automated immunostaining-free prediction of breast carcinoma ER and PR status, Ki67 count, patient therapy stratification index and quantification of prognostic quiescence burden in TNBC from pretreatment H&E stained histopathology images in breast cancer.
Authors: Dasgupta Tathagata , Mukhopadhyay Satabhisa , Orsi Nicolas M , Cummings Michele , Berwick Angelene
Published: June 2021

e12535

Background: Categorical combinations of ER, PR, HER2, and Ki67 levels are traditionally used to classify patients into luminal A and B-like subtypes in order to inform treatment choice. Accounting for nearly 70% of all breast malignancies, luminal cancer is heterogeneous, harboring subtypes with distinct molecular profiles and clinical outcomes. Although most patients with luminal-type disease respond well to endocrine therapy alone, some develop recurrences benefiting from additional cytotoxic therapy. Identifying such cases a priori remains a challenge but would enable patients to be spared the debilitating side-effects of ineffective chemotherapy. In this regard, the efficacy of chemotherapy and disease recurrence relate to (i) ER driven G1/S perturbations and/or (ii) quiescent cell populations arrested in the G0/G1 phase of cell cycle. This study aimed to develop a histopathology whole slide image (WSI)-based, low cost, rapid and automated approach to: (i) predict ER/PR/Ki67 status, (ii) quantify quiescence burden, (iii) develop a G1/S-based patient stratification system for luminal A/B patients, and (iv) achieve a quiescence burden-based stratification of TNBC patients. Methods: This investigation centered on the initial clinical validation of a novel, immunostaining-free technology which uses information extracted from pre-treatment hematoxylin and eosin (H&E) stained slide WSIs alone to achieve these aims. Unlike conventional artificial intelligence-based approaches, the underlying proprietary algorithm and its prediction criteria are based on deterministic, hard-coded observational relationships of continuous scales drawn from WSI morphological features. In this instance, these represent tumor-related biological pathway disruptions and mitotic checkpoint perturbations, where G1/S perturbations enable luminal subtype stratification, and G0/G1 perturbations reflect quiescence burden. Back projecting the algorithm’s quiescence burden output on to the original WSIs enables morphological patterns to be mapped to quiescence burden.
Scalp cooling to reduce alopecia as a barrier to chemotherapy.
Authors: Pupo Wiss Isabel M. , Hagigeorges Dina , Walker Chloe J. , Flanagan Kelly E. , James James T. , Geary Molly C. , Fay Mary , Senna Maryanne M , Isakoff Steven J.
Published: June 2021

e12537

Background: Chemotherapy induced alopecia (CIA) is one of the most distressing adverse events reported by patients undergoing chemotherapy, yet there is limited data addressing the impact of CIA on treatment acceptance. Scalp cooling (SC) has been shown to decrease CIA. Here we report our assessment of CIA as a barrier to chemotherapy and the efficacy of SC using pre- and post-treatment surveys of patient reported outcomes. Methods: Patients who received alopecia-inducing chemotherapy and utilized SC between November 2018 and September 2020 at our institution were enrolled in a prospective IRB approved registry. Surveys including the Chemotherapy Induced Alopecia Distress Scale (CADS) were administered before and within two weeks after treatment. Using the CADS survey, patients were asked about their hesitation to receive chemotherapy and the burden they feel about alopecia as a side effect of chemotherapy. Results: Of 90 patients who completed the first or last treatment survey, the most common treatment regimens were docetaxel/cyclophosphamide (TC), docetaxel/carboplatin/trastuzumab/ pertuzumab (TCHP), and paclitaxel/trastuzumab (TH). The most common disease type was breast cancer (92.2%) and all participants were females. Of 74 SC patients who completed the pre-treatment survey, the median age was 50.5 (range 26-75) and included 65 (87.8%) Caucasian, 4 (5.4%) Black, and 3 (4.0%) Asian patients. 89.2% used Paxman SC and 10.8% used Penguin SC. Of those who completed the CADS survey prior to treatment, 8 (10.8%) reported ‘quite a bit’ to ‘very high’ hesitation, and 34 (46.0%) reported feeling that alopecia was either ‘quite’ or ‘very much’ a burden of chemotherapy. All 40 SC patients (median age 53.5, range 31-76) who completed the post-treatment survey were Caucasian and used Paxman SC. Self-reported efficacy of SC in these 40 patients was less than 10% hair loss in 10 (25.0%), 11-25% hair loss in 7 (17.5%), 26-50% hair loss in10 (25.0%), 51-75% hair loss in 9 (22.5%), and 76-100% hair loss in 4 (10%). Overall, 27 (67.5%) patients reported SC limited alopecia ‘a lot’ to ‘perfectly’. Conclusions: In our study, alopecia was identified as a notable burden to nearly half our SC patients and 10.8% hesitated when making their decision to receive chemotherapy. After using SC during treatment, 67.5% of patients reported less than 50% hair loss, and 67.5% reported that SC reduced alopecia ‘a lot’ or ‘perfectly’. Our study highlights the significance of alopecia as a chemotherapy burden and potential barrier to accepting treatment, and suggests SC may be efficacious in decreasing CIA, which may allow patients to feel less hesitation towards chemotherapy.
COVID-19 outcomes in patients with a history of breast cancer: A diverse multicenter Los Angeles cohort study.
Authors: Kathuria-Prakash Nikhita , Antrim Lauren , Sun Alexander W , Kang Irene , Garcia-Jimenez Maria De Lourdes , Angell Trevor E , Lechner Melissa G , In Gino Kim
Published: June 2021

e12544

Background: Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has affected over 100 million individuals during the current pandemic. Cancer is a reported risk factor for worse outcomes from SARS-CoV-2 infection and its clinical syndrome COVID-19. However, risk associated with specific cancer subtypes, extent of disease, and treatment history remains unclear. Breast cancer is the most common cancer in women and is treated with multiple modalities that may affect COVID-19 severity and outcomes, including surgery, radiation (RT), hormone therapy (HT), and chemotherapy (CT). Methods: We conducted a retrospective cohort study of patients with SARS-CoV-2 and history of breast cancer at two academic centers in Los Angeles, CA between January – September, 2020. Demographic information, cancer diagnosis, treatment history, comorbid conditions, and clinical outcomes of COVID-19 were reviewed. The primary outcome was rate of hospitalization for COVID-19. Associations were evaluated for significance by chi-square test or Student’s T test, with a = 0.05. Results: Our cohort included 61 patients with history of breast cancer. 19 (31.1%) required hospitalization and 3 (4.9%) died from COVID-19. Median age was 61 years. 44% of patients were White/Caucasian, 37.7% Hispanic/Latinx, 8% Black/African American, 5% Asian, and 5% were of another race. 87% of patients had local or regional disease and 13% had distant metastases. 53% of patients had ever received CT historically, 66% HT, and 53% RT. 25% of patients received cancer treatment (surgery, CT, or RT) within 90 days of COVID-19 diagnosis. 38% were on HT at time of COVID-19 diagnosis. Patients with prior RT were more likely to be hospitalized from COVID-19 than those with no prior RT (44% vs 14%, p = 0.02), as were patients with 2 or more comorbidities (p = 0.01). In addition, there was a trend toward lower hospitalization rates for patients on HT [24% vs. 42% (p = 0.17)] and a trend toward higher hospitalization rate for non-white ethnicity [35% vs. 25% (p = ns)]. Extent of disease, history of CT, or receipt of any cancer treatment (e.g. surgery, RT, CT) within 90 days of COVID-19 diagnosis were not associated with hospitalization rate. Conclusions: In our diverse cohort of breast cancer patients with COVID-19 a history of RT and presence of multiple comorbidities were both associated with increased risk of hospitalization, while a history of HT was not. Further investigation is needed to validate these findings in larger cohorts. These findings may inform recommendations for breast cancer patients during the ongoing SARS-CoV-2 pandemic.
Heterogeneity between core needle biopsy and synchronous axillary lymph node metastases in early breast cancer patients: Comparison of HER2, estrogen and progesterone receptor expression profiles during primary treatment regime.
Authors: Weydandt Laura , Nel Ivonne , Kreklau Anne , Horn Lars-Christian , Aktas Bahriye
Published: June 2021

e12565

Background: Therapeutic decisions for the primary treatment of breast cancer is commonly based on the expression profiles of estrogen (ER), progesterone (PR) and the human epidermal growth factor 2 (HER2) receptors. However, breast cancer is a very heterogeneous disease, and receptor changes were manifold reported during progression. Little is known about receptor discordance in the primary setting. Here, we compared receptor expression profiles between core needle biopsy (CNB) of the breast tumor tissue and synchronous axillary lymph node metastases (LNM) not at recurrence, but at the primary treatment. Methods: In a German single center study, we retrospectively analyzed 175 breast cancer patients with axillary synchronous LNM. 69,7% of our patients were without any upfront therapy. Profiles of ER, PR and HER2 were immunohistochemically analyzed using the common cut-off at 10% positive tumor cells vs. the controversially discussed low-positive cut-off at 1%. Receptor status was compared between CNB specimens of the primary tumor tissue and axillary LNM. Further, clinicopathological characteristics were correlated to receptor changes. Results: The discordance rates between CNB and axillary LNM were 12.7% for HER2, 6.9% for ER and 22.6% for PR using the ≥1% cut-off, respective 7.5% for ER and 25.6% for PR when using the ≥10% cut-off-level. The most frequently occurring change was a PR loss. Analysis of clinical parameters revealed a significant association of ER change between CNB and LNM in younger patients (p < 0.01) with increased proliferation marker Ki-67 (p = 0.04). Conclusions: Receptor discordance between CNB and synchronous axillary LNM appears to exist at the primary setting already. Hence, receptor profiles of the tumor tissue and the synchronous axillary LNM should be considered for treatment decision.
A novel, computer-aided, scanning platform agnostic solution for grading carcinomas in breast biopsy whole slide images.
Authors: Orsi Nicolas M , Dasgupta Tathagata , Mukhopadhyay Satabhisa , Cummings Michele , Berwick Angelene
Published: June 2021

e12575

Background: The determination of breast cancer grade remains a problematic diagnostic issue in biopsies due to limited tissue sampling and the inherent inter-observer variability associated with the Nottingham (histologic) score. Significantly, biopsy grading corresponds only moderately with that based on excision specimens, with discordance rates of 21-30.0%, which is a concern for cases managed neoadjuvantly or with minimally ablative therapy. Although the advent of digital pathology has encouraged endeavors to automate breast cancer detection and grading, no method has yet received regulatory approval for clinical use or proven to be a platform agnostic solution. Methods: This study was the blinded clinical validation a novel, FDA breakthrough designation approved automated device-based predictive solution which uses a surrogate scale to determine breast carcinoma grade in core biopsies using H&E slide whole slide images (WSIs) only. Non-preselected malignant breast core biopsy clinical cases (n=173 WSIs; 107 cases) covering a broad spectrum of breast cancer morphological subtypes were scanned at x20 magnification on both on Aperio high-throughput T2/T3 systems (.SVS files) and Roche-Ventana DP200 scanners (.BIF files). The diagnostic gold standard reference was the reports of tertiary referral center breast subspecialty consultant histopathologists. Diagnostic outputs were also compared to case-matched resection specimen grades. Comparison of diagnostic outcomes with pathologists as gold standard was done using inter observer agreement (cohen kappa) with 95% CI and statistically significant chi-squared test p-value for two different scanner platforms. Results: Although biopsy-based diagnostic concordance with pathologists was very good, the device actually delivered a much better concordance between case-matched biopsy and resection specimen (accuracy: 95%, cohen kappa: 0.91) relative to pathologists’ assessments (accuracy: 80%). Conclusions: This indicates that the use of a single continuous surrogate grading scale is much less affected by limited tissue sampling than conventional ordinal morphological scales. This level of performance was independent of file format analyzed, demonstrating the device’s platform agnosia.
Composite scoring combining OncotypeDX risk with circulating tumor cell status improves prognostication.
Authors: Bilani Nadeem , Elson Leah , Elimimian Elizabeth Blessing , Liang Hong , Nahleh Zeina A.
Published: June 2021

e12577

Background: Genomic assays, such as the 21-gene OncotypeDX (ODX) and the 70-gene MammaPrint (MP) panels, can be used to personalize treatment for women with early-stage, hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC). We previously showed that 1) circulating tumor cell (CTC) status has prognostic and predictive value in BC, and that 2) there is no clear association between ODX risk and CTCs. We, hereby, assess the prognostic value of composite scoring combining ODX and CTC data. Methods: This analysis of the 2004-2017 National Cancer Database registry includes patients with early-stage (AJCC I-II), HR+/HER- BC, as well as ODX, MP, and CTC data. A composite model was created with ODX and CTC data: low-risk escalated to intermediate-risk, or intermediate- to high-risk, if positive for CTCs. The association between a) ODX, b) ODX-CTC composite, or c) MP and overall survival (OS) was examined using Cox regressions, controlling for age (50-70); and stratifying by race (White vs. Black) and tumor histology (ductal vs. lobular). Prognostic value was evaluated using Harrell’s C-index (i.e. area under ROC curve) for each model. Results: N = 841,716 patients with early-stage, HR+/HER2- BC were identified. N = 271,416 (32.2%) had ODX data, n = 12,417 (1.5%) had MP data, and n = 1,141 (0.14%) had both ODX and CTC data. Due to CTC-positivity, n = 46 patients were upstaged from low- to intermediate-risk (23.1% of all low-risk), while n = 63 patients were upstaged from intermediate- to high-risk (20.5% of all intermediate-risk) in the composite ODX-CTC model. All 3 prognostic scoring systems were associated (p < 0.05) with OS as per Cox regressions. As indicated by a C-index closer to 1, MP appears superior to ODX alone at differentiating high- from low-risk based on OS (0.597 versus 0.565) patients. However, composite ODX-CTC scoring was superior to MP alone (0.673 versus 0.597). This model could not be validated in Black patients (versus White) or those with lobular histology (compared to ductal) due to limited ODX-CTC data in these groups. Conclusions: Composite ODX-CTC risk scoring appears superior to MP alone. If confirmed, this prognostic model would more accurately identify early-stage, HR+/HER2- patients requiring escalated systemic therapy including chemotherapy compared to low-risk BC. More data is needed in ethnic minorities and patients with atypical histology to validate these promising results.[Table: see text]
Laser ablation of multifocal breast carcinoma: Assessing viability for patients not accepting surgery.
Authors: Bhalla Rusy
Published: June 2021

e12584

Background: Breast carcinoma is a major public health problem in India and world. It is the leading cause of cancer in women in India. The overall 5 year survival rate in western countries is over 90%. In India it drops to 40 to 60%. The various factors responsible for this include presenting late due to unacceptability of many women for mutilation of their breasts. Breasts being a very important feminine cosmetic benchmark. Methods: Laser ablation of Breast tumours is now a USFDA and CE approved procedure. The aim of this observational study was to observe completion of tumour ablation by intralesional laser ablation. Laser Ablation was performed as a single procedure in 10 women over a 7 year period. All women who consented to the procedure were in stage late stage 2 and 3 with multifocal and/or multilocational disease. As such they were not candidates for Breast Conservation surgery. Pre laser PET scans confirmed the absence of Metastatic disease outside breast and Axilla. Results: All Post Menopausal patients showed a complete necrosis of the tumour and axillary lymph nodes on a follow up of 2 to 7 years. The findings were confirmed on serial PET scans after 6 months and 2 years. Pre menopausal women showed recurrence in non laserised areas and were given follow up Laser Ablation procedure. Conclusions: Laser Ablation is a viable procedure for patients unwilling for mastectomy in stage 3 Breast cancer. The skill sets required for the procedure are new and surgeons will have to be trained for the procedure.
H&E-like histology of unstained fresh and formalin fixed breast tissue with Photo Acoustic Remote Sensing (PARS) microscopy.
Authors: Mackey John Robert , Ecclestone Benjamin , Dinakaran Deepak , Bigras Gilbert , Reza Parsin Haji
Published: June 2021

e12590

Background: Approximately 30% of breast cancer patients undergoing breast-conserving surgery (BCS) require re-excision(s) to obtain clear margins, causing delays in adjuvant treatment, poor aesthetic results, and increased infection rates, costs, and patient anxiety. Frozen section pathology assessment (FSA) reduces re-excision rates from 27% to 6%, but FSA extends operative times and has a false negative rate of 17%. Photo-Acoustic Remote Sensing (PARS) is a new laser-based light microscope that permits non-contact cellular resolution imaging of unstained tissues. Methods: We used an ultraviolet reflection-mode PARS microscope to study i) formalin-fixed, paraffin embedded (FFPE) breast tissue blocks, ii) unstained thin sections of FFPE invasive ductal carcinoma and ductal carcinoma in situ, iii) formalin fixed bulk surgical specimens of benign and malignant human breast tissue, and iv) benign and malignant fresh rodent mammary tissue without fixation, processing, or staining. Fresh tissues were imaged after a range of warm ischemic times and across a range of cold ischemic times in neutral phosphate buffered saline at 4°C. For each condition, an ultraviolet laser was used to excite DNA and other cellular components in these samples, and signals were captured using a continuous-wave detection laser. The PARS signal was false-colored to closely replicate traditional hematoxylin and eosin staining. Results: In all fixed tissues, PARS virtual histology images were of diagnostic quality, permitted margin assessment, and analogous to transmission light microscopy of standard hematoxylin and eosin-stained FFPE slides, achieved without tissue sectioning or tissue staining. Furthermore, PARS microscopy also provided cellular level virtual histology images in fresh breast tissue with warm and cold ischemic times ranging from twenty minutes to two hours; these images have no available clinical comparators as non-contact cellular level imaging of unprocessed fresh tissue has not previously been reported. In aggregate, we demonstrate the feasibility of PARS to provide diagnostic and margin assessment images across a range of tissues including formalin fixed and freshly resected, unstained, unprocessed breast tissue. Conclusions: PARS is a new microscope technology addressing the practical needs of intraoperative margin assessment during BCS: i) no requirement for tissue staining, ii) rapid acquisition of hematoxylin and eosin-like images without the requirement for tissue freezing, embedding, or sectioning, iii) diagnostic quality cellular resolution, and iv) assessment of resected bulk tissue margins. In principle, this technology may also permit label-free non-contact intraoperative margin assessment of the surgical cavity. These data support the clinical development and evaluation of PARS microscopic intraoperative assessment of BCS margins.
Prior DCIS and overall mortality in women with stage I breast cancer.
Authors: Nelson Rebecca A. , Lai Lily L. , Mortimer Joanne E. , Soto Perez De Celis Enrique , Chlebowski Rowan T. , Kruper Laura
Published: June 2021

e12593

Background: Whether a prior diagnosis of ductal carcinoma in situ (DCIS) impacts women later diagnosed with invasive breast cancer is unclear. If localized breast cancer following DCIS is more aggressive than localized breast cancer alone, this could inform therapy decisions. To our knowledge, no study has examined the impact of prior DCIS on overall mortality in women with stage I invasive breast cancer. The study objective was to determine if overall mortality for women with stage I breast cancer with prior DCIS is different from those with stage I disease without prior DCIS. Our hypothesis was that women with prior DCIS would have higher mortality compared to those without prior DCIS. Methods: 302,484 patients with stage I cancer diagnosed from 1998 to 2016 were ascertained from SEER. Of these, 5,011 (1.7%) had prior DCIS. Patients with DCIS were matched 1:2 to women with no prior DCIS based on age, year of diagnosis, race/ethnicity, marital status, and invasive breast cancer characteristics including histology, tumor grade, tumor size, T stage, N stage, ER/PR status, surgery type, radiation, and chemotherapy status. The primary study outcome was overall mortality. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI). Results: Cases and controls had similar demographics. Compared to women with stage I breast cancer without prior DCIS, overall mortality was statistically significantly lower in women with stage I breast cancer with prior DCIS (hazard ratio [HR] 0.89 95% confidence interval [CI]0.80-0.98). Other factors associated with overall mortality were bilateral mastectomy (adjusted HR: 0.62; 95% CI: 0.49-0.78), radiation therapy (adjusted HR: 0.64; 95% CI: 0.56-0.75) and chemotherapy (adjusted HR: 0.85; 95% CI: 0.72-0.99). Factors associated with higher overall mortality included age (trend p < 0.001), tumor grade (trend p = 0.003), and negative PR receptor status (adjusted HR: 1.29; 95% CI: 1.13-1.45). Breast cancer specific mortality, however, was statistically significantly higher in women with prior DCIS to their breast cancer diagnosis compared to women without prior DCIS to their breast cancer diagnosis (HR 1.24 95% CI 1.01-1.52). Conclusions: Contrary to our hypothesis, women with prior DCIS and subsequent stage I breast cancer have lower overall mortality compared to matched controls with stage I breast cancer without prior DCIS. In contrast, those with prior DCIS have higher breast cancer specific mortality than those without prior DCIS. Reasons for this discrepancy are unknown, but since DCIS is most commonly diagnosed on mammogram, differences may be related to sociodemographic characteristics that are associated with both higher screening adherence and higher overall survival, such as higher income, higher education achievement , and higher access to health care.
Does pathological complete remission after neoadjuvant chemotherapy translate to longer relapse-free survival in patients with triple-negative breast cancer in the Indian population?
Authors: Sharma Rakesh Kumar , Gogia Ajay , Deo SVS , Sharma Dayanand , Mathur Sandeep , Sagiraju Hari Krishna Raju
Published: June 2021

e12618

Background: Attainment of pathological complete remission (pCR) with neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) is associated with improved survival outcomes. However, data corroborating this fact is lacking from the Indian subcontinent. Methods: We evaluated 179 cases of TNBC, registered at Dr. B.R.A., I.R.C.H., AIIMS, New Delhi, from a period of May 2013 to July 2020, who were treated with neo-adjuvant chemotherapy (NACT) followed by surgery. Patients with oligometastatic disease who were treated with NACT with curative intent were also included in the analysis. Multivariate logistic regression analysis was done to explore the factors associated with the achievement of pCR. Survival analysis was done to study the correlation of pCR with relapse-free survival (RFS) and overall survival (OS). Results: The median age of our cohort was 43 (18-67) years. Study population comprised 104 (58.1%) pre-menopausal, 67 (37.4%) post-menopausal and 8(4.5%) peri-menopausal patients respectively. Twenty-three patients (12.9%) presented with early breast cancer, 144 (80.5%) were locally advanced and 12 (6.7%) were oligo-metastatic. Forty (22.4%), 127 (71.0%) and 12 (6.7%) patients were at clinical stages-II, III, and IV respectively at the time of presentation as per AJCC 7th edition. The median duration of symptoms was 4 (0.25-36) months. Forty-seven (26.3%) patients underwent breast conservation surgery and 128 (71.5%) patients had modified radical mastectomy. Overall pCR was attained in 29.6%(n=53) of the patients, with rates of 55%(n=22) and 23.6%(n=30) in patients with stage-II and stage-III respectively. Stage-II patients were more likely to achieve pCR after NACT [OR (95% CI: 4.3 (2.0-8.9)] when adjusted for other clinical covariates. Three-year RFS in patients achieving pCR was 94.7%, whereas in patients not achieving pCR was 43.9%, with a hazard of relapse or death significantly less in patients attaining pCR [HR (95% CI): 0.14 (0.06-0.37), p <0.0001]. Similarly, three-year OS was 97.4 % vs 73.8% in patients attaining pCR vs not attaining pCR, with a hazard of death significantly less in patients with pCR [HR (95% CI): 0.06 (0.01-0.45) p<0.006]. Conclusions: Our results confirm that attainment of pCR following NACT leads to better survival outcomes in TNBC. Factors associated with improved pCR rates in the Indian population needs further evaluation.
Efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCH-P) in HER2-positive breast cancer: An Indian experience.
Authors: Gogia Ajay , Arora Shalabh , Deo SVS , Mathur Sandeep , Sharma Dayanand
Published: June 2021

e12619

Background: Dual targeted therapy with chemotherapy is one of the therapeutic approaches as neoadjuvant treatment in HER2/neu positive breast cancer (BC). However the safety and efficacy data of dual-targeted, chemotherapy regimen (docetaxel, carboplatin, trastuzumab, & pertuzumab [TCH-P] is limited from the Indian subcontinent. Methods: This retrospective study aims to evaluate the efficacy and toxicity of neoadjuvant TCH-P regimen in early, locally advanced, and oligometastatic (OM) HER2-positive BC, at All India Institute of Medical Sciences, New Delhi, India, in between the period 2015-2020. Total 6 cycles of 3-weekly neoadjuvant chemotherapy (NACT) protocol containing docetaxel (75 mg/m2), carboplatin (AUC = 6), trastuzumab (8 mg/kg loading followed by 6 mg/kg) and pertuzumab ( 840 mg loading followed by 420 mg) were planned. Subcutaneous peg-filgrastim was prophylactically administered on day 2 of each cycle. The primary outcome was the pathological complete response (pCR), which was defined as an absence of invasive and noninvasive cancer in breast or lymph node and secondary outcome were clinical overall response rate (ORR), rate of breast conservation surgery( BCS) for patients for whom modified radical mastectomy( MRM)was planned and toxicity. Results: Forty-five patients with a median age of 48 years (31-65) were included in this study. The TNM (AJCC-7th edition) stage distribution was stage II, 14 (31.1%); stage III, 29 (64.5%); and stage IV (OM), 2 (4.4%). Clinical node positivity disease was found in 26 (57.8%) cases. Nineteen (42.2%) patients had hormone-positive and 26(57.8%) cases were premenopausal. The clinically ORR and CR were seen in 100% and 60% respectively. Overall pCR rate was observed in 25 (55.6%) patients (70% in stage II). BCS was performed in 23(51.1%) cases. In 12(26.6%) cases, planned MRM was changed to BCS following NACT. Grade 3 and 4 toxicities were diarrhea 7 cases, thrombocytopenia in 6, neutropenia in 4, febrile neutropenia in 1, and anemia in 2 cases. Ten patients required dose modification and interruption. No patient had congestive heart failure or induction death. Conclusions: This is the first study of the non-anthracycline-based neoadjuvant protocol in HER2 positive BC from India. The TCH-P is an effective, safe, and well-tolerated, protocol with a path CR rate of 55.6% and 26.6% BCS conversion rate from planned MRM.
The predictive value of neutrophil-to-lymphocyte ratio on overall survival and pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy.
Authors: Tang Wenjie , Wang Linlin , Yu Jinming , Yu Yishan
Published: June 2021

e12625

Background: Neutrophil-to-lymphocyte ratio (NLR) has been found to offer clear predictive utility for the overall survival (OS) and pathologic complete response (pCR) in breast cancer (BC) patients receiving neoadjuvant chemotherapy(NAC). However, previous studies mainly focused on pre-NLR. The aim of this study was to explore the role of pre-/post-NLR towards OS and longitudinal NLR kineticsonpCR for BC patients undergoing NAC. And we also tried to build a nomogram for OS prediction based on these parameters. Methods: In this study, we retrospectively collected 501 female patients with locally advanced BC receiving 4-8 cycles of NAC from 2009 to 2018. Clinicopathological characteristics, NLR at pre-, mid-(every two cycles of NAC) and post-treatment were collected. The primary endpoint was OS. Among the patients, 421 patients with available pre- and post-NLR were included in the survival analysis. These patients were randomly divided into a training cohort (n = 224) and a validation cohort (n = 197). Multivariate survival model was built by including all the significant prognostic factors from the univariate analysis in the training cohort, and a nomogram model was established by “R” version 3.4.3. The performance of the model was further tested in the validation cohort by the concordance index. The second endpoint was pCR. Longitudinal analysis of NLR was performed using a mixed-effects regression model to predict pCR among 176 patients who finished 8 cycles of NAC. Results: The median follow-up time was 43.2 months for 421 patients. In the training cohort, multivariate analysis revealed that ER status, clinical node stage , pCR , pre-NLR, and post-NLR (all Ps＜0.05) were independent predictors of OS. Nomogram for OS prediction was established by combining all these significant factors. The C-indexes of the nomogram were 0.764 and 0.693, respectively in the training and validation cohort. In the longitudinal analysis, patients achieved pCR experienced a reduction of NLR every 2 cycles (Coef = -0.032, std error = 0.014, P = 0.024). Conclusions: This study demonstrated the prognostic value of pre-NLR and post-NLR towards BC patients received NAC. Based on that , a novel nomogram was established to predict the 3- and 5- year OS for BC patients. And we also found patients who experienced a decline of NLR during NAC seems to be more likely to achieve pCR from chemotherapy. Routine assessment of NLR may be an easy and affordable tool for defining prognosis.
Real-world starting dose and outcomes of palbociclib plus an aromatase inhibitor for metastatic breast cancer.
Authors: Patt Debra A. , Liu Xianchen , Li Benjamin , McRoy Lynn , Layman Rachel M. , Brufsky Adam
Published: June 2021

e13021

Background: Palbociclib (PA) has been approved for HR+/HER2–advanced/metastatic breast cancer (mBC) in combination with an aromatase inhibitor (AI) or fulvestrant for more than 6 years. Regardless of the labeled recommended starting dose of 125mg/day, some patients initiate palbociclib at lower doses in routine practice. This study described real-world starting dose, patient characteristics, and effectiveness outcomes of first line PA+ AI for mBC in the US clinical setting. Methods: We conducted a retrospective analysis of Flatiron Health’s nationwide longitudinal electronic health records, which came from over 280 cancer clinics representing more than 2.2 million actively treated cancer patients in the US. Between February 2015 and September 2018, 813 HR+/HER2– mBC women initiated PA+AI as first-line therapy and had ≥ 3 months of potential follow-up. Patients were followed from start of PA+AI to December 2018, death, or last visit, whichever came first. Real-world progression-free survival (rwPFS) was defined as the time from the start of PA+AI to death or disease progression. Real-world tumor response (rwTR) was assessed based on the treating clinician’s assessment of radiologic evidence for change in burden of disease over the course of treatment. Multivariate analyses were performed to adjust for demographic and clinical characteristics. Results: Of 813 eligible patients, 68.3% were white, median age was 65.0 years, and 42.9% had visceral disease (lung and/or liver). Median duration of follow-up was 21.0 months. 805 patients had records of PA starting dose, with 125mg and 75/100mg/day being 86.5% and 13.5%, respectively. Patients who started at 75/100mg/day were more likely to be ≥75 years than those who started at 125mg/day (38.5% vs 17.1%). Other baseline and disease characteristics were generally evenly distributed. Patients who started at 125mg/day had longer median rwPFS (27.8 vs 18.6 months, adjusted HR=0.74, 95%CI=0.52-1.05) and higher rwTR (54.0% vs. 40.4%) than those patients who started 100/75mg/day (adjusted OR=1.76, 95%CI=1.13-2.74). Table presents results in detail. Conclusions: Most patients in this study initiated palbociclib at 125mg/day and dose adjustment was similar regardless of starting dose. These real-world findings may support initiation of palbociclib at a dose of 125mg/day in combination with AI for the first-line treatment of HR+/HER2- mBC. [Table: see text]
Development of orally bioavailable prodrugs of fulvestrant for the treatment of metastatic/advanced breast cancer.
Authors: Purohit Parva , Brahmkshatriya Pathik , Goswami Vishalgiri
Published: June 2021

e13027

Background: Fulvestrant, a potent, selective estrogen receptor degrader, is a primary drug of choice for treating advanced metastatic hormone receptor-positive breast cancer in postmenopausal women following anti-estrogen therapy. However, the existing therapy limits to inconvenient intramuscular injections due to low solubility, weak permeation, high metabolism, and poor pharmacokinetics profile. Additionally, it takes 30 days to reach maximal steady-state plasma concentration, limiting clinical efficacy. To overcome these issues, we modulated physicochemical properties of fulvestrant, enabling its oral delivery to improve bioavailability. Methods: Structurally diverse pro-moieties were appended on fulvestrant to improve solubility and ADME profile. Thermodynamic solubility, plasma/liver microsomal stability, and Caco-2 permeability studies were performed to identify lead molecules. Pharmacokinetic studies were performed for selected molecules in mice. Antitumor activity of once-daily oral dose of three molecules was evaluated in female nude mice using the MCF-7 xenograft model. The efficacy of lead molecules was compared with subcutaneously administered faslodex in terms of percentage tumor growth inhibition. Results: Several prodrugs of fulvestrant were synthesized and evaluated for their intrinsic properties suitable for increasing bioavailability of fulvestrant. Remarkable improvements (̃500 to 2000-fold increase) were achieved in solubility and permeability. The PoC established an increase in systemic plasma exposure of fulvestrant upon oral administration of prodrugs in mice with enhanced bioavailability (1.5-8.7-fold) as compared to fulvestrant given subcutaneously (Table). Herewith, we report the identification of KSHN001022, KSHN001075, and KSHN001126, the prodrugs of fulvestrant, which showed enhanced efficacy with better tumor volume reduction (̃48-88% regression in tumor volume) as compared to that of fulvestrant (78%) in the estrogen-dependent MCF-7 xenograft model. Conclusions: KSHN001 lead candidates demonstrated significantly higher bioavailability, hence, provides a novel strategy to deliver fulvestrant orally to pursue the potential benefits in patients with advanced metastatic disease.[Table: see text]
The effectiveness and safety of eribulin therapy in HR-positive HER2-negative metastatic breast cancer post-CDK4/6 inhibitor therapy in Russian clinical practice.
Authors: Kolyadina Irina Vladimirovna , Bolotina Larisa , Zhukova Lyudmila , Vladimirova Liubov Yu , Sultanbaev Alexander , Karabina Elena , Ganshina Inna , Ovchinnikova Elena , Kolyadina Irina Vladimirovna , Antonova Galina , Volkonsky Mikhail , Kolokolov James , Zueva Elena , Akopyan I , Fadeeva Natalia , Evstigneeva Irina , Orlova Svetlana , Vasilevskaya Anna , Shalaeva Oxana , Shirokova Oxana
Published: June 2021

e13035

Background: EMPOWER trial demonstrated the benefit of eribulin administrated post CD4/6i in patients (pts) with HR+ HER2-negative (HR+HER2-) metastatic breast cancer (MBC). There are several important limitations to this trial: > 60% of pts were stage IV at the time of treatment initiation, eribulin used in late lines (2L only in 30% pts) and follow-up data were immature. Current study aimed to provide additional data on the real-world effectiveness and safety of eribulin monotherapy in this setting. Methods: Observation study of eribulin monotherapy in standard regimen enrolled 54 pts (median age 56; range 29-79 years) with HR+ HER2- MBC received at least one dose of eribulin post CDK 4/6i in metastatic settings; 24% pts had de novo metastatic BC, 76% - recurrent BC; 77% received palbociclib, 21% ribociclib, 2% both drugs; 49% pts received CDK4/6i with fulvestrant and 51% with AI. CDK4/6i was used: 49% pts in 1L, 36% in 2L, 16% in 3L. Median DOR of CDK4/6i treatment was 9.07 months (range 2-38). 94% pts received anthracyclines and taxanes, eribulin was used in 2L in 60%, 30% in 3L, 8% in 4L, 2% in 5L. The most common sites of metastases (Mts) were bones (78%), liver (73%), lung (56%) and brain (8%); visceral Mts were seen in 90% pts. Median follow-up – 11,5 months (range 3-36). Results: Median cycles of eribulin therapy was 10,5 (range 1-44); objective response rate was seen in 24%, stabilization - 67%, progression - in 9%. Median PFS was 10.0 months, there were no significant differences in the different subgroups (visceral/no visceral; recurrent/de novo BC; age; CDK4/6i as 1L vs 2L, fulvestrant vs AI), p > 0,05. Median PFS was higher in pts with lung Mts vs non-lung (24 vs 9,1 months, p = 0.056). Most common AEs all grades were neutropenia (26%), anemia (9%), asthenia (9%), polyneuropathy (11.1%). AE did not affect the effectiveness of eribulin (p = 0.648). Dose reduction was in 19% pts and did not affect the effectiveness of eribulin (p = 0.612). At median follow-up of 11.5 months, 92.5% of patients still alive. Conclusions: As post-CDK4/6i therapy, eribulin in HR+HER2- MBC pts was effective and well tolerated, regardless of age, line of CDK4/6, CDK 4/6i combination partner. Patients with metastasis to the lung have better mPFS. Results in this real-world population of pts with HR+HER2- MBC were consistent with the EMPOWER study, and support administration of eribulin in 2-3 lines as an effective option for post-CD4/6i pts.
Impact of race on the utilization and efficacy of CDK4/6i: Result from a real world database.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen
Published: June 2021

e13036

Background: The combination of the CDK4/6 inhibitors(CDK4/6i) and endocrine therapy has improved overall survival(OS) in patients(pts) with endocrine sensitive or resistant disease. Only 43 pts of black race were included in the first line trials making interpretation of results in this group difficult. The goal of this retrospective analysis of a real world database was to look at the clinical utilization and prognostic impact of CDK4/6i among pts of white and black race who have hormone receptor positive (HR+ve)/HER2-ve metastatic breast cancer(MBC). Methods: For this analysis, we utilized a federated network of de-identified health data representing approximately 64 million pt lives available through the TriNetX Platform. We identified 5400pts with information on race who had HR+ve/HER2-ve MBC diagnosed between 2015 and 2020. OS was computed using the Kaplan Meier product limit method. Propensity score matching was performed on all comparisons of survival, matching patients from two cohorts on secondary malignancy location (as noted in ICD-10 diagnosis coding)and age group. Results: 4182 white pts and 1199 black pts were identified, and 1,194 pts in each group remained after matching. Mean age at diagnosis was 57.2 and 58.3 yrs among white and black pts respectively. OS among pts of white and black race was significantly different (HR 1.4, 95%CI 1.12-1.70, p < 0.0001), and 2-yr OS was 87.8% and 82.6% respectively. 599(20%) pts of white race and 148(18%) pts of black race received CDK4/6i therapy. The rate of uptake of use CDK4/6i was initially similar in 2015 however by 2020 some differences were observed with rate of uptake being 190 per 1000 and 264 per 1000 among pts of black and white race respectively. Pts of each race appeared to have a similar prevalence of CDK4/6i per line of treatment. OS among pts who received CDK4/6i and were of white and black race was not significantly different(HR 0.94, 95% CI 0.65- 1.38, p = 0.80), and 2-year OS was 69.9% and 69.5% respectively. Conclusions: Overall the proportional use of CDK4/6i was similar among pts of black and white and race. Although initial uptake appears to have been consistent between Black and White pts, further attention is necessary to assess potential disparities in use as time progresses. The use of CDK4/6i in the setting of HR+ve/HER2-ve MBC diminishes the differences in outcome between the two races.