Progesterone Receptor Positivity Research Articles

Abstract HER2-14: HER2-14 HER-2 low status in early stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series

Abstract Objectives: The concept of human epidermal growth factor receptor 2 (HER2)-low status has been proposed as a potential treatment target for breast cancers previously considered to be HER2-negative. Defined by an immunohistochemistry (IHC) score of 1+ or 2+ and negative fluorescent in situ hybridization (FISH) for HER2, HER2-low status predicts significant clinical benefit from novel therapeutic compounds in recent clinical trials. The prevalence and clinical implications of HER2-low status in patients with early stage invasive lobular carcinoma (ILC) has not been described. We aimed to describe the clinicopathologic features and prevalence of HER2-low status in ILC, and identify any potential differences in clinical outcome. Methods: We evaluated stage I-III ILC tumors from a prospectively maintained institutional database of patients where both IHC and FISH testing for HER2 status was performed as standard clinical care. Tumors were classified as HER2 negative (IHC=0), HER2-low (IHC=1+ or 2+ and negative FISH), or HER2 positive (IHC=3+ or FISH ratio ⇒2). Data were analyzed in Stata 16.1 using chi-squared tests, t-tests, and Cox proportional hazards models for disease free survival (DFS). Results: 666 ILC tumors with available HER2 status were available for analysis. The mean age at diagnosis was 59.8 years (range 21-91). The majority of patients had stage I disease (63.1%) with an average follow up time of 6.7 years (standard deviation [5.4]). Overall, 184 (27.6%) tumors were HER2 negative, 434 (65.1%) were HER2-low, and 48 (7.2%) were HER2 positive. There were no associations between HER2 status and age, menopausal status, body mass index, tumor stage, grade, presence of lymphovascular invasion, or molecular assay results. Hormone receptor status was significantly associated with HER2 status, with HER2 positive tumors significantly less likely to be estrogen receptor (ER) positive than both HER2 negative and HER2-low tumors (89.6% versus 97.3% and 96.8% respectively, p=0.03). HER2-low tumors were also significantly more likely to have progesterone receptor (PR) positivity (86.6% compared to 79.9% of HER2 negative and 72.9% of HER2 positive tumors, p = 0.01). This difference remained significant when comparing just HER2-low to HER2 negative cases (p=0.034). While there were no differences in use of neoadjuvant or adjuvant chemotherapy by HER2 status, HER2-low patients were significantly more likely to undergo mastectomy versus lumpectomy when compared to HER2 negative and HER2 positive patients (53.7% versus 38.0% and 43.8% respectively, p= 0.001). In a multivariable Cox proportional hazards model adjusting for tumor size, number of positive nodes, ER/PR status, and local therapy received, patients with HER2-low status had worse DFS than those with HER2 negative tumors (hazard ratio 2.0, 95% confidence interval 1.0 - 4.1, p=0.05). Conclusions: In this analysis of 666 early stage ILC cases, we found that most tumors were HER2-low, and that those with HER2-low disease were significantly more likely to have PR positive tumors and to undergo mastectomy. When adjusting for these variables, we identified a difference in DFS between HER2 negative and HER2-low early stage ILC. These findings support the contention that HER2-low and HER2 negative disease represent two different clinical entities. Further investigation of the potential benefit of HER2 targeted therapy in ILC, which predominately lacks HER2-amplified disease, is needed to ensure optimal outcomes in this understudied tumor type. Citation Format: Harriet T. Rothschild, Elle Clelland, Anne Patterson, Julissa Molina-Vega, Mandeep Kaur, Mary Kathryn Abel, W. Fraser Symmans, Christopher J. Schwartz, Rita Mukhtar. HER2-14 HER-2 low status in early stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series [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 HER2-14.

Abstract P3-05-02: Trends in clinical treatment of early stage ER+PR- breast cancer in the National Cancer Database

Abstract Background Estrogen receptor positive (ER+) progesterone receptor negative (PR-) tumors are a distinct subset of breast cancers that are not well characterized. It is critical to better understand the biology of ER+PR- tumors and tailor therapy accordingly for this unique subgroup. The objective of this study is to compare the ER+PR- subgroup of breast cancer as compared to the double positive ER+PR+ group in a large, well-characterized database to determine if the tumors that are PR- are associated with higher rates of genomic testing and chemotherapy receipt. Methods We identified patients diagnosed with ER+Her2-, Stage 1-3 invasive breast cancer from 2010-2015 in the National Cancer Database. We excluded patients who received neoadjuvant therapy. Demographics and clinical characteristics for the ER+PR+ and ER+PR- groups were obtained. Differences between groups were assessed using the chi-square test. Multivariable logistic regression analysis was performed on both the node negative and node positive patients in order to identify factors independently associated with having a genomic test and receiving chemotherapy in the ER+PR+ and ER+PR- cohorts. Results Of the 363,945 eligible patients, 327,357 (89.9%) patients had ER+PR+ breast cancer and 36,588 (10.1%) had ER+PR- breast cancer. A trend towards larger tumor size in the ER+PR- population as compared to the ER+PR+ population was noted with 23.1% vs 17.3% of tumors 2-5cm and 2.2% vs 1.2% of tumors > 5cm, respectively. Higher grade was also seen in the ER+PR- group as compared to the ER+PR+ group with 27.1% versus 11.7% grade 3 tumors. In both the node negative and node positive populations, genomic testing was less likely to be sent on a PR- breast cancer than a PR+ breast cancer. When genomic testing was sent, there were more high risk Oncotype Recurrence scores (RS > 30) in the PR- group than the PR+ group. For node negative breast cancer high risk Oncotype recurrence scores were found in 32.4% of the ER+PR- population versus 5.6% in the ER+PR+ population. In the node positive cohort high risk Oncotype Recurrence scores were seen in 27.8% of the ER+PR- population as compared to 5.0% in the ER+PR+ population. Patients with discordant ER+PR- breast cancer were more likely to receive chemotherapy than their ER+PR+ counterparts in both the node negative cohort (32.2% vs 12.7%) and the node positive cohort (73.2% vs 64.5%). Conclusion There have been limited studies to date specifically focused on the ER+PR- subgroup. Patients with ER+PR- breast cancer have a higher grade, larger size, higher risk genomic testing, and are more likely to receive chemotherapy than their ER+PR+ counterparts. Discordance in hormone receptor status contributes to a more aggressive type of breast cancer that may impact clinical and treatment decisions. Citation Format: Poornima Saha, Angeline Yu, Priya Thakkar, Kristine Kuchta, Katharine Yao. Trends in clinical treatment of early stage ER+PR- breast cancer in the National Cancer Database [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 P3-05-02.

Invasive lobular triple negative carcinoma of breast: A clinico-pathological study done in south eastern part of India

Background: Triple Negative Breast Carcinomas (TNBC) are breast carcinomas which are negative for Estrogen receptor (ER) Progesterone receptor (PR) and no overexpression of Human Epidermal Growth Factor receptor-2 (HER-2). The five-year survival rate for breast carcinomas in general is good but the same is bad for TNBC. TNBC has got worse prognosis compared to hormone positive breast carcinomas. Aim: The aim of present study is to compare invasive lobular TNBC with invasive ductal TNBC with morphologic, immunohistochemical and prognostic parameters. Materials and Methods: One-year study was done at Tertiary Care Centre. Patients of all ages were included. Most of them were in 4th and 5th decade. Mammography, FNAC and Biopsy was done. Formalin-fixed mastectomy specimens received at MGM hospital are screened, diagnosed histopathologically for carcinoma of breast over a period of one year. Immunohistochemistry (IHC) was performed to diagnose TNBC. Results: Total no of cases – 72. No of Cases with positive ER, PR and or Her 2/neu are – 61. No of Cases with ER, PR and Her 2/neu negative (Triple negative) – 11 Percentage of Triple negative cases – 15 %. Most of the TNBCs show high grade and high mitotic count 74% and 82% respectively. Other hand, some cases 60% showed only ER and PR positivity without Her-2 and 25% showed only Her-2 positivity without ER and PR. Invasive lobular TNBC subtype is reported in 18%. Conclusion: Overall TNBCs are high grade aggressive tumors and are more common in younger age groups. Whereas TNBCs associated with invasive lobular carcinoma are more common in 5th decade and were more aggressive compared to other subtypes.

Effect of Moringa oleifera Extract on Inflammatory Status in Cancer Patients with Aromatase-Induced Arthralgia

BACKGROUND: Aromatase inhibitor therapy is commonly used for breast cancer patients with characteristics of positive estrogen and progesterone receptors test without metastases. Thus, this kind of therapy generally gives side effects of aromatase-induced arthralgia (AIA). Moringa oleifera has a strong anti-inflammatory substance that has the potential to reduce inflammation and pain in a patient with AIA. AIM: This study aims to assess the effect of M. oleifera extract administration on pain response and inflammatory status in breast cancer with aromatase inhibitor-induced arthralgia patients. METHODS: Forty-two patients breast cancer patients with estrogen and progesterone receptor-positive in Dr. Kariadi General Hospital were assessed for pain response and inflammatory status before and after the treatment with M. oleifera leaf extract for one month. Assessment of pain response is using the Australian Canadian osteoarthritis hand index (AUSCAN) questionnaire and inflammation is measured by ANA serum level. This study is experimental with two parallel pre-test and post-test group. RESULTS: In the treatment group, there was a significant decrease of the AUSCAN score 13.5 ± 5.11 (p ≤ 0.001), while in the control group, there was an increase in the AUSCAN score 2.7 ± 4.96 (p = 0.022). In the measurement of ANA serum level, a significant decrease of the treatment group found 0.3 ± 0.40 (p ≤ 0.001). CONCLUSIONS: Moringa oleifera extract can help reduce pain response and inflammatory status of patients with chronic inflammation as an additional therapy.

Bilateral mastectomy associated with higher breast cancer mortality among patients with estrogen receptor positive progesterone receptor negative localized breast cancer.

Rates of mastectomy for patients with localized breast cancer remain high despite decades of evidence that breast conservation therapy is equally effective. The impact of progesterone receptor (PR) status on the relative efficacy of surgical extent for localized estrogen receptor (ER) positive breast cancer on breast cancer mortality has not been studied. This retrospective cohort study included patients diagnosed with breast cancer between 1998 and 2015 using data from the Surveillance, Epidemiology and End Results (SEER) program. Female patients aged 40-70 with T1-2N0M0 ER positive breast cancer were included. Patients in this study either underwent lumpectomy without radiation, lumpectomy with radiation, unilateral mastectomy without radiation, or bilateral mastectomy without radiation for their disease. Breast cancer specific mortality was the main outcome of interest, calculated using competing risks methods to estimate cumulative incidence and hazard ratios among the treatment groups. After one-to-one matching, 23,080 patients were included with median follow-up time 7.6 years (interquartile range, 4.0-8.3 years). Median age at diagnosis was 52 years (interquartile range, 47-59 years). Among patients, 19,996 (86.6%) had PR+ disease and 3,084 (13.4%) of patients had PR-. Among patients with PR- disease, bilateral mastectomy was associated with higher cumulative incidence of breast cancer mortality relative to patients undergoing lumpectomy with radiation, with 10-year cumulative incidences of 9.2% [95% confidence interval (CI): 6.6-12.7%] vs. 4.4% (95% CI: 3.0-6.6%). This difference was significant in the adjusted multivariate model [hazard ratio (HR) =1.77; 95% CI: 1.12-2.82; P=0.02]. Bilateral mastectomy was associated with significantly increased risk of breast cancer mortality relative to lumpectomy with radiation for patients with PR- disease. Unilateral mastectomy and lumpectomy without radiation were associated with increased risk for breast cancer mortality relative to lumpectomy with radiation for patients with PR+ disease.

Meme kanserinde neoadjuvan kemoterapi yanıtlarını öngörmede belirleyici olarak açlık kan şekeri ve vücut kitle indeksi

Aim: Obesity is a well-known modifiable risk factor for breast cancer. Impaired fasting glucose is a component of metabolic syndrome and a significant risk for diabetes. We aimed to research the effect of these two major components of metabolic syndrome on neoadjuvant chemotherapy (NAC) response in breast cancer.Methods: We conducted 161 patients who had received NAC from January 2016 to January 2022. Fasting plasma glucose levels were measured at least two times and BMI was recorded before starting NAC. Impaired fasting glucose is defined as plasma glucose levels of 100 to 125 mg per dL. Analyses were compared into two groups according to FPG levels below or above 100 mg/dl and according to BMI obese (BMI30≥ kg/m2), or non-obese (BMI <30 kg/m2). The pathologic response was evaluated, and patients were divided into five groups according to the Miller-Payne grading system classified from grade V to I, complete pathologic response, loss of more than 90% of tumor cells, reduced 30% and 90% of tumor cells, lost less than 30% of tumor cells, and had no reduction in cellularity and no change malignant cells respectivelyResults: In the pathologic responses, 70.8% of patients with impaired fasting glucose levels were grade 1 non-reduction with NAC. Disease free-survival was shorter in the group that had impaired fasting glucose than in the group that had normal fasting plasma glucose (FPG) (p=0.031). In univariate analysis clinical stage 3 (p <0.001), postmenopausal status (p=0.037), human epidermal growth factor receptor 2 (HER-2) negativity (p<0.001), estrogen receptor (ER) positivity (p <0.001), progesterone receptor (PR) positivity (p <0.001) rate were higher in grade 1 unresponsive patients compared to patients with pathological response grade 2, grade 3 and grade 4. In multivariate analysis showed that fasting plasma glucose, clinical stage, HER-2 status, and ER status were independent predictor factors for pathological complete response (pCR). BMI had no impact on pCR. Our trial showed that the ratio of pCR in patients with impaired fasting glucose was 2.5 times lower than that in patients who had normal FPG levels [HR: 2.5, 95%CI 1.08–5.92, p = 0.03].Conclusion: Fasting plasma glucose significantly impacted both pCR and recurrence.

The clinical value of progesterone receptor expression in luminal breast cancer: A study of a large cohort with long-term follow-up.

The routine assessment of progesterone receptor (PR) expression in breast cancer (BC) remains controversial. This study aimed to evaluate the role of PR expression in luminal BC, with emphasis on the definition of positivity and its prognostic significance as compared to Ki67 expression. A large cohort (n=1924) of estrogen receptor (ER)-positive/HER2-negative BC was included. PR was immunohistochemically (IHC) stained on full face sections and core needle biopsies (CNB) where the optimal scoring cutoff was evaluated. In addition, the association of PR with other clinicopathological factors, cellular proliferation, disease outcome, and response to adjuvant therapy were analyzed. Although several cutoffs showed prognostic significance, the optimal cutoff to categorize PR expression into two clinically distinct prognostic groups on CNB was 10%. PR negativity showed a significant association with features of aggressive tumor behavior and poor outcome. Multivariate analyses indicated that the association between PR negativity and poor outcome was independent of tumor grade, size, node stage, and Ki67. PR negativity showed independent association with shorter survival in patients who received endocrine therapy whereas Ki67did not. PR IHC expression provides independent prognostic value superior to Ki67. Routine assessment of PR expression in BC using 10% cutoff in the clinical setting is recommended. In this study, we have established an optimal approach to determine the prognostic value of progesterone receptor expression in estrogen receptor-positive breast cancer patients. To do this, the levels of progesterone receptor were measured in a large cohort of estrogen receptor-positive breast cancer patients. We have refined the definition of progesterone receptor positivity in estrogen receptor-positive breast cancer. We show that progesterone receptor expression adds prognostic and predictive value of endocrine therapy in estrogen receptor-positive breast cancer patients, and our results show that the absence of progesterone receptor is associated with poorer outcomes independent of tumor grade, size, node stage, and Ki67 expression.

Abstract B027: PIK3CA hotspot mutations as biomarkers for prognosis and treatment prediction in low-risk postmenopausal breast cancer patients

Abstract The PIK3CA gene, encoding the p110α catalytic subunit of PI 3-kinase (PI3K), is mutated in more than 30% of breast cancers. Most mutations concentrate to the hotspots E542K and E545K and H1047R and are associated with hyperactivation of the phosphatidylinositol 3′-kinase/Akt pathway in vitro. The estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) (ER+/HER2-) breast cancers stand for more than 40% of the PIK3CA mutations where these constitute a new therapeutic target for endocrine-treatment resistant advanced breast cancers. Although PIK3CA is an oncogene, its mutations are associated with good prognosis. Here, we explored the prognostic and predictive role of PIK3CA hotspot mutations for low-risk postmenopausal breast cancer patients randomized to receive tamoxifen vs. no systemic treatment, followed for over 25 years and with extensive clinical records. Mutation analysis was performed using formalin-fixed paraffin-embedded tumors with digital droplet PCR (ddPCR). PIK3CA mutations were present in 35,6% of patients, predominantly within the ER+/HER2- subtype (49,8%) compared with the HER2+ and TNBC subtypes. The most frequent mutation found in all patients was H1047R (18%) followed by E545K (14%) and E542K (6%). Significant associations were found between all hotspot mutations and low grade, positive progesterone receptor (PR) expression, HER2 negative status, low Ki-67 (proliferation marker), and high expression score of a PIK3CA-mutation-associated gene module. Moreover, PIK3CA mutations were often found in patients with ultralow risk to develop distant recurrences according to the 70-gene signature. All PIK3CA mutations were coupled with longer distant recurrence-free interval (DRFI) in all patients in univariate and multivariable analysis after adjusting for tumor size, receptor status (ER, PR, HER2), tumor grade, Ki-67 and tamoxifen: HR multivariable (95% CI)=0.53 (0.28-0.98). In agreement with our previous results, PIK3CA mutations indicated good prognosis for patients with highly proliferative tumors (Ki-67>15%): H.R multivariable (95% CI)=0.15 (0.03-0.69) and high risk by the 70-gene signature: HR multivariable (95% CI)=0.14 (0.03-0.61) but not for low proliferative tumors (Ki-67<15%). In fact, PIK3CA mutations indicated adverse prognosis within those patients with ultralow risk where the registered survival was 100% in presence of the PIK3CA wild type genotype. PIK3CA mutations did not have predictive value for tamoxifen. In conclusion, PIK3CA mutations predominate within the ER+/HER2- subtype, are coupled with good clinical markers and longer DRFI in all patients and especially among aggressive tumors but not in ultralow risk patients. Further investigation will be needed to decipher the role of PIK3CA in patients with ultralow risk or indolent tumors who may present long-term relapses and specially benefit from PI3K inhibition. Citation Format: Carolin Jönsson, Zeinab Alkashaf, Josefine Sandström, Annelie Johansson, Tommy Fornander, Linda S. Lindström, Gizeh Perez Tenorio. PIK3CA hotspot mutations as biomarkers for prognosis and treatment prediction in low-risk postmenopausal breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B027.

Endometrial Stromal Nodule with Intense Decidual Changes. Findings during Delivery of the Placenta

Background: Endometrial stromal nodules involving the placental membranes are exceptionally rare. Only two cases have been described in the literature. We report a new case of endometrial stromal nodule with intense decidual changes as an incidental finding during delivery of the placenta. Case: A 31-years-old female patient with no history of interest presented after a normal term delivery, a 3.5 x 2.6 x 1cm well circumscribed nodule independent of the placenta and not attached to it. The tumor was asymptomatic and was not identificated ultrasonographically. Microscopically, the neoplastic nodule was composed of spindle and epithelioid cells with extensive eosinophilic cytoplasm with a decidualized appearance without associated glands, except for minimal epithelial remnants in the periphery. Characteristic features of endometrial stromal tumor were identified, such as CD10, WT-1, and progesterone receptor positivity, and an expanding noninfiltrating linear pushing rim. There were also pregnancy-related changes, such as decidualization and myxoid change. The lesion was considered a endometrial stromal nodule with an unusual morphology and increased proliferation rate due to the hormonal stimuli of pregnancy. Conclusion: We report a rare case of an incidental endometrial stromal nodule during delivery of the placenta, representing only the third such case reported in the world literature. In all likelihood, this neoplasm originated from the decidua of the free membranes

Can TILs be associated with prognostic factors and survival rates in breast cancer? A retrospective analysis

Introduction: The relationship between the tumor inflammatory infiltrate, also known as tumor-infiltrating lymphocytes (TILs), and invasive breast carcinomas has been extensively studied in recent years to verify its association with prognosis and response to treatment. The goal of this study was to associate the presence of TILs with patient’s survival time. Methods: We studied prognostic clinicopathological characteristics already established in the literature and their impact on overall five-year survival time of patients with invasive breast cancer treated at Hospital Santa Casa in Belo Horizonte, Minas Gerais, Brazil, in 2011 (n=290). This was an observational and retrospective study. Results: The presence of TILs was associated with tumors of no special type (p=0.018) and with younger age of the patients (p=0.042). Smaller tumor size (HR: 19.24; 95%CI 4.30–86.15; p<0.001), absence of metastasis to the axillary lymph nodes (HR: 2.80; 95%CI 1.02–7.70; p=0.002), positivity for progesterone receptor (HR: 0.39; 95%CI 0.17–0.87; p=0.022), and presence of TILs (HR: 0.23; 95%CI 0.08–0.65; p=0.005) were associated with longer survival times. Conclusions: This study suggests that the presence of TILs, along with other clinicopathological characteristics, is a prognostic factor in breast cancer.

Characterization of Expression and Function of the Formins FHOD1, INF2, and DAAM1 in HER2-Positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as trastuzumab, benefit patients with HER2-positive metastatic breast cancer; however, owing to traditional pathway activation or alternative signaling, resistance persists. Given the crucial role of the formin family in shaping the actin cytoskeleton during cancer progression, these proteins may function downstream of the HER2 signaling pathway. Our aim was to uncover the potential correlations between formins and HER2 expression using a combination of public databases, immunohistochemistry, and functional in vitro assays. Using online databases, we identified a negative prognostic correlation between specific formins mRNA expression in HER2-positive cancers. To validate these findings at the protein level, immunohistochemistry was performed on HER2 subtype breast cancer tumors to establish the links between staining patterns and clinical characteristics. We then knocked down individual or combined formins in MDA-MB-453 and SK-BR-3 cells and investigated their effects on wound healing, transwell migration, and proliferation. Furthermore, we investigated the effects of erb-b2 receptor tyrosine kinase 2 (ERBB2)/HER2 small interfering RNA (siRNA)-mediated knockdown on the PI3K/Akt and MEK/ERK1 pathways as well as on selected formins. Our results revealed that correlations between INF2, FHOD1, and DAAM1 mRNA expression and ERBB2 in HER2-subtype breast cancer were associated with worse outcomes. Using immunohistochemistry, we found that high FHOD1 protein expression was linked to higher histological grades and was negatively correlated with estrogen and progesterone receptor positivity. Upon formins knockdown, we observed effects on wound healing and transwell migration, with a minimal impact on proliferation, which was evident through single and combined knockdowns in both cell lines. Notably, siRNA-mediated knockdown of HER2 affected FHOD1 and INF2 expression, along with the phosphorylated Akt/MAPK states. Our study highlights the roles of FHOD1 and INF2 as downstream effectors of the HER2/Akt and HER2/MAPK pathways, suggesting that they are potential therapeutic targets in HER2-positive breast cancer.

Value of Breast MRI and Nomogram After Negative Axillary Ultrasound for Predicting Axillary Lymph Node Metastasis in Patients With Clinically T1-2 N0 Breast Cancer.

There are increasing concerns about that sentinel lymph node biopsy (SLNB) could be omitted in patients with clinically T1-2 N0 breast cancers who has negative axillary ultrasound (AUS). This study aims to assess the false negative result (FNR) of AUS, the rate of high nodal burden (HNB) in clinically T1-2 N0 breast cancer patients, and the diagnostic performance of breast magnetic resonance imaging (MRI) and nomogram. We identified 948 consecutive patients with clinically T1-2 N0 cancers who had negative AUS, subsequent MRI, and breast conserving therapy between 2013 and 2020 from two tertiary medical centers. Patients from two centers were assigned to development and validation sets, respectively. Among 948 patients, 402 (mean age ± standard deviation, 57.61 ± 11.58) were within development cohort and 546 (54.43 ± 10.02) within validation cohort. Using logistic regression analyses, clinical-imaging factors associated with lymph node (LN) metastasis were analyzed in the development set from which nomogram was created. The performance of MRI and nomogram was assessed. HNB was defined as ≥ 3 positive LNs. The FNR of AUS was 20.1% (81 of 402) and 19.2% (105 of 546) and the rates of HNB were 1.2% (5/402) and 2.2% (12/546), respectively. Clinical and imaging features associated with LN metastasis were progesterone receptor positivity, outer tumor location on mammography, breast imaging reporting and data system category 5 assessment of cancer on ultrasound, and positive axilla on MRI. In validation cohorts, the positive predictive value (PPV) and negative predictive value (NPV) of MRI and clinical-imaging nomogram was 58.5% and 86.5%, and 56.0% and 82.0%, respectively. The FNR of AUS was approximately 20% but the rate of HNB was low. The diagnostic performance of MRI was not satisfactory with low PPV but MRI had merit in reaffirming negative AUS with high NPV. Patients who had low probability scores from our clinical-imaging nomogram might be possible candidates for the omission of SLNB.

ESR1-мутації як предиктор прогресії та метастазування гормонозалежного раку молочної залози

The relevance of the work is due to the need for additional research to better understand the prevalence of ESR1 mutations at different stages of recurrent disease and their prognostic implications. The purpose of the study was to determine the incidence of ESR1 mutations in ER-positive breast cancer, its prognostic value in the choice of treatment. Materials and methods. A systematic review of quality studies, which were taken from PubMed and Thomas Reuters Web of Science databases, published between 2007 and 2019 was performed. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrence, metastasis, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English on the development of ESR1 mutations and their outcomes on disease progression were included. Studies were selected using predefined data fields, taking into account the quality of the study. This prospective clinical study is conducted by means of molecular genetic analysis, namely, gene polymorphism analysis by polymerase chain reaction. This study is carried out on the basis of the Kyiv City Clinical Oncology Center and the Department of Oncology of the Bogomolets National Medical University. A retrospective cohort of hormone receptor positive breast cancer patients experiencing either local or metastatic recurrence was collected from available archival specimens. All clinical data were obtained from the patients' clinical records by an expert breast oncologist. This included age, TNM stage, grade, immunohistochemistry scores for estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and treatment lines. Results and discussion. Estrogen receptor and progesterone receptor positivity was determined based on local pathology practice (> 1% positively stained cells). The article demonstrated that ESR1 mutations often occur during AI therapy in the setting of metastasis and may play a role in metastasis progression. Advances in DNA sequencing technology have led to more sensitive detection of ESR1 mutations in clinical samples, and there are now several studies using sequencing and ddPCR techniques to track ESR1 and other mutations during treatment and progression. Targeted DNA sequencing and ddPCR technologies have shown that ESR1 mutations may pre-exist in approximately 5% of primary tumors and are significantly enriched by 30-40% in the setting of metastasis. The ctDNA analysis provides a simple, non-invasive and relatively inexpensive method for monitoring mutations that may arise during treatment, which can ultimately be used to guide treatment decisions. Conclusion. Importantly, ESR1 mutation monitoring alone is not clinically predictive of treatment; however, monitoring the acquisition of stem cell or other mutations may predict response and/or progression of treated cancers. Currently, patients with tumors expressing ESR1 mutations are best treated with the combination of fulvestrant and palbociclib, as this combination has significantly improved PFS in patients with most identified ESR1 mutations. Ongoing clinical trials using fulvestrant with specific PI3K-alpha inhibitors are showing promising clinical results, but analysis of whether patients with specific ESR1 mutations will benefit from this treatment has not yet been published

Breast biomarkers profile of invasive lobular carcinoma in a cohort of arab women shows no significant differences from carcinoma of no special type.

Invasive lobular carcinoma (ILC) of the breast is known for its common presentation at an older age, and the frequent expression of favourable profile of estrogen and progesterone receptors (ER & PR) positivity, and human epidermal growth factor receptor 2 (HER2) negativity combined with low proliferation rate as measured by Ki67. This study aimed to test these clinicopathological features of ILC in an Arabic cohort. All breast biopsies diagnosed as IDC or ILC were retrospectively reviewed over 2 years period (2017-2018) in an academic centre. Variables were compared using Fisher's exact test for statistical significance. A total of 134 cases were recruited, 12.7% were ILC. The median age was 52 years for both types. Clustering of ILC cases was noticed in luminal A subtype (47.1%), but there was no statistically significant difference in subtyping between the 2 histologic groups. Ki67 was significantly lower in ILC than IDC category. Our study showed that ILC in our cohort lacks the advantage of older age and the common high expression of ER positivity in comparison to IDC. There is, however, significant difference of the value of Ki67 proliferation marker. The prognosis of lobular morphology is questionable in our cohort.

Use of clinicopathological factors to predict prognosis of fertility-sparing treatment for endometrial endometrioid carcinoma and atypical hyperplasia.

The incidence of endometrial endometrioid carcinoma (EEC) has been gradually increasing over the past decade. Fertility-sparing therapy with progestin is a treatment option for EEC or endometrial atypical hyperplasia (AH). The present study evaluated the role of numerous prognostic factors following fertility-sparing therapy for EEC or AH. Furthermore, the present study assessed the strength of various clinicopathological indicators for the prediction of treatment efficacy. A retrospective analysis was performed of patients with EEC and AH who received fertility-sparing therapy between August 2013 and September 2021 at Peking University People's Hospital (Beijing, China). Endometrial specimens were obtained from each patient after 3 months of treatment and at the end of the fertility-sparing therapy, before treatment efficacy and prognosis were evaluated using the χ2 test. Furthermore, the protein expression levels of EEC biomarkers, such as estrogen receptor (ER), progesterone receptor (PR), paired box 2 (PAX2), PTEN and p53 were assessed using immunohistochemistry. The overall complete response (CR) rate of fertility-sparing treatment in the EEC group was 67.39% (31/46), whereas that in the AH group was 86.49% (32/37). The difference between the CR rates in the EEC and AH groups was statistically significant (P<0.05). There was no association between prognosis after treatment and ER, PAX2, PTEN or Ki-67 expression in the initially untreated AH or EEC groups. However, tissues with >50% positive PR expression were demonstrated to have a higher CR rate compared with those with ≤50% positive PR expression in both the EEC and AH groups. Furthermore, the PAX2-positive group tended to demonstrate higher CR rates compared with the PAX2-negative group in the patients with EEC. In conclusion, these data suggested that fertility-sparing therapy is effective for patients with EEC and AH who wish to remain fertile after treatment. Specifically, in the AH group, a higher proportion of patients achieved a CR whilst also achieving this more rapidly. Furthermore, PR was demonstrated to be a useful marker for the evaluation of EEC and AH.

The frequencies of CYP2D6 alleles and their impact on clinical outcomes of adjuvant tamoxifen therapy in Syrian breast cancer patients

BackgroundTamoxifen is one of the fundamental pillars of adjuvant endocrine therapy for hormone receptor-positive breast cancer; however, 30–50% of patients receiving tamoxifen experience tumor relapse. CYP2D6, encoded by an extremely polymorphic CYP2D6 gene, is the rate-limiting enzyme of tamoxifen bioactivation. This study aimed at determining the frequencies of the most clinically relevant CYP2D6 alleles and evaluating their impact on the responsiveness to tamoxifen in a cohort of Syrian breast cancer patients.MethodsThis case–control study encompassed positive estrogen and/or progesterone receptor, stage 1–3 breast cancer female patients receiving tamoxifen at Al-Bairouni University Hospital, the major National Oncology Center in Syria. Successfully genotyped eligible patients (n = 97) were classified according to their response into; no recurrence group (n = 39) who had completed a five-year recurrence-free adjuvant tamoxifen therapy, and recurrence group (n = 58) who had experienced recurrence. Several star alleles including CYP2D6*4, CYP2D6*10, CYP2D6*41, and CYP2D6*69 were identified via targeted sequencing of specific polymerase chain reaction (PCR) products and phenotypes were assigned according to activity score (AS). The correlation between genotypes and disease-free survival (DFS) was assessed using Kaplan–Meier method and log-rank test. Hazard ratios were estimated using Cox proportional hazards regression models.ResultsThe allelic frequencies of CYP2D6*41, CYP2D6*10, CYP2D6*4, and CYP2D6*69 were found to be 9.28%, 7.22%, 7.22%, and 2.58%, respectively. No statistically significant differences were observed in the frequencies of CYP2D6 phenotypes between the two arms (P = 0.24), nor the incidence of tamoxifen-induced hot flashes (P = 0.109). Poor metabolizers (PMs) tended to display shorter DFS than intermediate metabolizers (IMs) and normal metabolizers (NMs) combined (adjusted HR = 2.34, 95% CI = 0.84–6.55, P = 0.104). Notably, patients homozygous for the null CYP2D6*4 allele (1847A/A) had an elevated risk of disease recurrence compared to patients with 1847G/G genotype (adjusted HR = 5.23, 95% CI = 1.22–22.49, P = 0.026).ConclusionsOur findings show no association between CYP2D6 phenotype and treatment outcomes of tamoxifen in Syrian breast cancer patients. Nevertheless, a worse DFS was revealed in patients with 1847A/A genotype (*4/*4).

Factors Predicting Positive Sentinel Lymph Node Biopsy in Clinically Node-Negative Breast Cancer.

PurposeSentinel lymph node (SLN) biopsy (SLNB) is the standard tool to stage the axilla of breast cancer patients. This study aimed to identify the predictors of positive SLNB in patients with clinically node-negative breast cancer.Patients and MethodsA retrospective, single-institution cohort of patients with early-stage breast cancer without clinically identifiable axillary lymphadenopathy was chosen from January 2010 to December 2018. Logistic regression was used to identify possible predictors of positive SLNB.ResultsFour hundred and seventy patients were identified; their mean age was 50±11 years. Most patients had the following characteristics: invasive ductal carcinoma (n=382, 81.3%), unilateral tumor (n=461, 98.1%), unifocal disease (n=351, 74.7%), intermediate grade (n=276, 59.0%), and estrogen and progesterone receptor positivity with human epidermal growth factor receptor 2 negativity (n=305, 64.9%). The mean size of the breast mass was 2.3±1.5 cm. SLNB was positive in 128 (27.2%) cases. The mean number of SLNs was 2±1.2. Axillary lymph node dissection was performed in 109 patients. The mean number of lymph nodes removed was 15±6. In 66 (60.6%) of the 109 patients with metastatic axillary nodes, only the SLNs were found to be positive. The number of SLNs, tumor size, tumor grade, receptor status, prominent axillary lymph nodes, and lymphovascular invasion predicted positive SLNB (P = 0.01, 0.03, 0.03, and 0.04 and <0.001 and <0.001, respectively).ConclusionOur results suggest that a number of histopathological and radiological characteristics of breast cancer can predict SLNB positivity in clinically node-negative breast cancer patients.

Breast cancer heterogeneity

Background:Breast cancer (BC) is the most prevalent cancer in women and the leading cause of women's cancer-related deaths and morbidity worldwide. Conventionally considered as a single disease, recent advances suggest that BC is rather a heterogeneous disease with different molecular subtypes exhibiting distinct clinical presentation, anatomo-pathological features, response to treatment and survival outcomes. The purpose of this study was to compare tumor characteristics and epidemiologic risk factors associated with premenopausal versus postmenopausal BC and to assess heterogeneity by menopausal status.Methods:This was a comparative cross-sectional study. A total of 340 patients were included in the study (170 premenopausal vs. 170 postmenopausal BC). Patients' and tumor characteristics were compared in both populations. Percentages and means have been used for descriptive statistics. For categorical variables with comparison groups not exceeding 2, Fischer's exact test was used, otherwise, Chi-square test was used. For continuous variables, Mann–WhitneyU-test has been used to compare the numerical ranked variables. A value ofP= 0.05 or less was considered statistically significant. Odds ratio (OR) and 95% confidence interval (CI) was estimated using logistic regression analysis.Results:The median age of patients was 49 years (range: 18–89 years), with premenopausal median age of 41 years (range 18–50 years) and postmenopausal median age of 58 years (range 48–89 years). Factors associated more with the occurrence of premenopausal BC than postmenopausal BC were obesity/overweight in adolescence/early adulthood (OR = 0.29 95% CI 0.18–0.49,P&lt; 0.001) and history of benign breast disease (OR 0.34 95% CI 0.14–0.83,P= 0.014), while factors associated more with postmenopausal than premenopausal BC included alcohol intake (OR = 2.47 95% CI 1.54–3.98,P&lt; 0.001), history of breastfeeding (OR = 2.75 1.12–6.78,P= 0.036). However, sports activities (OR = 0.33 95% CI 0.16–0.65,P= 0.0015) and contraceptive use (OR = 0.19 95% CI 0.12–0.32,P&lt; 0.001) seem to be protective for postmenopausal BC. In premenopausal period, patients presented more at advanced stages (Stage III and IV) (51.2% of premenopausal vs. 44.7% for postmenopausal,P= 0.0246), reported more intermediate-to-rapid disease progression (92% in premenopausal vs. 81.1% in postmenopausal (P&lt; 0.001), had more invasive ductal carcinoma (98% in premenopausal vs. 93.5% in postmenopausal (P= 0.053) and had more poorly differentiated tumors (72% compared to 19.4% of postmenopausal BC patients (P&lt; 0.0001). There was no statistically difference in molecular subtypes distribution between premenopausal and postmenopausal women (P= 0.062). However, progesterone receptor (PR) positivity was more associated with postmenopausal BC (P= 0.0165).Conclusion:BC is a heterogeneous disease. Premenopausal BC seems to be more aggressive than postmenopausal BC, with a relatively high prevalence of poorly differentiated and high-grade tumors with rapid progression. However, pre- and postmenopausal BC have similar molecular subtypes with different PR expression but similar ER and human epidermal growth factor receptor 2/Neu oncogene expression.

Efficacy of cyclin-dependent kinase 4/6 inhibitors in patients with metastatic hormone positive breast cancer: a single institutional study from India.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have shown marked benefit in the treatment of hormone positive metastatic breast cancer (HR+ MBC). There are limited real-world studies with palbociclib and ribociclib. Here we report our experience with CDK4/6 inhibitors in these groups of patients. Patients with HR+ MBC who have received either palbociclib or ribociclib during the course of their treatment from January 2017 to January 2022 were included in the study. The baseline demographic features, treatment details and toxicity were recorded. Patients who received at least 1 month of therapy were included in the survival analysis. A total of 144 patients received CDK4/6 inhibitors during the time period. The median age of the population was 53 (30-80) years. Ninety-eight (71.4%) patients presented with de novo metastatic disease. The most common site of metastasis was to the skeleton (74.2%). Most patients (75%) received palbociclib as their therapy. At a median follow-up of 20.2 months, the median progression free survival (PFS) of the whole population was 16.5 (95% confidence interval (95% CI): 11.6-25.5) months and the median overall survival (OS) was 29.7 (95% CI: 21.7-44.6) months. The presence of liver metastases, low progesterone receptor positivity (Allred score < 6) and prior systemic treatment were poor prognostic factors for both PFS and OS in multivariate analysis. Drug was discontinued for only 2.1% of the patient population. Use of CDK4/6 inhibitors has led to improvement in PFS and OS in patients with HR+ MBC and it is well tolerated. The presence of liver metastases and low progesterone receptor positivity (Allred score < 6) and prior treatment are poor prognostic factors.

Role of progesterone receptor status in determining treatment response among premen-opausal breast cancer Libyan patients.

Breast cancer is the most common type of cancer affecting women in Libya. Treatment strategy for premenopausal women involves Tamoxifen as an anti-estrogen in estrogen receptor-positive tumors. Many factors have been identified as predictors of treatment response, such as the receptor status of the tumor. In relation to progesterone receptors, a small number of studies have been performed regarding targeting progesterone receptors in cases of breast cancer. Subject &amp;Methods: a case series study of 46 premenopausal breast cancer females. A retrospective hospital record-based study of the clinicopathological features of premenopausal breast cancer cases admitted to the oncology department in the Benghazi medical center (BMC) Benghazi, Libya during two years, 2010 and 2013. Results: The mean age of the study sample is 39.9×5.6 years, 56.5% of cases were in stage II at diagnosis, 47% of cases were infiltrating ductal carcinoma, 84.8% had positive progesterone receptor, 89.1% of the cases received Chemotherapy, 95.7% had radiotherapy, 28.3 had a history of either local recurrence or distant metastasis during the five years follow up period. Although approximately 92% of the relapsed cases were PR positive, this study revealed no statically significant relationship between progesterone receptor status and the treatment outcome in premenopausal breast cancer cases admitted to BMC at Benghazi (x219= 4.7 &amp; P=0.74). Conclusion: The study concluded that there was no clear role of the progesterone receptors in the tamoxifen treatment response, and further advanced research needed to understand the role of progesterone receptors in determining responders from non-responders to Tamoxifen treatment.