Progesterone Receptor Negative Tumors Research Articles

Co-expression of Matrix Metalloproteinase 9 (MMP9) and Motility-related Protein-1 (MRP-1/CD9) in Human Breast Cancer

Background: Controversial evidence exists regarding the metastasis-suppressor or promoting activity of motility-related protein-1 (MRP-1/CD9) in breast cancer (BC). Objectives: we aimed at investigating the possible correlation of CD9 with a metastasis marker matrix metalloproteinase 9 (MMP9) in human BC tissues. Methods: A total of 19 BC and 5 normal breast tissues were analyzed. The mRNA expression of CD9 and MMP9 was measured by quantitative PCR. The correlation of genes’ expression with each other and clinicopathological features (i. e. tumor pathology, grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), P53, and KI67) was tested by relevant statistical analysis methods. Results: There was no significant difference between patients with BC and the control group regarding the expression of MMP9 (P = 0.394) and CD9 (P = 0.887). A significant strong positive correlation was observed between CD9 and MMP-9 expressions (r = 0.761 and P = 0.0002). The MMP9 expression was significantly higher in ER or PR positive compared to ER or PR negative tumors (P = 0.046). Conclusions: Given the strong correlation with MMP9, it seems that CD9 might have a role in metastasis in human BC. However, much more studies are required to further support this hypothesis.

Genomic copy number alterations as biomarkers for triple negative pregnancy-associated breast cancer

BackgroundPABC, commonly defined as breast cancer diagnosed during or ≤ 1 year after pregnancy, accounts for 7% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is characterized by a particularly aggressive histopathologic profile with poorly differentiated and estrogen- and progesterone receptor negative tumors and associated high mortality rates. This study assessed the genomic background of triple-negative PABC tumors by detection of copy number alterations (CNAs).MethodsMLPA was used to compare CNAs in breast cancer-associated chromosomal loci between triple-negative PABC- and subtype-matched non-PABC patients. Both CNA patterns were evaluated by cluster analysis; associations between individual gene CNAs, pathological characteristics and survival were explored.ResultsTriple-negative PABC tumors exhibited unique CNAs compared to non-PABC tumors, including enrichment for TOP2A copy number loss, an independent predictor of worse overall survival (HR 8.96, p = 0.020). Cluster analysis based on CNA profiles identified a triple-negative PABC-subgroup with a particularly poor prognosis, characterized by chromosome 8p copy number loss. Individual gene CNAs analysis revealed that FGFR1 copy number loss on chromosome 8p11.23 was an independent predictor of poor outcome in multivariate analysis (HR 3.59, p = 0.053) and predicted the development of distant metastases (p = 0.048).ConclusionThis study provides novel insights into the biology of triple-negative PABC tumors suggesting that CNAs, particularly 8p loss and TOP2A loss, are involved in the development of breast cancer during pregnancy. FGFR1 loss and TOP2A loss seem to be promising new biomarkers that independently identify subgroups of PABC patients with poor prognosis. These genomic biomarkers may provide clues for personalized therapy.

Prognostic factors for relapse in young breast cancer patients

Objective. Breast cancer is the leading cause of cancer mortality in women. Most deaths from breast cancer are due to recurrences or metastatic disease. The purpose of this study is to determine the impact of age in treatment strategy correlated with clinicopathological features. Methodology: In this retrospective study, 60 female patients with histologically-confirmed primary breast cancer were included. The women were treated in the Oncofort Hospital Bucharest, Romania between 2018 and 2020. The estrogen receptor (ER), progesterone receptor (PR) and HER2 status were determined using immunohistochemistry. Results. The mean age was 34.14 years (range = 24 – 40 years). Invasive ductal carcinoma of no specific type was seen in 84.1% of patients. The rates of grade I, II and III carcinomas were 6.7%, 28,3% and 65%, respectively. Among all patients, 33.3% had estrogen receptor, progesterone receptor positive tumors and 66.66% had estrogen receptor, progesterone receptor negative tumors. The proportion of patients overexpressing oncoprotein HER2 was 13.3%. Conclusion. Prognostic value of proliferation index (Ki-67) and hormonal receptors, may vary depending on age.

Healthy Eating and Mortality among Breast Cancer Survivors: A Systematic Review and Meta-Analysis of Cohort Studies.

This systematic review examined the effect of diet quality, defined as adherence to healthy dietary recommendations, on all-cause and breast cancer-specific mortality. Web of Science, Medline, CINAHL, and PsycINFO databases were searched to identify eligible studies published by May 2021. We used a random-effects model meta-analysis in two different approaches to estimate pooled hazard ratio (HR) and 95% confidence interval (CI) for highest and lowest categories of diet quality: (1) each dietary quality index as the unit of analysis and (2) cohort as the unit of analysis. Heterogeneity was examined using Cochran’s Q test and inconsistency I2 statistics. The risk of bias was assessed by the Newcastle–Ottawa Scale for cohort studies, and the quality of evidence was investigated by the GRADE tool. The analysis included 11 publications from eight cohorts, including data from 27,346 survivors and seven dietary indices. Both approaches yielded a similar effect size, but cohort-based analysis had a wider CI. Pre-diagnosis diet quality was not associated with both outcomes. However, better post-diagnosis diet quality significantly reduced all-cause mortality by 21% (HR = 0.79, 95% CI = 0.70, 0.89, I2 = 16.83%, n = 7) and marginally reduced breast cancer-specific mortality by 15% (HR = 0.85, 95% CI = 0.62, 1.18, I2 = 57.4%, n = 7). Subgroup analysis showed that adhering to the Diet Approaches to Stop Hypertension and Chinese Food Pagoda guidelines could reduce breast cancer-specific mortality. Such reduction could be larger for older people, physically fit individuals, and women with estrogen receptor-positive, progesterone receptor-negative, or human epidermal growth factor receptor 2-positive tumors. The risk of bias in the selected studies was low, and the quality of evidence for the identified associations was low or very low due to imprecision of effect estimation, inconsistent results, and publication bias. More research is needed to precisely estimate the effect of diet quality on mortality. Healthcare providers can encourage breast cancer survivors to comply with healthy dietary recommendations to improve overall health. (Funding: University of Central Florida Office of Undergraduate Research, Registration: PROSPERO-CRD42021260135).

Relation of Receptor Status and Tumor Grade with Menopausal Status in Patients of Carcinoma Breast

Background: Carcinoma of the breast is the most common female cancer and its incidence is rapidly increasing over the last few decades. In Bangladesh, breast cancer is an issue of gaining concern. Receptor status and histological grade are two important prognostic factors of carcinoma breast. Aim of the study: To assess the relation and distribution of receptor status and tumor grade among pre and postmenopausal patients of carcinoma breast. Methods: This cross-sectional observational study was carried out in the Department of General Surgery, Bangabandhu Sheikh Mujib Medical University (BSMMU) Dhaka over a period of one year, a total of 59 admitted female patients with histologically proven carcinoma of the breast were divided into two groups included in this study. The premenopausal age group was considered as a group I (n=31) and the postmenopausal age group was considered as group II (n=28). Data regarding the tumor histopathological type, grading, and receptor status along with other variables were included in a pre-designed data collection sheet. After compiling data, Statistical analyses of the data were done with Statistical Packages for Social Sciences (SPSS- 22). Results: Sociodemographic variables and personal histories leading to a risk of breast cancer have no significant difference between pre and postmenopausal groups. Invasive ductal carcinoma (grade-II) was predominant in both groups. Estrogen and progesterone receptor-negative tumors were more frequent in premenopausal patients and estrogen and progesterone receptor-positive tumors were more frequent in a postmenopausal patient, but no statistically significant difference between the two groups. More than eighty percent of tumors were human epidermal growth factor-2 negative in both groups. The frequency of estrogen and progesterone receptor positivity gradually reduce from grade I to III in both groups and the frequency of estrogen and progesterone receptor negativity gradually increase from grade

Role of MicroRNA-31 (miR-31) in Breast Carcinoma Diagnosis and Prognosis.

Breast cancer (BC) is among the most widespread malignant tumors in women. In the current study, we evaluated the role of miR-31 in BC patients and its relation to the different prognostic, clinical, and pathological features. MiR-31 levels were determined by RT-PCR in BC and adjacent normal breast tissues from 100 BC patients. BC diagnosis was established through histopathological examinations. The expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) receptor in all tumors was determined using immunohistochemistry. MiR-31 expression was reduced in BC tissues relative to adjacent healthy breast tissue (mean levels were 0.93 and 7.2, respectively). Also, the low expression of miR-31 in BC patients was significantly correlated with adverse clinical and pathological features such as: young patient's age, premenopausal status, infiltrative lobular carcinoma, ER and PR negative tumors, HER2 positive tumors, and advanced clinical stage. MiR-31 was expressed at low levels in BC tissues and correlated with adverse clinical and pathological features, and poor survival.

Prognostic Factors and a Nomogram Predicting Survival in Patients with Breast Ductal Carcinoma in situ with Microinvasion: A Population-Based Study.

PurposeDuctal carcinoma in situ with microinvasion (DCISM) can be challenging to balance the risks of overtreatment versus undertreatment. We aim to identify prognostic factors in patients with DCISM and construct a nomogram to predict breast cancer-specific survival (BCSS).Materials and MethodsA retrospective cohort study of women diagnosed with DCISM from 1988 to 2015 who were identified in the Surveillance, Epidemiology and End Results database. Clinical variables and tumor characteristics were evaluated, and Cox proportional-hazards regression was performed. A nomogram was constructed from the multivariate logistic regression to combine all the prognostic factors to predict the prognosis of DCISM patients at 5 years, 10 years, and 15 years.ResultsWe identified 5438 total eligible breast cancer patients with a median and max survival time of 78 and 227 months, respectively. Here, patients with poorer survival outcomes were those diagnosed between 1988 and 2001, African-American race, under 40 years of age, higher tumor N stage, progesterone receptor-negative tumor, and received no surgery. The nomogram was constructed by the seven variables and passed the calibration and validation steps. The area under the receiver operating characteristic (ROC) curve (AUC) of both the training set and the validating set (5-year AUC: 0.77 and 0.88, 10-year AUC: 0.75 and 0.73, 15-year AUC: 0.72 and 0.65). Receiving chemotherapy was associated with a better BCSS (hazard ratio, HR=0.45, 95% confidence interval, 95% CI = 0.23–0.89), especially in patients with estrogen receptor (ER) negative, progesterone receptor (PR) negative (HR = 0.35, 95% CI = 0.13–0.97) and ER+PR-/ER-PR+ DCISM (HR = 0.07, 95% CI = 0.01–0.59).ConclusionOur current study is the first to construct nomograms of patients with DCISM which could help physicians identify breast cancer patients that more likely to benefit from more intensive treatment and follow-up. Chemotherapy might benefit patients with ER-PR- and ER+PR-/ER-PR+ DCISM.

Prognostic Implications of Immune Infiltrates in the Breast Cancer Microenvironment: The Role of Expressions of CTLA-4, PD-1, and LAG-3.

The assessment of immune infiltrate in invasive breast carcinomas (IBCs), most commonly referred to as tumor infiltrating lymphocytes (TILs), is gaining importance in the current quest for optimal biomarker selection and prediction of prognosis. In this study, the impact of intensity of TILs and expressions of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and lymphocyte activation gene 3 (LAG-3) in a group of breast carcinomas with regards to the prognosis and conventional pathologic parameters was scrutinized. For this purpose, 238 patients with IBCs containing different proportions of TILs were included in the study. IBCs with higher proportion of TILs were usually grade III carcinomas and correlated with poor prognostic features like receptor negativity, nonluminal intrinsic subtype (P<0.001). Similarly, PD-1 and LAG-3 positivity in immune cells (IC) were more likely to be positive in grade III IBC cases (P=0.004). In addition, PD-1 positivity in IC was more frequent in estrogen receptor-negative tumors (P=0.011) whereas LAG-3 positivity increased in large sized, estrogen receptor and progesterone receptor-negative tumors (P=0.050, 0.023, 0.04, respectively). CTLA-4 positivity in IC was more frequent in large-sized tumors (P=0.040). These 3 markers were also significantly associated with one another and also with the amount of TILs. In survival analysis, cases with prominent-TILs especially displaying CTLA-4, PD-1, and LAG-3 positivity appeared to have longer disease-free and overall survival (CTLA-4: P=0.027, P=0.024; PD-1: P=0.030, P=0.026; LAG-3: P=0.006, P=0.012, respectively). We conclude that the high proportion of TILs and as well as high expression of CTLA-4, PD-1, and LAG-3 in TILs have positively contributed to the outcome despite their correlation with poor conventional pathologic features. We suggest that these 3 immune markers can be used for the determination of proper treatment as well as prediction of prognosis in IBCs with TILs.

Abemaciclib as initial therapy for advanced breast cancer: MONARCH 3 updated results in prognostic subgroups

In MONARCH 3, continuous dosing of abemaciclib with an aromatase inhibitor (AI) conferred significant clinical benefit to postmenopausal women with HR+, HER2− advanced breast cancer. We report data for clinically prognostic subgroups: liver metastases, progesterone receptor status, tumor grade, bone-only disease, ECOG performance status, and treatment-free interval (TFI) from an additional 12-month follow-up (after final progression-free survival [PFS] readout). In the intent-to-treat population, after median follow-up of approximately 39 months, the updated PFS was 28.2 versus 14.8 months (hazard ratio [HR], 0.525; 95% confidence interval, 0.415–0.665) in abemaciclib versus placebo arms, respectively. Time to chemotherapy (HR, 0.513), time to second disease progression (HR, 0.637), and duration of response (HR, 0.466) were also statistically significantly prolonged with the addition of abemaciclib to AI. Treatment benefit was observed across all subgroups, as evidenced by objective response rate change from the addition of abemaciclib to AI, with the largest effects observed in patients with liver metastases, progesterone receptor-negative tumors, high-grade tumors, or TFI < 36 months. Extended follow-up in the MONARCH 3 trial further confirmed that the addition of abemaciclib to AI conferred significant treatment benefit to all subgroups, including those with poorer prognosis.

Prognostic significance of hedgehog signaling network-related gene expression in breast cancer patients.

Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as co-expression of SHH and ELP1 were associated with worse relapse-free survival in patients with HER2-positive tumors. Moreover, GLI1 expression in progesterone receptor-negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH,in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2-positive and basal-like. Expression of SHH, HHAT, GLI2, and GLI3 was differentially affected by overexpression of the heparan sulfate sulfotransferases HS2ST1 and HS3ST2 in vitro. Althoughhigh HS2ST1 expression was associated with poor prognosis in KMplotter analysis, high levels of HS3ST2 were associated with a good prognosis, except for ER-positive breast cancer. We suggest the GLI transcription factors as possible markers for the diagnosis, treatment, and prognosis of breast cancer especially in HER2-positive tumors, but also in progesterone receptor-negative and grade-3 tumors. The pathway interaction and prognostic impact of specific heparan sulfate sulfotransferases provide novel perspectives regarding a therapeutical targeting of the hedgehog pathway in breast cancer.

Breast cancer among Asian Indian and Pakistani Americans: A surveillance, epidemiology and end results-based study.

Breast cancer incidence is increasing among Asian Indian and Pakistani women living in the United States. We examined the characteristics of breast cancer in Asian Indian and Pakistani American (AIPA) and non-Hispanic white (NHW) women using data from the surveillance, epidemiology and end results (SEER) program. Breast cancer incidence rates were estimated via segmented Poisson regression using data between 1990 and 2014 from SEER 9 registries, including New Jersey and California. Disease characteristics, treatment and survival information between 2000 and 2016 for 4900 AIPA and 482 250 NHW cases diagnosed after age 18 were obtained from SEER 18 registries and compared using descriptive analyses and multivariable competing risk proportional hazards regression. Breast cancer incidence was lower in AIPA than NHW women, increased with age and the rate of increase declined after age of 46 years. AIPA women were diagnosed at significantly younger age (mean (SD) = 54.5 (13.3) years) than NHW women (mean (SD) = 62 (14) years, P < .0001) and were more likely than NHW cases (P < .0001) to have regional or distant stage, higher grade, estrogen receptor-negative, progesterone receptor-negative, triple-negative or human epidermal growth factor receptor 2-enriched tumors, subcutaneous or total mastectomy, and lower cumulative incidence of death due to breast cancer (hazard ratio = 0.79, 95% CI: 0.72-0.86, P < .0001). AIPA had shorter median follow-up (52 months) than NHW cases (77 months). Breast cancer in AIPA women has unique characteristics that need to be further studied along with a comprehensive evaluation of their follow-up patterns.

Preoperative Predictive Factors of Positive Margin Status After Breast Conserving Therapy (BCT) with Intraoperative Radiation Therapy (IORT): A Retrospective Study of 400 Patients

IntroductionSingle-fraction intraoperative radiation therapy (IORT) has emerged as a therapeutic option in patients undergoing breast conserving therapy (BCT) for early stage breast cancer, often eliminating the need for postoperative external beam radiation therapy. However, if a positive margin is encountered after BCT, the patient will ultimately require external beam radiation therapy. The purpose of this study was to identify preoperative factors from patient demographics, preoperative workup, or biopsy results that may be predictive of postoperative margin status. Materials and MethodsA retrospective chart review was performed on 396 patients who underwent BCT with IORT. Logistic regression models were utilized for statistical analysis. ResultsThe majority of studied variables were similar; however, differences were noted for high-grade tumors, in situ status, and progesterone receptor-negative (PR−) tumors. Grade 3 tumors were significantly associated with positive margin status when compared with Grade 1 (odds ratio, 2.30; P = .036). PR− status tumors were found to be approximately 2 times more likely to have a positive margin (P = .028). Patients with in situ (stage 0) status tumors were 1.986 times more likely to have positive margins when compared with those with an invasive tumor (P = .030). ConclusionsHigher grade PR− tumors are at increased risk of having a positive margin, which should be taken into consideration when considering treatment with IORT.

Abstract P1-19-09: Updated subgroup tumor response of abemaciclib plus aromatase inhibitor for hormone receptor positive (HR+), HER2 negative advanced breast cancer (MONARCH 3)

Abstract Background: Abemaciclib plus nonsteroidal aromatase inhibitors (AI) demonstrated efficacy with a tolerable safety profile as initial treatment for postmenopausal women with HR+, HER2− advanced breast cancer in the MONARCH 3 trial. In the intent-to-treat (ITT) population, the updated progression-free survival (PFS) with 12 months of additional follow-up was 28.2 versus 14.8 months (HR [95% CI]: 0.525 [0.415, 0.665]; p&amp;lt;.0001) in the abemaciclib plus AI versus placebo plus AI arms, respectively. Here we report data from the additional 12 months of follow-up on tumor response for the ITT population and exploratory subgroups previously identified as significantly prognostic (Di Leo et al. 2018). Methods: In MONARCH 3, a randomized, double-blind, phase III trial, 493 postmenopausal women with HR+, HER2− advanced breast cancer and no prior systemic therapy in the advanced setting, received an AI (anastrozole or letrozole) plus abemaciclib or placebo. From the October 31, 2018 cutoff, secondary endpoints including objective response rate ([ORR], complete response [CR] + partial response [PR]), time to response (TTR), and duration of response ([DoR], time from a confirmed CR or PR until disease progression or death) were assessed in the ITT population and exploratory subgroups previously reported as significantly prognostic. Waterfall plots will be used to illustrate the magnitude of change in tumor size for each subgroup (to be presented). Results: In patients with measurable disease, the ORR was 62.5% (95% CI: 56.7, 68.2) in the abemaciclib plus AI arm and 44.7% (95% CI: 36.2, 53.2) in the placebo plus AI arm (p≤.001). Additional follow-up confirmed that all prognostic subgroups received benefit from the addition of abemaciclib to AI, consistent with the ITT population, as evidenced by change in ORR, with the largest effects observed in subgroups of patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or treatment-free interval of &amp;lt;36 months (Table). Median TTR was similar between the two treatment arms (abemaciclib plus AI: 3.62 months; placebo plus AI: 3.65 months), and this was generally consistent across subgroups. Responses were more durable in the abemaciclib plus AI arm (median DoR: 32.71 months; 95% CI: 25.74, -) versus the placebo plus AI arm (median DoR: 17.49 months; 95% CI: 11.61, 22.19), including in poor prognostic subgroups. Conclusions: Extended follow-up in the MONARCH 3 trial further confirmed that the addition of abemaciclib to AI is associated with durable tumor responses, including those in patients with clinically poor prognostic characteristics.

Abstract A031: Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer

Abstract Background: The sensitivity of plasma-based oncological assays is influenced by the amount of tumor DNA shed into the circulation (ctDNA fraction). Higher ctDNA fraction has been shown to correlate with later-stage cancers and poorer overall survival (Bettegowda C, et al. Sci Transl Med. 2014; Dawson SJ, et al. N Engl J Med. 2014). Other factors affecting ctDNA fraction are poorly understood. We present results from three large Phase III breast cancer studies (MONALEESA-2, -3, and -7) to evaluate correlations between ctDNA fraction and clinical characteristics and impact on progression-free survival (PFS) and best overall tumor response. Methods: Baseline plasma samples were collected from patients (pts) in the MONALEESA-2, -3, and -7 studies, which are Phase III registration trials testing ribociclib, a cyclin-dependent kinase 4/6 inhibitor, in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. For each trial, cell-free DNA was extracted from plasma and sequenced using a validated next-generation sequencing assay targeting approximately 550 genes. ctDNA fraction was estimated by analyzing short-read sequences using PureCN (Riester M, et al. Source Code Biol Med. 2016) and tested for correlations with various tumor characteristics (size at baseline, Ki67 expression, number and type of metastatic sites, hormone receptor status) and pt characteristics (type of prior therapy, line of therapy, ECOG performance status, age, body mass index, race, histological grade, menopausal status). We also evaluated the prognostic value of ctDNA fraction on PFS and best overall response. To evaluate the prognostic effect on PFS, ctDNA fraction was binned into 3 categories (not detectable; low, 0.5%-10%; high, &amp;gt; 10%). Results: Higher ctDNA fractions were observed in pts with more metastatic sites (P &amp;lt; 0.0001), larger tumor diameter (P &amp;lt; 0.0001), higher Ki67 expression (P = 0.0001), higher lactate dehydrogenase levels (P &amp;lt; 0.0001), higher-grade tumors (P = 0.0004), worse ECOG performance status (P &amp;lt; 0.0001), progesterone receptor–negative tumors (P = 0.01), presence of liver metastases (P &amp;lt; 0.0001), and shorter disease-free intervals (P &amp;lt; 0.0001). ctDNA fractions were also higher in younger pts (continuous variable; P &amp;lt; 0.0001) and pts with lower BMI (P = 0.0003), prior chemotherapy (P = 0.002), and prior endocrine therapy (P = 0.01). Lower ctDNA fractions were observed in pts with better overall response (P &amp;lt; 0.0001), with median ctDNA fractions lowest in pts with complete responses followed by partial response, stable disease, and progressive disease. Pts with low (0.5%-10%) ctDNA fractions had longer PFS than pts with high (&amp;gt; 10%) ctDNA fractions (HR [95% CI], 0.63 [0.48-0.82], 0.64 [0.51-0.80], and 0.67 [0.52-0.86] in the MONALEESA-2, -3, and -7 trials, respectively). A more pronounced effect on PFS was observed in pts with undetectable levels of ctDNA vs pts with higher ctDNA fractions (HR [95% CI], 0.35 [0.23-0.52], 0.34 [0.21-0.55], and 0.31 [0.21-0.47] in the MONALEESA-2, -3, and -7 trials, respectively). Conclusions: Generally, higher ctDNA fraction was associated with more aggressive tumor characteristics and prior exposure to therapy. Lower ctDNA fraction was associated with longer PFS and better overall response. Together these data suggest that ctDNA fraction is a robust prognostic factor. Citation Format: Nadia Solovieff, Faye Su, Rebecca Leary, Alejandro Balbin, Arunava Chakravartty, Karen Rodriguez Lorenc, Tetiana Taran, Naveen Babbar. Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A031. doi:10.1158/1535-7163.TARG-19-A031

The association of D-dimer with clinicopathological features of breast cancer and its usefulness in differential diagnosis: A systematic review and meta-analysis.

Studies have shown that D-dimer levels are significantly correlated with the differential diagnosis and clinicopathological features of breast cancer. However, the results are currently limited and controversial. Therefore, we performed this meta-analysis to evaluate the relationship between D-dimer levels and breast cancer. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature, and Wanfang databases were searched to find studies that assessed the association of D-dimer with clinicopathological features of breast cancer and its usefulness in aiding with differential diagnosis. The standardized mean difference (SMD) was applied as the correlation measure. A total of 1244 patients with breast cancer from 15 eligible studies were included in the meta-analysis. D-dimer levels were higher in the breast cancer group than in the benign (SMD = 1.02; 95% confidence interval [CI] = 0.53-1.52) and healthy (SMD = 1.27; 95% CI = 0.85-1.68) control groups. In addition, elevated D-dimer levels were associated with progesterone receptor-negative tumors (SMD = -0.25; 95% CI = -0.44--0.05). Similarly, there was a significant correlation between D-dimer levels and tumor node metastasis staging (n = 11, SMD = 0.82; 95% CI = 0.57-1.06) and lymph node involvement (n = 8, SMD = 0.79; 95% CI = 0.50-1.09). In contrast, other clinicopathological factors, including estrogen receptor expression and human epidermal growth factor receptor 2 expression, were not associated with D-dimer levels. The results of this meta-analysis indicate that plasma D-dimer levels can be used as an important reference for the early identification and staging of breast cancer.

Co-mutation of TP53 and PIK3CA in residual disease after neoadjuvant chemotherapy is associated with poor survival in breast cancer.

The prevalence and clinical relevance of TP53 and PIK3CA mutations in pretreatment breast cancer have been previously reported. However, little is known regarding these mutations in residual tumor tissues after neoadjuvant chemotherapy. Here, we investigated the association between TP53 and PIK3CA mutations in residual disease and survival of breast cancers. TP53 and PIK3CA somatic mutations were examined in 353 post-neoadjuvant chemotherapy residual tumor tissues by Sanger sequencing. Survival curves of patients with TP53 and PIK3CA mutations were compared using the Kaplan-Meier method. Fifty-six (15.9%) of the 353 patients carried a TP53 somatic mutation and 79 patients (22.4%) carried a PIK3CA somatic mutation. A total of 18 patients carried co-mutation of TP53 and PIK3CA. Patients with somatic co-mutation were more likely to have high-grade tumors (35.3% vs. 10.6%, P = 0.010), estrogen receptor-negative tumors (55.6% vs. 26.7%, P = 0.009), progesterone receptor-negative tumors (61.1% vs. 30.5%, P = 0.008) and triple-negative tumors (35.3% vs. 13.3%, P = 0.025) compared with non-carriers. More importantly, co-mutation of TP53 and PIK3CA carriers had a significantly worse disease-free survival (DFS) and distant disease-free survival (DDFS) than non-carriers (5-year DFS: 58.0% vs. 83.2%, P < 0.001; 5-year DDFS: 70.3% vs. 86.4%, P = 0.024). Furthermore, in multivariate regression analysis, TP53 and PIK3CA co-mutation carriers showed a significantly worse DFS (adjusted hazard ratio = 3.70; 95% confidence interval, 1.79-7.63; P < 0.001). Patients with somatic co-mutation of TP53 and PIK3CA were associated with unfavorable survival compared with non-carriers. Co-mutation of TP53 and PIK3CA could be used as a potential prognosis marker in post-neoadjuvant chemotherapy breast cancer patients.

Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy

CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI ≥ 36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.

Precision Medicine in Hormone Receptor-Positive Breast Cancer.

In recent decades, breast cancer has become largely manageable due to successes with hormone receptor targeting. Hormone receptor-positive tumors have favorable outcomes in comparison to estrogen receptor (ESR1, ER)/progesterone receptor-negative tumors given the targetable nature of these tumors, as well as their inherently less aggressive character. Nonetheless, treatment resistance is frequently encountered due to a variety of mechanisms, including ESR1 mutations and loss of ER expression. A new era of precision medicine utilizes a range of methodologies to allow real-time analysis of individual genomic signatures in metastases and liquid biopsies with the goal of finding clinically actionable targets. Preliminary studies have shown improved progression-free survival and overall survival with implementation of this information for clinical decision making. In this review, we will discuss the opportunities and challenges in integrating precision medicine through next-generation genomic sequencing into the management of breast cancer.

Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification.

Molecular subclassification of endometrial carcinoma (EC) with Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifies four subtypes [DNA polymerase epsilon (POLE) mutant, mismatch repair‐deficient, p53 wild‐type (wt), and p53 abnormal]. The aim of this study was to evaluate additional EC biomarkers in the context of these subtypes. Tissue microarrays encompassing 460 previously characterized ECs were assessed for L1‐cell adhesion molecule (L1CAM), progesterone receptor (PR), estrogen receptor (ER) alpha, stathmin, and phosphatase and tensin homolog (PTEN), by immunohistochemistry (IHC). Associations with clinicopathological parameters, molecular subtype, and outcomes were determined. About 413 ECs (75% endometrioid, >15% serous) had complete data. L1CAM overexpression was found in 16%, associated with older age, lower body mass index (BMI), advanced stage, grade 3 (97%), non‐endometrioid histology (84%), deep myometrial invasion, lymphovascular space invasion (LVSI), and ER‐negative, PR‐negative status. Tumours overexpressing L1CAM were associated with poor outcomes {hazard ratio (HR) [95% confidence interval (CI)] 3.35 [2.10–5.23] for disease‐specific survival [DSS], p < 0.0001}. PR positivity was associated with younger women, higher BMI, early stage (77% stage I), low grade (61%), endometrioid histology (90%) without LVSI or nodal disease, ER positivity (90%), p53wt tumours (55%), and favourable outcomes [HR (CI) 0.39 (0.25–0.62) for DSS, p < 0.0001]. ER positive tumours were early stage (73%), low grade, endometrioid histology, with improved DSS. Stathmin and PTEN IHC were not associated with outcomes. There was minimal agreement between IHC and mutation status for PTEN. L1CAM overexpression was significantly associated with the p53 abnormal molecular subtype, which accounted for more than 70% of the tumours overexpressing L1CAM. PR expression also correlated with molecular subtype, with most PR negative tumours being p53 abnormal. Multivariable analysis demonstrated that only ProMisE subtype [overall survival (OS), DSS, and progression‐free survival] and age (OS only) maintained an association with outcomes. The prognostic significance of the single biomarkers tested could be explained based on their being covariable with the ProMisE molecular subtype.

Abstract 2305: Residential airborne heavy metal concentrations and breast cancer characteristics

Abstract Background: Ambient air metal concentrations have recently been implicated in the etiology of breast cancer. Previous studies have shown airborne concentrations of arsenic and cadmium are associated with the development of estrogen receptor-negative tumors. This study aims to replicate these findings and examine the role of other toxic and essential heavy metals. Methods: Participants were women who were diagnosed with breast cancer in Chicago between 2005 and 2008. We examined estrogen and progesterone receptor-negative (ER-/PR-) and high-grade tumors as markers of aggressive breast cancer, and estimated 15-year markers of exposure of 11 heavy metals. Exposures were calculated using census tract-level airborne concentrations from the National-scale Air Toxics Assessment and participants’ residential histories. We adjusted all models for socioeconomic status and reproductive factors. Results: We found that prevalent ER-/PR- tumors were associated with increased residential exposure to airborne concentrations of antimony (Q4 vs Q1: OR= 1.81; 95% CI: 0.95, 3.44; Ptrend= 0.04), cobalt (Q4 vs Q1: OR= 2.37; 95% CI: 1.26, 4.45; Ptrend &amp;lt; 0.01), manganese (Q4 vs Q1: OR= 2.55; 95% CI: 1.24, 5.24; Ptrend= 0.04), and selenium (Q4 vs Q1: OR= 1.85; 95% CI: 1.03, 3.29; Ptrend= 0.05), and also identified marginally significant trends for arsenic (Ptrend= 0.06), chromium (Ptrend= 0.08), lead (Ptrend= 0.08), and mercury (Ptrend= 0.07). We did not identify any overall associations with high-grade tumors, however when stratifying by menopausal status we found that antimony (Q4 vs Q1: OR= 6.97, 95% CI: 1.61-30.19) and arsenic (Q4 vs Q1: OR= 6.97, 95% CI: 1.61-30.19) were associated with prevalent high-grade tumors in premenopausal women only. Discussion: This study found further support for a role of airborne arsenic concentrations, and novel evidence implicating other airborne estrogen-pathway disrupting metal concentrations, in the development of aggressive breast cancer subtypes. Additionally, this is the first study to implicate heavy metal exposure in the etiology of high-grade tumors. These results suggest that long-term, low-dose exposures to certain heavy metals play a role in the etiology of aggressive breast cancer characteristics. Airborne exposures have the ability to affect large populations and findings from this and similar studies have large public health implications. Citation Format: Jacob K. Kresovich, Serap Erdal, Maria Argos, Hua Yun Chen, Peter H. Gann, Garth H. Rauscher. Residential airborne heavy metal concentrations and breast cancer characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2305. doi:10.1158/1538-7445.AM2017-2305