Negative Progesterone Receptor Status Research Articles

Prognostic prediction for HER2-low breast cancer patients using a novel machine learning model

BackgroundsTo develop a machine learning (ML) model for predicting the prognosis of breast cancer (BC) patients with low human epidermal growth factor receptor 2 (HER2) expression, and to investigate the association between clinicopathological characteristics and outcomes in HER2-low BC (HLBC) patients.MethodsA retrospective analysis was conducted on data from 998 female HLBC patients treated at the Breast Center of the Fourth Hospital of Hebei Medical University (Hebei, China) between January 1, 2017, and December 31, 2020. To address class imbalance, the synthetic minority over-sampling technique was applied. Feature selection was performed using the least absolute shrinkage and selection operator, followed by construction of the prediction model using the random forest algorithm. Model performance, including specificity and accuracy, was assessed using the receiver operating characteristic (ROC) curve and confusion matrix, comparing it against other ML models. Additionally, the log-rank test was employed to examine the relationship between selected features and patient outcomes in HLBC.ResultsThe random survival forest model demonstrated superior accuracy and specificity in predicting survival outcomes for HLBC patients. Compared with other ML models, it achieved more precise predictions of Disease-Free Survival (DFS) at 1, 2, and 3 years, with the area under the ROC curve (AUC) in the test and training cohorts measured at 0.726 and 0.819, 0.712 and 0.776, and 0.685 and 0.774, respectively. The analysis further identified a strong correlation between poor prognosis in HLBC patients and factors such as axillary lymph node dissection, family history, elevated topoisomerase (TOPO)-2 expression, advanced clinical stage, negative progesterone receptor status, P53 mutation, and increased Ki67 expression, observed across both cohorts.ConclusionsA novel ML model was developed for accurate prognosis prediction in HLBC patients, offering valuable insights into prognostic risk factors. This model equips clinicians with enhanced data to guide treatment decisions, ultimately contributing to improved patient outcomes.

High chromosomal instability is associated with higher 10-year risks of recurrence for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients: clinical evidence from a large-scale, multiple-site, retrospective study.

Long-term survival varies among hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients and is seriously impaired by metastasis. Chromosomal instability (CIN) was one of the key drivers of breast cancer metastasis. Here we evaluate CIN and 10-year invasive disease-free survival (iDFS) and overall survival (OS) in HR+/HER2-- breast cancer. In this large-scale, multiple-site, retrospective study, 354 HR+/HER2- breast cancer patients were recruited. Of these, 204 patients were used for internal training, 70 for external validation, and 80 for cross-validation. All medical records were carefully reviewed to obtain the disease recurrence information. Formalin-fixed paraffin-embedded tissue samples were collected, followed by low-pass whole-genome sequencing with a median genome coverage of 1.86X using minimal 1 ng DNA input. CIN was then assessed using a customized bioinformatics workflow. Three or more instances of CIN per sample was defined as high CIN and the frequency was 42.2% (86/204) in the internal cohort. High CIN correlated significantly with increased lymph node metastasis, vascular invasion, progesterone receptor negative status, HER2 low, worse pathological type, and performed as an independent prognostic factor for HR+/- breast cancer. Patients with high CIN had shorter iDFS and OS than those with low CIN [10-year iDFS 11.1% versus 82.2%, hazard ratio (HR) = 11.12, p < 0.01; 10-year OS 45.7% versus 94.3%, HR = 14.17, p < 0.01]. These findings were validated in two external cohorts with 70 breast cancer patients. Moreover, high CIN could predict the prognosis more accurately than Adjuvant! Online score (10-year iDFS 11.1% versus 48.6%, HR = 2.71, p < 0.01). Cross-validation analysis found that high consistency (83.8%) was observed between CIN and MammaPrint score, while only 45% between CIN and Adjuvant! Online score. In conclusion, high CIN is an independent prognostic indicator for HR+/HER2- breast cancer with shorter iDFS and OS and holds promise for predicting recurrence and metastasis.

PD-L1 and CD8+ T cell evaluation in breast cancers and their correlation with clinicopathological parameters.

To determine the immunohistochemical expression of Programmed cell Death Ligand 1 and intratumoural cluster of differentiation-8-positive T lymphocyte count in primary breast cancer cases, and to ascertain their association with different clinicopathological parameters. The cross-sectional study was conducted at the Pakistan Navy Station Shifa Hospital, Karachi, from January 2020 to December 2021, and comprised patients of breast cancer regardless of age. Representative tissue blocks, both prospective and from the 2019 institutional archives, were exposed to immunohistochemical staining with Programmed cell Death Ligand 1 and intratumoural cluster of differentiation-8-positive T lymphocyte antibodies. Pathological and clinical records were used for assessing clinicopathological parameters. Data was analysed using SPSS 23. Of the 70 women with mean age 52.04±12.54 years, 30(42.9%) expressed high Programmed cell Death Ligand 1 positivity, and 55(78.6%) revealed low intratumoural cluster of differentiation-8-positive T lymphocyte count, while 23 (32.9%), had both Programmed cell Death Ligand 1 high positivity and low intratumoural cluster of differentiation-8-positive T lymphocyte count. The association between Programmed cell Death Ligand 1 and intratumoural cluster of differentiation- 8-positive T lymphocytes was not significant (p=0.813). A strong significant association was observed between Programmed cell Death Ligand 1 expression and progesterone receptor negative status (p=0.008). No significant association was observed with any other clinicopathological parameter. Programmed cell Death Ligand 1 high positivity and low intratumoural cluster of differentiation-8-positive T lymphocyte count were together observed in one-third of the breast cancer cases. A strong significant association existed between Programmed cell Death Ligand 1 high positivity and progesterone receptor negative status.

Survival analysis for patients with metachronous contralateral breast cancer: Insights from a retrospective study.

Continued advances in the diagnosis and treatment of breast cancer (BC) have led to an increase in the number of long-term BC survivors and an increase in the incidence of metachronous BC in the contralateral breast. Therefore, it is important to understand the factors that influence the development of metachronous BC; however, the impact of the laterality of the initial ipsilateral (I)BC as a risk factor for the development of metachronous contralateral (MC)BC has not been extensively investigated. The present study included 17,082 female patients with stage 0-3 IBC from the prospectively maintained Korean Breast Cancer Registry from 1989-2013 and divided them into two groups: Patients with MCBC (n=88) and those without MCBC (n=16,994). Risk factors that present at the initial BC diagnosis that could significantly influence the development of MCBC were screened for and risks were evaluated using the Fine-Gray subdistribution hazard model. Significant differences in baseline characteristics between MCBC and non-MCBC groups were demonstrated. Patients aged <40 years, those with histological and nuclear grade 3 tumors, and those with the triple-negative BC subtype were significantly more prevalent in the MCBC group than in the non-MCBC group. Additionally, the cumulative incidence of MCBC increased over time, with a notable increase from 0.1% in year 1 to 1.6% in year 10. Survival analysis revealed no significant differences in overall or BC-specific survival between the two groups. Key predictive factors identified for MCBC included an age of <40 years at initial diagnosis, a negative progesterone receptor status, and a Ki-67 score of >14%. Overall, the present study revealed several factors associated with MCBC and emphasized the need for long-term monitoring of BC survivors, considering these newly identified risk factors.

Comparison between 18F-FDG PET/CT and diffusion-weighted imaging in detection of invasive ductal breast carcinoma.

Breast carcinoma is the most common type of cancer in females. This study aims to compare fluorine-18-fluorodeoxyglucose (18F-FDG) uptake pattern and apparent diffusion coefficient (ADC) value for the detection of the primary tumour and axillary metastases of invasive ductal breast carcinoma. This study included 40 breast carcinoma lesions taken from 39 patients. After staging by positron emission tomography-computed tomography (PET/CT) and diffusion-weighted magnetic resonance imaging (MRI), breast surgery with axillary lymph node dissection or sentinel lymph node biopsy was performed. Primary lesion detection rate for PET/CT and diffusion-weighted MRI was high with 39 of 40 lesions (97.5%). The sensitivity and specificity for the detection of metastatic lymph nodes in axilla were 40.9%, 88.9%, with 18F-FDG PET/CT scans and 40.9%, 83.3%, for dw-MRI, respectively. No significant correlation was detected between ADC and SUVmax or SUVmax ratios. Estrogen receptor (p=0.007) and progesterone receptor (p=0.036) positive patients had lower ADC values. Tumour SUVmax was lower in T1 than T2 tumour size (p=0.027) and progesterone receptor-positive patients (p=0.029). Tumour/background SUVmax was lower in progesterone receptor-positive patients (p=0.004). Tumour/liver SUVmax was higher in grade III patients (p=0.035) and progesterone receptor negative status (p=0.043). This study confirmed the high detection rate of breast carcinoma in both modalities. They have same sensitivity for the detection of axillary lymph node metastases, whereas the PET/CT scan had higher specificity. Furthermore, ADC, SUVmax and SUVmax ratios showed some statistical significance among the patient groups according to different pathological parameters.

Breast Cancer Clinicopathology based on Neutrophil Levels at Adam Malik Hospital Medan in 2018-2021

Introduction: Breast cancer is the most frequently diagnosed cancer in the world. Breast cancer occurs due to abnormal cell growth in breast tissue so that it becomes malignant. In Indonesia, breast cancer is the most common cancer in women. That way, many markers are needed as prognostic and predictive of breast cancer. One of the prognostic factors for breast cancer is neutrophil levels combined with clinicopathological factors. Objective: Knowing the clinicopathology of breast cancer based on neutrophil levels at the Haji Adam Malik Medan General Hospital in 2018-2021. Methods: The research design is observational with a descriptive method and calculated using the Lemeshow formula. Results: Majority aged 40-49 years (39.6%), high school (44.8%), housewives (67.7%), no family history (97.9%), tumor grade II (38.5%) %), Tumor Infiltrating Lymphocytes (TILs) severe (47.9 %), mitotic score 1 (38.5 %), metastatic positive lymph node status (87.5 %), tumor size T1 (36.5 %), The number of positive and negative Estrogen Receptors is the same (50.0%), Progesterone Receptor is negative (56.3%), HER2 is 1+ (60.4%), Ki-67 is positive (84 .4 %), positive angioinvasion (63.5 %), Invasive Ductal Carcinoma (90.6 %), high neutrophil levels (77.1 %). Conclusion: High levels of neutrophils tend to result in severe Tumor Infiltrating Lymphocytes (TILs) which will increase tumor growth, occurrence of metastases, increased positive angioinvasion, negative Estrogen Receptor status, negative Progesterone Receptor status, HER2 1+ status, positive Ki-67 status.

Efficacy, safety, and prognosis prediction in patients treated with ribociclib in combination with letrozole: Final results of phase 3b RIBECCA study in hormone receptor positive, human epidermal growth factor receptor-2 negative, locally advanced or metastatic breast cancer

BackgroundIn MONALEESA-2, addition of ribociclib to letrozole resulted in significantly longer progression-free survival (PFS) in postmenopausal women with HR+HER2− advanced breast cancer (ABC). RIBociclib for the treatment of advanCed breast CAncer (RIBECCA) study investigated ribociclib plus letrozole in a patient population reflecting routine clinical practice. Patients and methodsIn this multicenter, open-label, single-arm, phase 3b study, patients with HR+HER2− ABC not amenable to curative therapy and ECOG performance status ≤ 2 received ribociclib plus letrozole (cohort A: postmenopausal women and men in first-line; cohort B: pre-/perimenopausal women in first-line [B1], patients pretreated for advanced disease [B2]). The primary endpoint was clinical benefit rate (CBR) by week 24; secondary endpoints included overall response rate (ORR), PFS, overall survival (OS), and safety. Association of patient and tumor characteristics with PFS was analyzed by multivariable Cox regression analysis. ResultsOverall, 487 patients were evaluable for efficacy, 502 for safety. By week 24, CBR was 60.8 % (95 % CI, 56.3–65.1), ORR was 19.3 % (95 % CI, 15.9–23.1). Median PFS was 21.8 months (95 % CI, 13.9–25.3) in first-line postmenopausal patients and 11.0 months (95 % CI, 8.2–16.4) in premenopausal and pretreated patients. Median OS was not reached. Higher baseline ECOG performance status, higher histological grade, and negative progesterone receptor status showed an unfavorable effect on PFS. Most common adverse events were neutropenia (50.0 %), nausea (42.0 %), and fatigue (39.2 %). ConclusionIn this broad population of patients with HR+HER2− ABC, efficacy and safety results of ribociclib plus letrozole were similar to those observed in pivotal trials.

Abstract PD13-11: PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer

Abstract Background Abemaciclib is approved for patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) with progression on prior endocrine therapy (ET). The MONARCH 2 trial showed a statistically significantly benefit in progression-free survival (PFS) (hazard ratio [HR]: 0.553; 95% CI: 0.449-0.681; p &amp;lt; 0.001), overall survival (OS) (HR: 0.757; 95% CI: 0.606-0.945; p = 0.01) and a manageable safety profile for abemaciclib plus fulvestrant compared with fulvestrant alone. Here we report the pre-specified final overall survival (OS) analysis from the MONARCH 2 trial (NCT02107703). Methods MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib or placebo, plus fulvestrant for treatment of pre-, peri- or postmenopausal women with CDK 4 &amp; 6 inhibitor naïve HR+, HER2- ABC that progressed during ET. Pts were randomized 2:1 to receive abemaciclib or placebo, 150 mg twice daily, plus fulvestrant. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary versus secondary). OS and safety were key secondary endpoints, and chemotherapy-free survival was an exploratory endpoint defined as the time from randomization to initiation of chemotherapy or death, whichever occurs the earliest. Kaplan-Meier (KM) method was used to analyze time-to-event variables. A stratified Cox proportional hazards model was used to estimate treatment effect hazard ratio (HR). The prespecified final analysis was planned to occur based on approximately 441 OS events. Data cutoff was March 18, 2022. Results 669 women were randomized 2:1 to receive abemaciclib (n = 446) or placebo (n = 223), plus fulvestrant. Baseline characteristics have been previously reported (Sledge et. al., Jama Oncol 2020). The median follow-up time was approximately 80 months and at the time of the data cutoff, 11% of pts were still receiving study drug in the abemaciclib arm versus 2% in the placebo arm. 440 OS events were observed in the ITT population (abemaciclib arm: 283 events; placebo arm: 157 events). The median OS was 45.8 months in the abemaciclib arm and 37.2 months in the placebo arm (HR: 0.784; 95% CI: 0.644-0.955). The maintained separation of the KM curves beyond the medians is illustrated by the differences in the estimated 5- and 6-year OS rates between arms (5-year: 41.2% versus 29.2%; 6-year: 34.7% versus 23.7%; abemaciclib versus placebo respectively). While OS benefit was generally consistent across subgroups, a more pronounced benefit is noted in subgroups associated with a poorer prognosis such as visceral disease (HR: 0.643; 95% CI: 0.499-0.829), primary resistance to ET (HR: 0.634; 95% CI: 0.436-0.922) or negative progesterone receptor status (HR: 0.623; 95% CI: 0.405-0.959). Moreover, the addition of abemaciclib to fulvestrant deferred the initiation of chemotherapy (HR: 0.674; 95% CI: 0.562-0.809), with substantial difference in yearly chemotherapy-free survival rates (3 year: 42% vs 29.3%; 4 year: 37% vs 18.6%; 5 year: 32.4% vs 14.7%). Notably with longer exposure to abemaciclib, no new additional safety risks or cumulative toxicities were identified. Conclusions At the prespecified final OS analysis of the MONARCH 2 trial, with a median follow-up of 6.5 years, the statistically significant benefit previously demonstrated was confirmed and maintained. OS benefit was generally consistent across subgroups, with numerically greater effect size observed among patients with poorer prognosis. Importantly, the survival benefit came with a substantial extension of the chemotherapy-free survival time, which is an important consideration for pts with ABC. The results also provide assurance of the safety of abemaciclib with longer-term use. Citation Format: Antonio Llombart-Cussac, George Sledge, Masakazu Toi, Patrick Neven, Joo Hyuk Sohn, Kenichi Inoue, Xavier Pivot, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Valerie Andre, Yuanyuan Bian, Ashwin Shahir, Gertjan van Hal. PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-11.

Sub-Classification of Triple-Negative Breast Cancer using Androgen Receptor and Cytokeratin 5/6

Background: Triple negative breast cancer (TNBC) is a unique heterogenous subtypes of breast cancer which is characterized by negative estrogen, progesterone, and human epidermal growth factor receptor (HER-2) status. TNBC displays different molecular phenotype with which basal-like tumour can be identified using high molecular weight basal cytokeratin 5/6 (CK5/6).&#x0D; Methods: Ninety-five (95) formalin fixed cases from Korle Bu Teaching Hospital in Ghana’s (KBTH) archives were sampled in a retrospective study from 2012-2016. Blocks of these triple-negative breast cancer was subclassified using CK5/6 and Androgen Receptor (AR) antibodies. Subclasses were also identified.&#x0D; Results and Conclusion: In all ninety-five (95) TNBC cases, hormonal subtyping was sub-classified using CK 5/6 and AR. The mean ±SD of these cases was recorded as 53.96 (±13.56) years and the age range of these cases was 22-104 years. The average size (±SD) of the tumour was recorded to be 14.43(±7.62) and it had a range of 2.4-45cm. lymph nodes retrieved also had a mean ± SD of 10.35(±6.05) with an average tumour lymph nodes involvement of 2.6(± 3.697).&#x0D; Invasive Ductal carcinoma was identified as the commonest histologic type of TNBC with approximately 95% of the cases. This was followed by invasive lobular (2.1%), medullary carcinoma (2.1%) and metaplastic carcinoma (1.1%).&#x0D; Approximately 30% of TNBC stained positive for CK5/6.&#x0D; It can however be concluded that, most TNBC are not basal-like when the basal marker CK5/6 is used.

Abstract OT2-19-06: Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL

Abstract Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase &amp;gt;1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-06.

Prognostic value of programmed death ligand-1 expression in breast carcinomas

ObjectivesTo assess the prognostic value of programmed death ligand-1 (PDL-1) expression in patients with nonmetastatic breast carcinoma patients both in tumor cells and tumor-infiltrating lymphocytes (TILs).BackgroundPDL-1 has emerged as important immune biomarkers in breast cancer. It can be targeted with immunotherapy, which represents a significant advancement in the management of this disease.Patients and methodsParaffin blocks of patients with breast cancer will be tested for the expression of PDL-1 both on TILs and malignant epithelial cells and correlated with patients and disease features.ResultsThis retrospective study included 60 patients. PDL-1 expression was positive in 33 (55%) patients on TILs and was positive in tumor cells in 27 (45%) patients of the studied patients. There was no significant relation between PDL-1 expression on TILs and patients and disease features. There was significant relation between positive PDL-1 expression on epithelial cells and triple-negative breast cancer, estrogen receptor negative, progesterone receptor negative status (P = 0.006, 0.006, and 0.006). PDL-1 intensity in intratumoral lymphocytes is significantly related to tumor stage (P = 0.006). PDL-1 H score in malignant epithelial cells was significantly related to disease stage (P = 0.021). Tumor size, HER-2neu status, and PDL-1 H score on malignant epithelial cells were independent risk factors for disease progression.ConclusionPDL-1 expression is common in both malignant tumor cells and TILs. A higher PDL-1 H score on malignant epithelial cells was associated with longer time to progression.

Evaluation of Number Density of Tumor-Associated Macrophages by Immunohistochemistry and Semiquantitative Scoring in Invasive Breast Cancer: An Indian Study.

Tumor microenvironment is emerging as a critical factor for progression of breast cancer. Tumor-associated macrophages (TAMs) play an important role in promoting tumor growth. This study was aimed at correlation of number density (ND) of TAMs with invasive ductal carcinoma (IDC) grading utilizing an image morphometric technique. We also sought to compare the TAMs and ND in the tumoral area and stromal region. We also explored the relationship between the clinical and pathological prognostic parameters. The study included 75 cases of IDC that had undergone modified radical mastectomy. The Institutional Ethics Committee approved the study. Samples were classified as Grade 1, 2, and 3. Cases were graded as per the modified Bloom and Richardson criterion. Mean with standard deviation was calculated for each group. We utilized CD68 and CD163 immunostained sections for determining the ND of TAMs. TAMs were evaluated using computerized digital photomicrograph system with image analyzing software. ND was defined as the number of TAMs in total number of TAMs in five high-power fields/total area of five fields. ND was calculated separately in tumor and tumor stroma (TS). Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2/neu (HER2/neu) were scored in accordance with recommendations. Ki-67 was scored as per the recommended guidelines. Data were tabulated in Microsoft Excel. SPSS version 20.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. To determine the relationship between macrophage density and clinicopathologic parameters, we used the independent t-test. To determine the differences in the parameters, analysis of variance (ANOVA) was utilized. Age of the patients ranged from 34 to 58 years (mean: 55.5). One-way ANOVA between various grades of tumor indicating significant differences in terms of CD68 and CD163 densities in tumor and stroma (P < 0.0001). i.e., significant increased density of CD68 and CD163 was observed in Grade 3 tumor as compared to other two groups. A greater histological grade, ER, PR negative status, and a high Ki-67 index were all associated with TAM ND. There was no relation to HER2/neu status. Result of unpaired t-test indicates increased density in stroma as compared to tumor among various grades of IDC. We analyzed images with a software using photographs of the stained slides. This helped in quantitative analysis of TAMs on the CD68 and CD163 stained sections. This approach standardizes and reproducibly counts TAMs per unit area. We found significant difference between the number densities of TAMs in grades of invasive breast carcinoma. There were statistically significant differences in numerical densities of TAMs with ER, PR negativity, and Ki-67. There was no correlation with HER2/neu. Densities of CD68 and CD163 densities are more prevalent in TS as compared to intratumoral region.

Real-Life Analysis of Efficacy and Safety of Everolimus Plus Exemestane in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Patients: A Turkish Oncology Group (TOG) Study

Purpose This study evaluated the efficacy and safety of everolimus (EVE) plus exemestane (EXE) in hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) metastatic breast cancer (MBC) patients in real-life settings. Methods Overall, 204 HR+, HER2− MBC patients treated with EVE + EXE after progressing following prior endocrine treatment were included. Overall survival (OS) and progression-free survival (PFS) and safety data were analyzed. Results The objective response rate, median PFS, and median OS were 33.4%, 8.9 months, and 23.4 months, respectively. Multivariate analysis revealed that negative progesterone receptor status was a significant determinant of poor treatment response (p = 0.035) and PFS (p = 0.024). The presence of bone-only metastasis was associated with better treatment response (p = 0.002), PFS (p < 0.001), and OS (p = 0.001). Conclusion We confirmed the favorable efficacy and safety profile of EVE + EXE for HR+, HER − MBC patients.

High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma.

Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells’ proliferative capacity, and overall disease-free patients’ survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells’ proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients’ survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients’ survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.

Lost but Not Least-Novel Insights into Progesterone Receptor Loss in Estrogen Receptor-Positive Breast Cancer.

Simple SummaryMost breast cancers co-express estrogen receptor α (ERα) and progesterone receptor (PgR). These cancers are sensitive to endocrine therapy and, in general, have superior outcomes. However, a subset of tumors expresses ERα but loses expression of PgR in various mechanisms. The processes driving the loss of PgR may cause resistance to hormonal treatment and a more aggressive clinical course. The current review summarizes current knowledge on the biology of ERα-positive PgR(−)negative breast cancer and discusses the associations between molecular mechanisms and clinical characteristics.Estrogen receptor α (ERα) and progesterone receptor (PgR) are crucial prognostic and predictive biomarkers that are usually co-expressed in breast cancer (BC). However, 12–24% of BCs present ERα(+)/PgR(−) phenotype at immunohistochemical evaluation. In fact, BC may either show primary PgR(−) status (in chemonaïve tumor sample), lose PgR expression during neoadjuvant treatment, or acquire PgR(−) phenotype in local relapse or metastasis. The loss of PgR expression in ERα(+) breast cancer may signify resistance to endocrine therapy and poorer outcomes. On the other hand, ERα(+)/PgR(−) BCs may have a better response to neoadjuvant chemotherapy than double-positive tumors. Loss of PgR expression may be a result of pre-transcriptional alterations (copy number loss, mutation, epigenetic modifications), decreased transcription of the PGR gene (e.g., by microRNAs), and post-translational modifications (e.g., phosphorylation, sumoylation). Various processes involved in the down-regulation of PgR have distinct consequences on the biology of cancer cells. Occasionally, negative PgR status detected by immunohistochemical analysis is paradoxically associated with enhanced transcriptional activity of PgR that might be inhibited by antiprogestin treatment. Identification of the mechanism of PgR loss in each patient seems challenging, yet it may provide important information on the biology of the tumor and predict its responsiveness to the therapy.

Prognostic Factors in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative (HR+/HER2-) Advanced Breast Cancer: A Systematic Literature Review.

PurposeAdvanced breast cancer is a heterogeneous disease with several well-defined subtypes, among which, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) is most prevalent. Determination of HR and HER2 status influences prognosis and, thus, disease management. Although literature on these prognostic factors exist, especially in the early breast cancer setting, it remains unclear to what extent these factors can guide clinical decision-making in the advanced disease setting. Therefore, we sought to identify the strength and consistency of evidence for prognostic factors in patients with HR+/HER2– advanced breast cancer.MethodsA systematic literature review (SLR) of the major electronic databases was conducted in November 2018 for primary research studies published since 2010. Endpoints of interest were tumor response, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS).ResultsSeventy-nine studies were included wherein all patients were diagnosed with advanced breast cancer and ≥50% of the population were HR+/HER2–. OS was the most commonly assessed endpoint (n=67) followed by PFS (n=33), BCSS (n=5) and tumor response (n=3). The prognostic factors with strongest evidence of association with worse OS were negative progesterone receptor status, higher tumor grade, higher circulating tumor cell (CTC) count and higher Ki67 level, number of metastatic sites (eg multiple vs single) and sites of metastases (eg presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, poor performance status, prior therapy attributes in the early or metastatic setting (type of therapy, treatment line, response of prior therapy), and race (black vs white). The prognostic factors that had strongest evidence of association with PFS included CTC count, number and sites of metastases, and absence of prior therapy or higher lines of therapy in the early or metastatic setting. The directionality of association was consistent for all prognostic factors except between lymph node and OS, and de novo metastatic breast cancer and PFS.ConclusionMultiple disease, treatment, and patient-related prognostic factors impact survival, particularly OS, in patients with HR+/HER2– advanced breast cancer. Treatment outcomes can vary considerably due to these factors. Understanding poorer prognostic factors for patients can result in improved clinical decision-making.

Real-world clinical profile, treatment patterns and patient-reported outcomes in a subset of HR+/HER2- advanced breast cancer patients with poor prognostic factors: data from an international study

BackgroundPatients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) and disease-related poor prognostic factors are not well characterized. We aimed to describe patient demographics, disease characteristics, treatment patterns and patient-reported outcomes in a subset of HR+/HER2− ABC patients with these factors [at the time when cyclin-dependent kinase (CDK) 4 and 6 inhibitors were being introduced] and understand how these factors informed treatment decisions at the time of the survey.MethodsReal-world data were derived from a large, multinational, point-in-time survey of oncologists and their consulting patients with HR+/HER2− ABC in the EU5 and USA over March-June 2017, at the start of the changing treatment landscape. Analysis focused on four poor prognostic factors: visceral metastases, liver metastases (subset of visceral metastases), progesterone receptor-negative status and high tumor grade.ResultsIn total, 2259 patients with HR+/HER2− ABC had records eligible for this analysis. At least one poor prognostic factor was present in 63% of patients (most common visceral metastases; least common progesterone receptor-negative status), with varying degrees of overlap between factors. For physician-reported outcomes, pain increased, whereas performance status and activities of daily living declined with presence of poor prognostic factors, especially liver metastases. No clear trends were observed for patient-reported outcomes. Treatment with combined endocrine therapy plus CDK4 and 6 inhibitors was infrequent, as these agents were entering the market.ConclusionsMore than 60% of the HR+/HER2− ABC Adelphi Real World Disease Specific Programme™ sample had ≥1 disease-related poor prognostic factor, and patients appeared to be heterogeneous regarding occurrence and distribution of these factors. These patients typically have increased pain and reduced performance status, highlighting the importance of implementing effective therapy with CDK4 and 6 inhibitors. Future studies could inform how the treatment landscape has evolved over time with respect to patients with poor prognostic factors.

Locally Advanced Breast Cancer: Treatment Patterns and Predictors of Survival in a Saudi Tertiary Center.

Background Breast cancer (BC) is the most common cancer in the Kingdom of Saudi Arabia (KSA) and the second leading cause of cancer-related mortality. About 40% of BC in KSA is locally advanced BC (LABC), which has been associated with poorer survival compared with early diagnosed BC.ObjectiveTo review the presentation and outcomes of LABC, including the characteristics of the disease, different treatment modalities, overall survival (OS), disease-free survival (DFS), and local recurrence in relation to different radiotherapy (RT) techniques.Methods We retrospectively reviewed the medical records of 153 female patients with pathologically proven LABC diagnosed at King Abdulaziz University Hospital, Jeddah, KSA, between 2009 and 2017. We obtained data on patient demographics, stage of cancer at diagnosis, tumor characteristics (subtype and receptor status), type of surgery, systemic treatments received (hormonal, targeted therapy, and chemotherapy), RT variables, and recurrence and death dates. Data were analyzed to assess OS and DFS by using Kaplan-Meier analyses and the log-rank test. Univariate and multivariate Cox proportional hazard regression analyses were used to explore and identify factors associated with survival.Results The median survival time in the study population was 9.16 years. Older age (65+ years) was associated with worse OS and DFS than was younger age (<65 years) (hazard ratio (HR) 3.20, 95% CI 1.48-6.90, P = 0.003 and HR 2.21, 95% CI 1.12-4.36, P = 0.022, respectively). Regarding the type of surgery, having a mastectomy was associated with worse OS and DFS than was having a lumpectomy (HR 2.44, 95% CI 0.97-6.12, P = 0.05 and HR 2.41, 95% CI 1.13-5.14, P = 0.023, respectively). Positive estrogen and progesterone receptor status was associated with better OS and DFS than was a negative estrogen or progesterone receptor status (HR 0.13, 95% CI 0.05-0.30, P < 0.001 and HR 0.21, 95% CI 0.11-0.41, P < 0.001, respectively). Patients who received RT had a lower risk of recurrence than did those who did not receive RT (P = 0.011). Moreover, three-dimensional conformal RT was associated with lower local recurrence than intensity-modulated RT or volumetric-modulated arc therapy (P = 0.003).Conclusion Multiple factors can affect the OS and DFS in LABC. Younger patients, having hormone-positive disease, and undergoing lumpectomy were associated with better outcomes. Adjuvant RT may improve local control and the use of three-dimensional conformal RT was superior for local control. Prospective studies with larger sample sizes are needed to further highlight these findings and to assess the role of chemotherapy and targeted therapy in patients with LABC.

Necessity of sentinel lymph node biopsy in ductal carcinoma in situ patients: a retrospective analysis

BackgroundSentinel lymph node biopsy (SLNB) is unnecessarily performed too often, owing to the high upstaging rates of ductal carcinoma in situ (DCIS). This study aimed to evaluate the upstaging rates of DCIS to invasive cancer, determine the prevalence of axillary lymph node metastasis, and identify the clinicopathological factors associated with upstaging and lymph node metastasis. We also examined surgical patterns among DCIS patients and determined whether SLNB guidelines were followed.MethodsWe retrospectively analysed 307 consecutive DCIS patients diagnosed by preoperative biopsy in a single centre between 2014 and 2018. Data from clinical records, including imaging studies, axillary and breast surgery types, and pathology results from preoperative and postoperative biopsies, were extracted. Univariate analyses using Chi-square tests and multiple logistic regression analyses were used to analyse the data.ResultsThe rate of upstaging to invasive cancer was 19.2% (59/307). DCIS diagnosed by core-needle biopsy (odds ratio [OR]: 6.861, 95% confidence interval [CI]: 2.429–19.379), the presence of ultrasonic mass-forming lesions (OR: 2.782, 95% CI: 1.224–6.320), and progesterone receptor-negative status (OR: 3.156, 95% CI: 1.197–8.323) were found to be associated with upstaging. The rate of sentinel lymph node metastasis was only 1.9% (4/202), and all were total mastectomy patients diagnosed by core-needle biopsy. SLNB was performed in 37.2% of 145 breast-conserving surgery patients and 91.4% of 162 total mastectomy patients. Among the 202 patients who underwent SLNB, 145 (71.7%) without invasive cancer on final pathology had redundant SLNB. Two of 59 patients (3.4%) with disease upstaged to invasive cancer had inadequate primary staging of the axilla, as the rate seemed sufficiently small.ConclusionsIn patients with a preoperative diagnosis of DCIS, although an unavoidable possibility of upstaging to invasive cancer exists, axillary metastasis is unlikely. Only 2.7% of patients with DCIS undergoing total mastectomy were found to have sentinel lymph node metastases. SLNB should not be performed in breast-conserving surgery patients and should be reserved only for total mastectomy patients diagnosed by core-needle biopsy.

Podoplanin expression in cancer-associated fibroblasts predicts unfavorable prognosis in node-negative breast cancer patients with hormone receptor-positive/HER2 − negative subtype

Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an indicator for poor prognosis in patients with invasive breast carcinomas, but little is known about its clinical significance in node-negative breast cancer patients with hormone receptor (HR) + /HER2 - subtype, who are expected to have a favorable prognosis. Immunohistochemical analyses were performed on 169 resected specimens of node-negative invasive carcinoma of no special type with HR + /HER2 - subtype using antibodies for podoplanin. When more than 10% of CAFs showed immunoreactivity with podoplanin as strong as that of internal positive controls, the specimens were judged as podoplanin-positive. Podoplanin-positive status in CAFs was observed in 16.0% (27 of 169 cases) and it associated with high Ki67 labeling index (LI) (> 30%) (p = 0.03), higher stromal tumor-infiltrating lymphocytes (p < 0.001) and progesterone receptor-negative status (p = 0.045). Log-rank test showed that podoplanin-positive status in CAFs correlated with shorter disease-free survival (DFS) (p = 0.007) and disease-specific survival (DSS) (p < 0.001). Univariate analysis showed a significant correlation between shorter DFS and podoplanin-positive status in CAFs (hazard ratio [HR] = 3.380; p = 0.012), the presence of lymphatic invasion (HR = 5.621; p < 0.001), high Ki67 LI (HR = 5.217; p < 0.001), and histological grade III (HR = 3.748; p = 0.008). According to Cox multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DSS (HR = 37.759; p = 0.003) followed by high Ki67LI (HR = 27.664; p = 0.007). Podoplanin expression in CAFs could be an independent predictor for poor prognosis in node-negative breast cancer patients with HR + /HER2 - subtype.