bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of blood inflammatory/immune markers with outcomes in (neo)adjuvant breast cancer: A large single institutional study.
Authors: Mohd Ishak Hanis Mariyah , Nitar Phyu , Wong Fuh-Yong , Kusumawidjaja Grace , Leong Lester , Sim Yirong , Hakim Mohamed , Chay Wen Yee , Wong Ru Xin
Published: June 2021

e12540

Background: An inflammatory state in various cancer populations may correlate with mortality. Neutrophil-lymphocyte ratio is a surrogate marker of an inflammatory state. A recent meta-analysis showed the predictive value of neutrophil to lymphocyte ratio in breast cancers, but series are generally small. We aim to study the associations of Neutrophil-Lymphocyte Ratio (NLR) with outcomes in stage I–III breast cancer in patients who received neo-adjuvant chemotherapy (NAC) or upfront surgery. The endpoints are overall survival (OS) and breast cancer-specific survival (BCSS). In the NAC group, association with pathological complete response (PCR) rate was also studied. Methods: Data of patients with stage I–III breast cancer treated from 2011–2017 were extracted from a prospectively maintained registry and merged with full blood count (FBC) results from a clinical management software. FBC were performed within one-month pre-chemo for NAC patients and one-month pre-surgery for upfront surgery patients. PCR is defined as stage ypT0/isN0M0. OS is defined as death from any cancer from diagnosis date, censored at last follow-up. BCSS is defined as death from breast cancer from diagnosis date, censored at last follow up or death from any cause. The NLR values with the maximal Youden’s indexes calculated for each outcome were used as cut-off, logistic regression was used to determine PCR association and cox regression and log rank for OS and BCSS. Results: A total of 2,479 eligible patients were analysed. Overall, treatment compliance was high (87.6% of ER+ patients received endocrine treatment, and 94.1% of HER2+ NAC patients had targeted therapy). In the NAC group (n = 357), 23% achieved PCR. NLR did not show any statistically significant association with PCR. In unadjusted analysis, high NLR was associated with worse BCSS (log-rank p = 0.003 figure 1). In multivariable analysis (MVA), only triple negative and HER-enriched cancers were significantly associated with PCR. In NAC patients, NLR was associated with OS (cut-off 2.63; OR 1.6, p = 0.077) and BCSS (cut-off 3.58; OR 2.2, p = 0.003) in MVA. In patients treated with up-front surgery (n = 2122), unadjusted analysis showed high NLR was associated with worse BCSS (OR 1.55, p = 0.05; figure 2). In MVA, NLR (cut-off 2.13, OR 1.57, p = 0.005), triple negative histology, stage and age were significant predictors of OS. BCSS was not significantly associated with NLR (OR 1.38 95%CI 0.90-2.12 p = 0.145). Conclusions: Using a large cohort of patients, a high NLR was found to be associated with worse outcomes in NAC and upfront surgery breast cancer patients.
Genetic instabilities as potential biomarkers for pregnancy-associated breast cancer.
Authors: Suelmann B.B.M. Berendine , Moelans Cathy B. , Rademaker Aniek , Bakhuis Carsten , Dooijeweert Carmen , van Diest Paul J. , Van Der Wall Elsken
Published: June 2021

e12559

Background: Pregnancy associated breast cancer (PABC), defined as breast cancer diagnosed during or within one year after pregnancy, occurs approximately once in every 3,000 pregnancies and accounts for up to 6.9% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is generally characterized by a particularly aggressive histopathologic profile (more ER-, PR- and HER2 negative tumors and tumors of higher grade) with a higher mortality rate. Whether these cancers arise before or during pregnancy, and whether their genetic profile differs from non-PABC tumors, is currently unknown. This study assesses the genetic background of PABC by detection of specific DNA copy number alterations (CNA). Methods: We assembled 29 triple-negative PABC patients from the Dutch nationwide pathology database (PALGA). From their formalin-fixed and paraffin embedded (FFPE) tumor tissue blocks, DNA was extracted. Multiplex Ligation-Dependent probe Amplification (MLPA) analysis was performed for detection of CNAs in 20 oncogenes and 2 tumor suppressor genes using the P078-D2 kit (MRC Holland). Individual gene copy number loss (MLPA ratio < 0.7), gain (ratio 1.3-2.0) and amplification (ratio > 2.0) was determined and unsupervised hierarchical cluster analysis was performed to identify differences in copy number (CN) patterns between PABC patients. Chi square statistics were used to interrogate associations with clinicopathologic characteristics. Log-Rank test was used to compare Kaplan Meier survival curves between CN subgroups. Results: Triple negative PABC tumors showed frequent copy number loss on chromosome 17q ( CPD, MED1, TOP2A, MAPT, PPM1D) and 8p ( ZNF703 and ADAM9), as well as frequent copy number gain/amplification of MYC (8q) and CCND1 (11q). Cluster analysis identified 2 clusters of PABC patients based on their tumor copy number patterns: a CN-neutral cluster and a CN-high cluster, the latter demonstrating significantly lower chromosome 17 copy numbers than the former (for PPM1D, ERBB2, CPD, MED1, TOP2A, CDC6 and MAPT). Patients with CN-neutral tumors more often showed lymph node metastases (p = 0.028), were of significantly higher stage (p = 0.031), and demonstrated a worse overall survival (p = 0.036) compared with PABC patients harboring CN-high tumors. Conclusions: We demonstrate different tumor CN patterns within a small group of triple negative PABC-patients, associated with distinct aggressiveness. This will form the basis for further in-depth genetic profiling within a larger Dutch PABC cohort, rendering insight in the disease progression and contributing to the development of more targeted and personalized treatments.
Oncotype Dx score associated to pathological features to better prognosticate the risk of recurrence for breast cancer patients.
Authors: Namuche Fernando , Ruiz Rossana , Morante Zaida , Flores Claudio J. , Gomez Henry Leonidas
Published: June 2021

e12562

Background: Oncotype Dx (ODX) prognosticates the risk of recurrence and predicts the benefit of adjuvant chemotherapy in estrogen-receptor-positive breast cancer (BC). However, it puts aside important clinical features. Our objective is to develop a model that uses routine clinical parameters associated with Oncotype Dx score to estimate the recurrence rate in our population. Methods: We retrospectively reviewed ODX and pathology reports from 371 early BC patients diagnosticated between 2014 and 2016 in a specialized cancer center, with a 5 year follow up. Variables were selected first with a univariate cox regression, then the statistically significant variables underwent a multivariate cox regression. The β coefficients from selected variables were used to create the prediction formula. Results: Among the tested variables, ki67, estrogen receptor (ER) and ODx score were significantly associated with Recurrence. The linear predictor is: (0.1331 x Ki67) + (0.4232 x ER)+(0.2112xODx score). The threshold score for this equation was set on 33 (median value) to discriminate low and high estimated risks for recurrence. The correct classification rate (CCR) for the training and validation sets was 76% and 68%, respectively. Conclusions: It is possible to optimize the Oncotype Dx to better determine a recurrence score with selected pathological features.
Study on relationship between chemokines and immune activation phenotype of breast cancer.
Authors: Wang Yanru , Wang Senming , Li Yingqiang , Lai Guorong
Published: June 2021

e12564

Background: Breast cancer is one of the most common malignant tumors in women. The incidence rate and mortality rate are increasing year by year. Studies have shown that chemokines may act as an important driver in the immune microenvironment of breast cancer. Understanding the potential immunobiological driving effect in breast cancer is important for the early diagnosis of breast cancer, which is helpful to determine the immunotherapy strategy for patients. Methods: Gene expression data of 1050 cases of breast cancer were downloaded from TCGA database. Cluster analysis was applied to investigate the level of immunity of the observations using ssGESA software. The observations were divided into three groups according to their immune score. The expression of CXCL9, CXCL10, CCL4 and CCL5 chemokines were checked for the three groups using PHEATMAP software. The differential expression analysis for the three groups was performed using Edger software. The enrichment analysis was conducted using clusterprofiler software. Results: Cluster analysis showed that the observations could be divided into three subgroups according to their immunity score, and the heatmap proved that expression level of CXCL9, CXCL10, CCL4 and CCL5 chemokines of the subgroup with high immune score were apparently higher than that of the other two subgroups. The differential expression analysis revealed that the expressions of T cell exhaustion genes were markedly different between high-level group and low-level group. A total of 402 differentially expressed genes were identified, among which 380 were up-regulated in high-level group, comparing to low-level group, and 22 were down-regulated in high-level group, comparing to low-level group. Enrichment analysis indicated they were enriched in T cell-related pathway, such as th17, th1, th3 cell differentiation and so on. Conclusions: Our study showed that the expression of four chemokines were obviously different between the groups with high immune score and low immune score. Observations with high expression of four chemokines had more active levels of immune infiltration. Differentially expressed genes were enriched in T cell-related pathway. These four chemokines could be potential biomarkers for breast cancer patients through their unique immune characteristics.
Simplified lymphatic microsurgical preventing healing approach (SLYMPHA) for the prevention of breast cancer-related lymphedema after axillary lymph node dissection.
Authors: Ozmen Tolga , Layton Christina , Friedman Eldar Orli , Melnikau Siarhei , Kesmodel Susan , Avisar Eli
Published: June 2021

e12581

Background: Lymphedema (LE) is a serious complication of axillary lymph node dissection (ALND) with an incidence rate of 16%. Simplified Lymphatic Microsurgical Preventing Healing Approach (SLYMPHA) is a safe and relatively simple method, which decreases incidence of LE dramatically. Our initial study showed an 88% decrease in clinical LE rate. In the initial study, we used arm circumference measurement for the diagnosis of LE and median follow up was 15 months. The aim of this study was to confirm these results after a long-term follow up period and by using bioimpedance spectroscopy (L-Dex) technology in detecting LE. Methods: All patients, undergoing ALND with or without SLYMPHA between January 2014 and November 2020 were included in the study. Patients with no postoperative L-Dex measurements were excluded. A L-Dex score outside the normal range (± 10 L-Dex unit) or >10 L-Dex unit increase above patient’s baseline was considered as LE. The incidence of LE was compared between patients with and without SLYMPHA. Results: 194 patients were included in the study. 57% of cohort underwent SLYMPHA. Mean follow-up time was 47 ±37 months. Patients, who underwent SLYMPHA, had a significantly lower rate of LE (16% vs 32%; p=0.01; OR 0.4 [0.2-0.8]). Conclusions: SLYMPHA is a safe and relatively simple method, which continued its efficacy after a long-term follow up period. It should be considered as an adjunct procedure to ALND for all patients during initial surgery. [Table: see text]
Developing and validating deep learning-based heterogeneous model to improve diagnostic performance of ultrasound elastography for axillary lymph node metastasis of early breast cancer.
Authors: Li Jian , Nian Cai , Ze-Ming Xie , Jingwen Zhou , Kemin Huang
Published: June 2021

e12583

Background: To improve the performance of ultrasound (US) for diagnosing metastatic axillary lymph node (ALN), machine learning was used to reveal the inherently medical hints from ultrasonic images and assist pre-treatment evaluation of ALN for patients with early breast cancer. Methods: A total of 214 eligible patients with 220 breast lesions, from whom 220 target ALNs of ipsilateral axillae underwent ultrasound elastography (UE), were prospectively recruited. Based on feature extraction and fusion of B-mode and shear wave elastography (SWE) images of 140 target ALNs using radiomics and deep learning, with reference to the axillary pathological evaluation from training cohort, a proposed deep learning-based heterogeneous model (DLHM) was established and then validated by a collection of B-mode and SWE images of 80 target ALNs from testing cohort. Performance was compared between UE based on radiological criteria and DLHM in terms of areas under the receiver operating characteristics curve (AUC), sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for diagnosing ALN metastasis. Results: DLHM achieved an excellent performance for both training and validation cohorts. In the prospectively testing cohort, DLHM demonstrated the best diagnostic performance with AUC of 0.911(95% confidence interval [CI]: 0.826, 0.963) in identifying metastatic ALN, which significantly outperformed UE in terms of AUC (0.707, 95% CI: 0.595, 0.804, P<0.001). Conclusions: DLHM provides an effective, accurate and non-invasive preoperative method for assisting the diagnosis of ALN metastasis in patients with early breast cancer.[Table: see text]
Comorbidities at time of diagnosis as a predictor of more or less aggressive treatment modalities in early-invasive breast cancer.
Authors: Raychaudhuri Sreejata , Kyko Jaclyn M , Ruterbusch Julie J. , Beebe-Dimmer Jennifer Lynn , Schwartz Ann G. , Simon Michael S.
Published: June 2021

e12591

Background: Comorbidities and advanced age have been shown to play important roles in breast cancer treatment and outcomes. Reduced doses of chemotherapy, worse treatment-related side-effects, poor performance status in patients with significant comorbidities, and the biological interplay between other diseases and cancer may also play roles. We evaluated the relationship between age and pre-existing comorbidities and receipt of local and systemic therapy in a cohort of African American (AA) women with early invasive breast cancer. Methods: The study population included 1,169 AJCC stage I-III invasive breast cancer survivors from the Detroit Research on Cancer Survivors (ROCS) study, a large cohort of AA cancer survivors. Comorbidities (both individual diseases and a combined count that was categorized as low/medium/high comorbidity burden), age at diagnosis, and other demographic variables were obtained from self-reported standardized questionnaires. Cancer-related variables including treatment were obtained from the Metropolitan Detroit Cancer Surveillance System registry. Recommended treatment was subdivided into localized (surgery ± radiation; N = 1,156), hormonal (N = 848) and chemotherapy (N = 680). Logistic regression estimated the associations between age and pre-existing comorbid conditions and the receipt of recommended treatments. Adjusted models included variables that were selected a priori and were significant predictors in univariate analysis. Results: Most women received recommended localized treatment (82.6%), hormone treatment (73.7%), and chemotherapy (79.9%). There were no differences in receipt of localized treatment based on age or comorbidity burden in adjusted analyses. However, arthritis and depression were significantly associated with not receiving recommended localized treatment (Odds ratio (OR): 0.66, 95% CI: 0.47, 0.93 and OR: 0.53, 95% CI: 0.36, 0.78, respectively). Women with a history of obesity (BMI ≥30) were more likely to receive recommended hormone therapy (OR: 1.64, 95% CI: 1.19, 2.26), while women with congestive heart failure were less likely (OR: 0.46, 95% CI: 0.23, 0.90). Receipt of recommended chemotherapy was less likely for those with increasing age (Ptrend< 0.01) and increasing comorbidity burden (Ptrend= 0.02). Those with a history of arthritis (OR: 0.66, 95% CI: 0.44, 0.99) and hypercholesterolemia (OR: 0.62, 95% CI: 0.41, 0.95) were also less likely to receive recommended chemotherapy. Conclusions: Advanced age and presence of pre-existing co-morbid medical conditions appears to influence the receipt of chemotherapy, while individual conditions were associated with receipt of local treatment or hormone therapy in a cohort of AA survivors, suggesting the importance of providing comprehensive medical care for all women with early invasive breast cancer.
Type of recurrence, cause of death and second neoplasms among 737 patients with ductal carcinoma in situ of the breast: 15-year follow-up.
Authors: Niwinska Anna , Kunkiel Michal , Wardzynska Katarzyna
Published: June 2021

e12592

Background: The aim of the study is to assess the results of the treatment of 737 consecutive patients with DCIS with particular attention to the character of recurrences, other neoplasms and causes of deaths. Methods: A retrospective analysis was carried out of 737 consecutive DCIS patients treated in one institution in the years 1996-2011. The percentage of failures, causes of death, cumulated recurrence risk, DFS, OS depending on the method of treatment (mastectomy, breast conserving treatment BCT, breast conserving surgery BCS), was calculated. Results: 66 recurrences (42% DCIS, 58% invasive) were reported: 61 recurrences in the breast, 5 outside the breast. The comparison of mammography images before the initial treatment and after local recurrence revealed the true recurrence in the breast in 48/61 (79%) of cases. The cumulated recurrence risk after 15-year observation, after mastectomy, BCT and BCS was 3.2%, 19.5% and 31.2 %, respectively (p < 0.001). 15-year DFS after mastectomy, BCT and BCS was 72%, 65% and 48%, respectively (p < 0.001). 15-year OS after mastectomy, BCT and BCS was 75%, 83% and 70%, respectively, p = 0.329. In the course of the whole observation period 124 other neoplastic lesions in 121 patients (16%) were reported including 58 (8%) contralateral breast cancers. Deaths due to DCIS progression were reported in 4 (0.5%) of patients. An overwhelming majority (74/86) of deaths was linked to the age of the patients or other diseases, including other neoplasms. Conclusions: The highest recurrence risk reported in patients after BCS was unacceptable and, moreover, it kept growing over the fifteen years of observation. 79% of recurrences in the treated breast were true recurrences. Local recurrences were effectively treated without influence on OS. The percentage of deaths due to DCIS was low.
Association of cytoplasmic HMGB1 (cHMGB1) expression with local tumor recurrence in triple-negative breast cancer.
Authors: Oliveira Iandra Freire , Rocha Jhonata Lima , Pereira Anamaria Falcão , Lopes Marina Helena Silva , Cajado Aurilene Gomes , Sant'Ana Rosane Oliveira , Almeida Paulo Roberto Carvalho , Lima Roberto César Pereira , Wong Deysi Viviana Tenazoa
Published: June 2021

e12595

Background: Breast cancer is one of the most frequent neoplasms worldwide, contributing to women's morbimortality. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of cancer marked by negative estrogen receptors, progesterone receptors, and lack of the human epidermal growth factor 2 (C-erbB2, HER2/neu) gene overexpression. The high mobility group box-1 (HMGB1) is a factor that regulates malignant tumorigenesis, proliferation, and metastasis. Aim: Here, the HMGB1 expression was investigated as a prognostic factor for TNBC. Methods: Clinico-pathological data and surgical paraffin histopathology blocks were assessed from 85 patients treated at Haroldo Juaçaba Hospital (Ethics committee approval number 407.395). Samples were analyzed by immunofluorescence using the Tissue Microarray technique to determine the percentage of fluorescent cells with cytoplasmic HMGB1 (cHMGB1) expression. Results: The clinico-pathological data analysis indicated that patients were older than 50 years (68.2%) and diagnosed with grade 2–3 ductal carcinomas (91.8%). Tumor metastasis was observed in 9.9% of cases. TNBC patients that tumor cells presented high cHMGB1 fluorescence demonstrated increased local tumor recurrence compared with low expressing tumors (P=0.019). Five-year overall survival was simmilar between the patients with low (63%) versus high (66%) cHMGB1 expression (P=0.7441). Additionally, the risk of death was 0.8 (95% CI = 0.21–2.96). Conclusions: The cHMGB1 expression is associated with an increased tumor relapse in TNBC, not affecting patients' survival.
Geographical disparities of incidence and prevalence of triple-negative breast cancers: Multistate study data analysis.
Authors: Jeon Hyein , Lee Myeong , Jaloudi Mohammed
Published: June 2021

e12599

Background: Higher prevalence of triple negative breast cancer (TNBC) in black women with associated poor outcomes due to various disparities is well documented within a single state. We examine multiple states to better understand the state effect on such differences in incidence and prevalence of TNBC in black women. Methods: Female patients of ages 19 years old and above with breast cancer from the Surveillance, Epidemiology and End Results (SEER) Program across 13 states (608 counties) from 2015 (n = 66,444) and 2016 (n = 66,122) were examined. The relationships between the proportion of black and white women and the rate of patients with different tumor subtypes (luminal A, luminal B, HR-HER2+, and triple negative) were examined at the county level using ordinary least-square regression models. In parallel, due to consideration of various state-specific healthcare policies, socio-cultural norms, and socio-economic disparities, multi-level regression models were applied to examine the nested, random effect of each state on TNBC prevalence in each county. Bonferroni correction was applied to reduce the Type I error caused by repeated use of the same variables in multiple tests. Results: The baseline breast cancer rates between black and white women were similar in the population (0.171% for black and 0.168% for white). Consistent to previous studies, we demonstrate a significant positive correlation (p < 0.001) in TNBC in black females in both years. Surprisingly, when accounted for the random effects on states, 38.2% (2015) and 34.3% (2016) increase in incidence of TNBC in black females were seen, suggestive of state-specific disparity affecting race-specific health. In 2015, other subtypes of breast cancer in both black and white females did not result in significant relationship. Interestingly, in 2016, there was a significant relationship seen between the TNBC rate in white females and the white female population rate only after adjusting for the state effect (p = 0.026). This indicates the impact of non-biological factors such as state-wide health policies. Additionally, HR-HER2+ black females had a significant relationship against respective population rate only after adjusting for the state effect as well (p = 0.0394). For luminal A white females, a 15% decrease in incidence was seen after adjusting for state effect (p = 0.0424). Conclusions: This is the first known across-state examination of breast cancer subtypes by race with random effects on state. This study shows the role of state-specific factors affecting incidence in black and white females and potentially indicates the importance of state-level management for breast cancer on health disparities in addition to race-driven effects. Further studies are needed to elucidate comparable differences between states affecting the rates of various subtypes of breast cancer and thus health outcomes.
The effects of vitamin D (Vit D) replacement on pathological complete response (PCR) in breast cancer (BC) patients receiving neoadjuvant systemic chemotherapy (NAC).
Authors: Ozmen Vahit , Ordu Cetin , Ilgun Ahmet Serkan , Unal Caglar , Soybir Gursel , Erdogan Zeynep , Aktepe Fatma , Tuzlali Sitki , Ozturk Alper , Alco Gul , Duymaz Tomris , Kayan Tapan Tuba , Ozmen Tolga
Published: June 2021

e12604

Background: Studies show that Vit D increases apoptosis by inhibiting the proliferation of BC cells. The aims of this study were to prospectively investigate the effects of Vit D replacement on PCR rates in patients receiving NAC. Methods: Breast cancer patients qualified for NAC between June 2019 and September 2020 and consent for the study were given weekly oral 50,000 IU Vit D (study group). The Control group consisted of patients who were given NAC between 2015-2020 and who did not receive Vit D replacement. Tumor characteristics and PCR compared between the study and control groups. Results: A total of 117 patients included in the study (55% in the study group). Both groups had similar patient, tumor, and treatment characteristics. PCR (ypT0/is ypN0 and ypT0/is) rates were significantly higher in the study group (28.1% vs 11.3%, p=0.025 and 37.5% vs 13.2%, p=0.003, respectively). In multivariate logistic regression analysis, estrogen receptor (ER) and HER 2 positivity, and Vit D3 replacement were identified as independent variables affecting PCR. Conclusions: Adding Vit D to NAC in breast cancer patients significantly increases PCR. This effect is more prominent in ER negative and HER2 positive breast cancer patients. Clinical trial information: NCT03986268. [Table: see text]
Determination of endocrine sensitivity by response of the proliferative marker KI67 after short-term preoperative endocrine therapy and their correlation to oncotype score platform.
Authors: Murillo Serafin Morales , Gasol Cud"S Ariadna , Morera Morillo Ester , Canosa Morales Carles , Olivé Jordi Melé , Vilardell Villellas Felipe , Sánchez Guzmán Douglas René , Salud Salvia Antonieta
Published: June 2021

e12609

Background: Endocrine sensitivity (ES) determined by response to the Ki67 index to short-term preoperative endocrine therapy (ET) is accepted but not included in adjuvant treatment decision. However, genomic platforms have been incorporated into decision guides. Therefore, it would be interesting to analyze the correlation between both tools to improve the determination of endocrine sensitivity. Methods: A prospective series of 129 patients with early N0/N1 ES breast cancer was analyzed and Oncotype Dx platform was performed. Clinicopathological variables, and changes in ki67 index less than 10% (ES) were correlated with Oncotype Dx Recurrence Score (RS). Results: Median age was of 58 (23-84), 32% were premenopausal, median tumor size was of 22mm (7-90), nodal involvement was of 31%, 20% were progesterone receptor negative and initial median ki67 index of 24% (5-70). RS distribution: 27% RS 0-11, 29% RS 11-18, 23% RS 18-25, 21% RS > 26. All premenopausal patients received Tamoxifeno as preoperative ET and letrozole for postmenopausal. Globally, 62% of patients had ES with a decrease < 10% of ki67 after preoperative ET: 24/41 in premenopausal and 56/87 in postmenopausal. In all series ES according to RS was distributed: 80% in RS < 11, 61% RS 11-18, 55% RS 18-25 and 50% RS > 26. In premenopausal patients, ES and RS distribution was: 75% RS < 11, 62% RS 11-18, 57% RS 18-25 and 33% RS > 26. In postmenopausal patients, ES and RS distribution was: 83% RS < 11, 61% RS 11-18, 55% RS 18-25 and 58% RS > 26. ES results were not conditioned by tumor size or nodal involvement. RS > 26 was strongly associated with less ES with an OD of 4 (p = 0.014) and RS 18-25 with an OD of 3.25 (p = 0.037). The sensitivity and specificity for ES and RS < 11, was of 80% and 44%, respectively. Conclusions: We have found an ES of 62% in the whole population with the following distribution according RS: 80% in RS < 11, 61% RS 11-18, 55% RS 18-25 and 50% RS > 26. Of note, in premenopausal patients, ES rate in RS > 26 is only of 33%. Determination of ES by response of ki67 is feasible and correlates with data of genomic platforms. Both tools could help to predict ES in this setting.
Tumor mutation burden and PIK3CA mutations are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment.
Authors: Shi Qiyun , Xuhong Juncheng , Ge Jia , Liu Feng , Lan Yang , Zhang Yi , Luo Tao , Bian Xiuwu , Qi Xiaowei , Jiang Jun
Published: June 2021

e12610

Background: Our previous study reported a good efficacy and safety of pyrotinib combined with trastuzumab neoadjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. We further explored the potential biomarkers for the efficacy of pyrotinib combined with trastuzumab neoadjuvant treatment in HER2-positive breast cancer patients. Methods: To date, a total of 96 patients with early-stage breast cancer were enrolled for the neoadjuvant pyrotinib combined with trastuzumab treatment clinical trial (ChiCTR1900022293). By the method of 425 genes next-generation sequencing (NGS), the genomic characteristics of them were evaluated for the potential correlation with postoperative pathological complete response (pCR). Results: Among the cohort of 96 cases, a total of 32 patients have completed the whole therapy as well as final surgery and acquired qualified sequencing analysis report, and 18 of them achieved total pCR. The most frequently mutated driver genes were TP53 (75%), PIK3CA (44%), NBN (9%), RUNX1 (9%), FANCD2 (9%), ATRX (9%), MAP3K1 (9%) and NF1 (9%), respectively. In terms of somatic copy number alterations, the most frequent alterations are gain or amplification of ERBB2 (63%), MYC (22%), CCND1 (19%), CDK12 (16%) and FGF19 (16%), respectively. The median tumor mutation burden (TMB) of the 36 patients was 4.23 mut/Mb (0.00-29.61). Compared with pCR populations, non-pCR populations had significantly higher median TMB (5.29 vs 3.17 mut/Mb, P = 0.025). In addition, the pCR rate of patients with wild-type PIK3CA is significantly higher than that of patients with mutated PIK3CA (88.9% vs 14.3%, P < 0.001). Conclusions: Preliminary results suggested that HER2-positive breast cancer patients with higher TMB and activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy, which need larger sample size to validate. *Qiyun Shi and Juncheng Xuhong contributed equally. #Co-corresponding author (Dr. Jun Jiang, jcbd@medmail.com.cn; Dr. Xiaowei Qi, qxw9908@foxmail.com). Clinical trial information: ChiCTR1900022293.
Association between body mass index and pathologic complete response in different breast cancer molecular subtypes.
Authors: Vaca-Cartagena Bryan , Becerril Gaitan Andrea , Ferrigno Ana Sofia , Aranda-Gutierrez Alejandro , Gonzalez-Mondellini Fabio A. , Roman-Zamudio Mariana , Acosta-Sandoval Marcos A , Torres-Leal Ma. Inés , Díaz-Pérez Héctor Marcelino , Cardona-Huerta Servando , Villarreal-Garza Cynthia
Published: June 2021

e12624

Background: Obesity (BMI ≥30 kg/m2) and breast cancer (BC) are two major public health concerns worldwide. Obesity has been linked with aggressive clinicopathological features and inferior survival rates in patients with BC, regardless of molecular subtype. In addition, obesity has been associated with decreased pathological complete response (pCR) rates in some BC cohorts. However, the impact of obesity on pCR rates in different BC molecular subtypes is still a subject of debate. This study aims to explore the impact of obesity on pCR rates in women with different BC subtypes in a public health-care center. Methods: Medical records of women diagnosed with primary BC between 2009 and 2020 in a center in Monterrey, Mexico were reviewed. Patients with stage II or III at diagnosis treated with neoadjuvant chemotherapy (NAC) were considered eligible. Associations between variables were examined using Fisher's exact test of independence, employing logistic regression to calculate odds ratios (OR) when appropriate. Results: A total of 559 patients with a median age at diagnosis of 48 years (range 25-85) were included. Patients were diagnosed with stages II (37%) and III (63%). The most common molecular subtype was HR+/HER2- (49%), followed by TNBC (25%), HR-/HER2+ (15%), and HR+/HER2+ (11%). Regarding BMI, a significant proportion of patients was either overweight (34%) or obese (47%). In this cohort, a total of 134 (24%) patients achieved pCR following NAC with anthracycline- and/or taxane-containing regimens. pCR rates by subtype were as follows: HR-/HER2+ (41%), TNBC (34%), HR+/HER2+ (31%), and HR+/HER2- (13%). A significant association between pCR rates and molecular subtype was found (p<0.001). Overall, obesity was not significantly associated with pCR rates. However, on a stratified analysis, obese patients with HR+/HER2+ tumors had significantly decreased pCR rates compared to their non-obese counterparts (OR=0.21; 95%CI 0.05-0.93; p=0.040). pCR rates according to molecular subtype and obesity status are shown in the table below. Conclusions: Obesity has an adverse influence on pCR rates in patients with HR+/HER2+ tumors. Given the endemic nature of obesity in several low- and middle-income countries, effective programs that focus on prevention, weight reduction strategies, and health promotion are warranted. Furthermore, women should be encouraged to improve their diet and engage in regular physical activity. Efforts to elucidate potential factors that underlie lower pCR rates in obese patients with certain BC subtypes are required. [Table: see text]
Neoadjuvant weekly carboplatin and paclitaxel followed by dose dense adriamycin/cyclophosphamide in locally advanced triple negative breast cancer: A single-center experience in a safety net hospital.
Authors: Chen Nan , Bulsara Shaun , Hilsenbeck Susan G. , Rimawi Mothaffar F. , Nangia Julie R.
Published: June 2021

e12629

Background: Locally advanced triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer comprising 10-15% of new diagnoses each year. Optimization of neoadjuvant therapy is necessary to decrease risk of relapse. Carboplatin has been explored as an addition to standard chemotherapy to increase rates of pathologic complete response (pathCR) and improve disease free (DFS) and overall survival. Studies have shown varying degrees of benefit, and the ideal usage of carboplatin remains unclear. Methods: A retrospective chart review was conducted in the Harris County Health System to examine outcomes of patients receiving carboplatin. 71 patients with TNBC were identified as treated with weekly carboplatin at an AUC of 2 and paclitaxel followed by dose dense adriamycin/cyclophosphamide (ddAC) between 2015 and 2020. Results: The average age at diagnosis was 50 (range 31 – 73). 44 (62%) patients were Hispanic, 19 (27%) were African American. 11 (15%) were BRCA carriers. 30 (42%) patients had clinical Stage II disease, 41 (58%) patients had clinical stage III disease. 53 (75%) patients had T3 or T4 disease. 48 (68%) patients had nodal disease at diagnosis. The pathCR rate for the overall population was 43%, of the patients who did not achieve a pathCR, 6 (15%) had residual cancer burden (RCB) I, 21 (51%) had RCB II, and 14 (34%) had RCB III at the time of surgery. 5 year disease free survival (DFS) after surgery for all patients was 70% (95% CI 56-86%). 5 yr DFS was 63% (95% CI 45-88%) for patients without pathCR compared to 79% (95% CI 62-100%) for patients with pathCR (p = 0.3, logrank test). 61% of patients had between 3 – 5 adverse events. 30 (42%) patients required a treatment delay. 12 (17%) patients required treatment discontinuation. The most common serious adverse event was neutropenia affecting 9 (12%) patients. Conclusions: Our single center data in a safety net clinical setting demonstrates that a neoadjuvant regimen of weekly carboplatin/taxol followed by ddAC was safe and efficacious in a high-risk group of primarily minority patients. Despite having more advanced disease compared to patients in randomized trials receiving weekly carboplatin such as GeparSixto, our patients still had similar response rates. Additionally, our data supports the continued use of pathCR as a valid indicator of disease free and overall survival.
Evaluation of pathologic and genomic characteristics in female breast cancer patients.
Authors: Hansra Damien Mikael , Moran Amber , Slawik Becky , Clark Shirelle , Doctor Vicki , Parikh Ankur Rasik , Crilley Pamela A. , Lynch Cynthia , Nixon Daniel W. , Markman Maurie , Ahn Eugene R.
Published: June 2021

e13001

Background: The genomic landscape of female breast cancer is rapidly evolving partially owing to advancements in next generation sequencing (NGS). Here we report the genomic characteristics of female breast cancer patients with locally recurrent inoperable and metastatic disease. Methods: IRB approval was obtained for a retrospective analysis of archived pathology on patients treated at Cancer Treatment Centers of America. Comprehensive genomic profiling of tumors was derived from Foundation One (F1) and Guardant 360 NGS. Clinical information was derived from retrospective chart review. Inclusions: adult females with breast cancer with stage IV metastatic disease or locally recurrent inoperable disease. Exclusions: Males, missing genomic and pathologic information. Results of clinical, pathologic, and genomic data were summarized. Results: 1788 patients met study criteria. Median age: 48 yrs., range 20-79 yrs. Race: Caucasian 1029/1788 (58%), African American 582/1788 (32%), Hispanic 77/1788 (4%), Asian 26/1788 (1%), other 73/1788 (4%). Receptor status: Hormone receptor ER(+) &/or PR(+) 950/1788 (53.1%); Triple negative 390/1788 (21.8%); HER2(+) 205/1788 (11.5%); missing/incomplete: 243/1788 (13.6%). Ki-67 status: High 548/705 (77.7%)/Low 57/705 (8.1%)/Intermediate (INT) 100/705 (14.2%). PD-L1 status: PD-L1(-) 346/544 (63.6%)/ PD-L1(+) 179/544 (32.9%)/PD-L1 (indeterminate or QNS) 19/544 (3.5%). NGS test total (1984 tests): F1 1023/1984 (52%), F1 CDx 703/1984 (35%), F1 Act 91/1984 (6%), F1 Liquid 82/1984 (6%), Guardant 360 85/1984 (4%). Biomarkers (1096 results): Microsatellite Instability (MSI) High 4/1096 (0.3%), MSI- Intermediate (INT) 2/1096 (0.1%), MS-stable 1017/1096 (93%), Cannot be determined (CBD) 73/1096 (7%). Tumor Mutation Burden (TMB) (842 results): TMB high 22/842 (3%), TMB INT 233/842 (28%), TMB low 513/842 (61%), CBD 74/842 (9%). Genomic abnormalities (% alterations per patient): TP53 999/1783 (56.03%), PIK3CA 610/1783 (34.21%), MYC 425/1783 (23.84%), CCND1 318/1783 (17.84%), FGF19 298/1783 (16.71%), FGF3 296/1783 (16.60%), FGF4 293/1783 (16.43%), ESR1 266/1783 (14.92%), FGFR1 276/1783 (15.48%), PTEN 239/1783 (13.40%), ZNF703 251/1783 (14.08%), ERBB2 218/1783 (12.23%), GATA3 178/1783 (9.98%), CDH1 165/1783 (9.25%), RAD21 157/1783 (8.81%). Pathway defects (expressed as total % of alterations): Alterations in FGF genes 10.64%, mTOR pathway 8.36%, HHR pathway 3.17%. Conclusions: Female breast cancer patients display a heterogeneous variety of complex genomic alterations. Mutations in FGF genes were most common. The single most common alteration was in TP53. Other common alterations include PIK3CA, MYC, CCND1, and ESR1.
Adherence to abemaciclib in patients receiving antidiarrheal medicine.
Authors: Shah Dipti , Byrd Brooke , Avalos-Reyes Elisea , McCarthy Amanda , Matlin Olga S. , Grover Rashmi , Feczko Lucia
Published: June 2021

e13016

Background: According to the National Cancer Institute, breast cancer is the most common form of cancer in the United States. Nearly 75% of patients with breast cancer have tumors that are hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. In 2017, the U.S. Food and Drug Administration (FDA) approved abemaciclib to treat adult patients who have HR+ and HER2- advanced or metastatic breast cancer. While the adverse events associated with abemaciclib have been well documented in clinical trials, it is unknown if adverse events, specifically diarrhea, impact adherence. The purpose of this study is to determine whether adherence to abemaciclib differs for patients who receive loperamide in welcome kits versus those who do not receive loperamide in welcome kits. Methods: This is a retrospective study of patients throughout the United States with HR+, HER2- breast cancer who received abemaciclib from a large specialty pharmacy from July 1, 2018 to December 31, 2019. Patients who received welcome kits (each welcome kit contains three boxes, each box contains ten 2mg tablets of loperamide) served as the intervention group; patients who did not receive welcome kits served as the standard of care group. Baseline characteristics of patients in each group were compared with t-tests for continuous data and the chi square test for categorical data. Medication possession ratio (MPR), dose reduction and dose omission rates in the first three months of taking abemaciclib were compared. Results: We identified 1,180 breast cancer patients who received abemaciclib. The intervention group had 317 patients, with an average age of 60.1 y (SD = 12.0); the control group had 863 members, with an average age of 58.7 y (SD = 11.8). Baseline characteristics did not differ significantly between groups, except for geography (p<0.001), as seen in the table. There was no significant difference (p = 0.858) in mean MPR between the intervention and standard of care groups. There were no significant differences in dose reduction rates (p= 0.390) and dose omission rates (p = 0.872) within three months of starting abemaciclib. Conclusions: Our findings suggest that patients who receive loperamide in welcome kits do not have better adherence to abemaciclib therapy. In this study, both groups showed high adherence to therapy, suggesting that the standard of care group manages diarrhea just as effectively as the intervention group. A welcome kit with loperamide did not impact a patient’s adherence to abemaciclib therapy.[Table: see text]
Everolimus and exemestane in hormone receptor-positive advanced breast cancer: A comprehensive cancer center’s experience.
Authors: Moreira Inês , Ferreira Marta , Afonso Ana , Ferreira Ana , Rodrigues Ana , Vieira Claudia , Oliveira Cristina , Savva-Bordalo Joana , Dias João , Cassiano Maria , Abreu Miguel , Alves Sara , Sousa Susana
Published: June 2021

e13017

Background: Activation of the mammalian target of rapamycin intracellular signaling pathway is one of the mechanisms of endocrine resistance in breast cancer. The addition of everolimus to exemestane improves progression-free survival (PFS) in patients with hormone receptor positive (HR+) advanced breast cancer (ABC) previously treated with nonsteroidal aromatase inhibitors (NSAIs). The aim of this study was to assess the effectiveness and safety of everolimus plus exemestane in patients with HR+ ABC. Methods: We retrospectively evaluated patients with HR+, HER2 negative ABC treated with everolimus/exemestane that recurred or progressed during/after treatment with NSAIs in a portuguese comprehensive cancer center. Study endpoints were PFS, overall survival (OS), overall response rate and adverse events. Results: Between April 2014 and September 2020, 63 female patients were treated with everolimus/exemestane. Median age was 59 years (36-79), and all had performance status ECOG ≤2. Seventeen (27.0%) patients had bone metastasis alone, 39 (61.9%) had bone and visceral metastasis, 25 (39.7%) had metastasis in 3 or more sites and 87.3% had previous hormone-sensitive disease. Before everolimus/exemestane, 61 (96.8%) patients were being treated with palliative endocrine therapy (alone or in combination with CDK4/6 inhibitors) or chemotherapy (ChT) and 2 (3.2%) patients were under adjuvant endocrine therapy. Median follow-up time was 12.8 months (1.4-74.6), with 39 patients alive. Overall response rate was 14.3% (1 complete response and 8 partial responses) and 45 patients had stable disease. Median PFS was 5.6 months (CI95% 2.4-8.8) and median OS was 25.4 months (CI95% 10.3-40.5). Subgroup analysis regarding PFS was statistically significant for previous treatment with CDK4/6 inhibitors (p = 0.026) and for site of metastasis (p = 0.025). In the subgroup of patients that previously underwent palliative ChT, median PFS was 4.0 months (CI95% 0.2-9.6) and median OS was 18.6 months (CI95% 8.2-29.0). For patients that did not receive previous palliative ChT, median PFS was 5.8 months (CI95% 3.8-7.8) and median OS was 43.5 months (CI95% 2.0-85.0). Grade 3 and 4 adverse events occurred in 21 (33.3%) patients, and were: nausea, anorexia, rash, headache, haematologic toxicity, hepatic cytolysis, hyperglycaemia, pneumonitis, oral mucositis and acute kidney failure with need for haemodialysis. Fifty-five (87.3%) patients suspended everolimus, 34 (54.0%) due to disease progression and 21 (33.3%) due to toxicity. Conclusions: Our results confirm the effectiveness and safety of everolimus/exemestane in real-world setting and support its use mainly before palliative ChT. Everolimus/exemestane in HR+ ABC is feasible in the clinic, with toxicity manageable under close surveillance.
Relative bioavailability of H3B-6545 tablets versus capsules and drug-drug interaction between H3B-6545 and pantoprazole.
Authors: Xiao Jianjun Alan , Coleman Hugh A , Sahmoud Tarek , Gao Lei , Chong Weili , McAuley Sonja , Scholz Catherine , Gualberto Antonio
Published: June 2021

e13022

Background: H3B-6545 is a selective, orally available, small molecule antagonist of the estrogen receptor (ER), covalently binding to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated preliminary clinical antitumor activity in breasts cancer patients in phase 1b/2. Methods: This was an open-label phase 1 study to evaluate the relative bioavailability of H3B-6545 from a tablet formulation compared to capsules, and the effect of pantoprazole on the pharmacokinetics of H3B-6545, in healthy post-menopausal women. Subjects were randomized (1:1 ratio) to a combined crossover and fixed sequence 3 periods treatment: A single oral dose (SOD) of 450 mg H3B-6545 fasted on day 1 (capsules or tablets), followed by a 4-day washout; A SOD of 450 mg H3B-6545 fasted on day 5 (crossover formulation from the first period), followed by a 4-day washout; daily oral doses of 40 mg pantoprazole on days 9 to 15 with coadministration of a SOD of 450 mg H3B-6545 (tablets) on day 15. Results: A total of 16 subjects were enrolled and received at least one dose of H3B-6545 and 15 subjects completed all 3 periods. One subject assigned to the tablet/capsule treatment sequence withdrew from the study due to subject decision on day 13 (Period 3), following completion of Period 1 (H3B-6545 tablet) and Period 2 (H3B-6545 capsule). Following a SOD of H3B-6545 capsules alone, tablets alone, or tablets at steady-state QD of pantoprazole, H3B-6545 geometric mean Cmax was about 1070, 1120 and 1330 ng/mL, respectively, AUC was about 16600, 17500 and 18300 ng.h/mL, respectively, half-life was about 11.0, 11.0 and 10.2 hours, respectively, and the median Tmax was about 3.0, 4.0, and 2.0 hours post dose, respectively. The ratio (capsule/tablet) of Cmax and AUC was both about 0.95; steady-state pantoprazole QD increased H3B-6545 Cmax by 20% with no change in AUC. Nine subjects (56.3%) reported at least 1 TEAE during the study with constipation being the most common (43.8%); all TEAEs were mild in severity. There were no SAEs reported. Conclusions: Plasma PK of H3B-6545 is similar between tablets and capsules, and in the absence or presence of pantoprazole. Concurrent use of gastric acid reducers had a minimal effect on H3B-6545 exposure and was not considered clinically meaningful.