Progesterone Receptor Positivity Research Articles

Abstract PO5-18-07: A Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein 2 Inhibits TNBC Lung Metastases

Abstract Introduction: A promising novel target for breast cancer is secreted frizzled-related protein 2 (SFRP2). SFRP2 protects tumors against apoptosis, promotes T-cell exhaustion, and induces angiogenesis. SFRP2 is expressed in breast cancer but has not been specifically evaluated in triple negative breast cancer. We previously developed a humanized monoclonal antibody to SFRP2, (hSFRP2 mAb) that inhibits primary breast cancer growth in mice without toxicity. The purpose of this study is to establish the presence of SFRP2 in human TNBC, evaluate the efficacy of hSFRP2 mAb in metastatic TNBC in vivo, and in a cell line resistant to chemotherapy. Methods: Immunohistochemistry (IHC) with SFRP2 antibody on a human TNBC tissue microarray (TMA) containing 88 FFPE cores. After IHC with primary antibody to SFRP2, the TMA was scanned and staining intensity was quantified using spatial analysis. Results for SFRP2 staining were analyzed as previously described for analyses of estrogen and progesterone receptor positivity; categories are: 0-absence of staining; low positive (0-10%), and positive >10%. Development of a doxorubicin (dox)-resistant cell line and induction of apoptosis with hSFRP2 mAb. MDA-MB-231 cells were treated with 4nM dox and increased 2nM at a time until the cells were resistant to 10µM dox after 12 months. WT and dox-resistant cells were treated for 4 hours with either hSFRP2 mAb (10uM,) or IgG control (10uM) (n=6). Apoptosis was detected with Promokine Apoptosis/Necrosis/Healthy cells kit. Cells were imaged using the EVOS FLc and counted using Imagej software. Differences between treated and control were compared with two-tailed T-test. hSFRP2 mAb treatment of mice with metastatic TNBC. PY8119 and E0771 TNBC murine cells (5 × 105/100 μL) were injected iv into 6–8-week-old C57BL/6 female mice. The next day the mice were treated with IgG1 control 8 mg/kg iv or hSFRP2 mAb 8 mg/kg iv every 3 days. After four weeks, the lungs were resected, and surface metastases were counted. Differences between treated and control were compared with Poisson distributions. FFPE sections of lungs were stained with ApopTag kit. Three metastases per lung were counted at 20 X, and the difference between IgG1 and hSFRP2 mAb groups compared with two-tailed T-test. Results: SFRP2 protein is present in human TNBC. Out of 88 cores, 83 cores (94%) were positive, 4 cores (4.5%) were minimally positive, and 1 core (1.1%) was negative for SFRP2. Development of a doxorubicin (dox)-resistant cell line and induction of apoptosis with hSFRP2 mAb treatment in vitro. The number of apoptotic cells in IgG1 control-treated MDA-MB-231 cells was 11.5 ± 3.7, and 76.6 ± 5.0 for hSFRP2 mAb-treated tumors (p< 0.001, n=9). The mean number of apoptotic MDA-MB-231 dox-resistant cells in IgG1 control was 16.7 ± 6.0, and 68.4 ± 6.4 for hSFRP2 mAb-treated tumors, (p< 0.001, n=9). hSFRP2 mAb inhibits the growth of metastatic TNBC in vivo and increases apoptosis. For E0771, the number of surface metastases was 8.9 ±2.8 in the IgG1 control group and 4.9 ± 1.1 in the hSFRP2 mAb treated group (p< 0.05, n=15). The number of apoptotic cells/HPF was 9.8 ± 1.8 for the IgG1 control group and 21.0 ± 4.6 for the hSFRP2 mAb group (n=15, p< .01). For Py8119 tumors there were 6.4 ± 1.0 metastases in the IgG1 control group and 3.6 ± 0.9 in the hSFRP2 mAb group (p< 0.05, n=11). The number of apoptotic cells/HPF was 6 ± 1.8 for the IgG1 control group and 14 ±1.3 for the hSFRP2 mAb group (n=10, p< 0.001). Conclusions: SFRP2 protein is abundantly expressed in human TNBC. A humanized monoclonal antibody to SFRP2 reduces TNBC lung metastases growth in two in vivo models and increases tumor apoptosis. TNBC resistant to doxorubicin remains sensitive to apoptosis induced by the hSFRP2 mAb. Citation Format: Lillian Hsu, Patrick Nasarre, Julie Siegel, Eleanor Hilliard, Rupak Mukherjee, Nancy Klauber-Demore. A Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein 2 Inhibits TNBC Lung Metastases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-07.

Abstract PO1-17-10: Impact of COVID19 on neoadjuvant endocrine therapy use in breast cancer: A National Cancer Database analysis

Abstract Background: Neoadjuvant endocrine therapy (NET) is associated with similar response rates as neoadjuvant chemotherapy in hormone receptor positive (HR+) breast cancer (BC), with less toxicity. While gene expression assays such as the 21-gene recurrence score (RS) have led to decreased chemotherapy use in early HR+/HER2- BC, NET is often underutilized. In 2020, the COVID19 pandemic led to disruption in oncologic care, including cancellation of surgeries. Guidelines for BC management during the pandemic recommended NET for HR+/HER2- BC patients unable to obtain surgery due to pandemic restrictions. We evaluated NET use in 2020, compared to NET use in prior years. Methods: Female pts with nonmetastatic HR+/HER2- BC diagnosed between 2016 and 2020 were identified from the 2004-2020 National Cancer Database (NCDB). Annual number of pts receiving NET, and duration of use, were compared between years, and characteristics of pts treated with and without NET were evaluated within and across years, using Chi-squared test for categorical variables and Wilcoxon rank-sum test or Kruskal-Wallis test for continuous variables. Results: 554,733 pts met inclusion criteria; 84.50% white, 9.19% Black, 4.06% Asian; 5.88% Hispanic. 25,553 (4.61%) pts received NET. Annual NET use increased slightly between 2016 and 2018 [3.25% vs 3.49% (p=0.021) vs 3.89% (p < 0.0001)], remained stable in 2019 (3.98%), and then increased to 8.67% in 2020 (p < 0.0001). Median duration of NET remained relatively stable between 2016 and 2019 [74 days (d), 68d, 73d and 61d, 2016-2019] but declined in 2020 (56d, p< 0.0001 for 2020 vs 2016, 2017, 2018, and 2019). Older age and greater comorbidities were associated with NET use in all years (p < 0.0001). No racial association with NET use was seen in 2016-2018, but Black race was associated with greater NET use in 2019 (p=0.0122) and 2020 (p < 0.0001). Lobular histology, moderate grade, larger tumor size, and node involvement were associated with increased NET use in all years (p < 0.0001). Progesterone receptor positivity (PR+) and lower Ki67 were associated with NET use in 2020 (p=0.0007 and p< 0.0001), but not prior. Median tumor size for pts receiving NET was smaller in 2020 (16mm) compared with prior years (22, 23, 22, and 21mm for 2016-2019, p< 0.0001). Annual RS use increased for all pts between 2016 (34.59%) and 2020 (43.47%). RS use in NET pts was stable in 2016 (27.79%) and 2017 (27.54%), with modest increase in 2018 (29.56%; p 0.094, 2016 vs 2018, p=0.045, 2017 vs 2018), and then increased annually in 2019 (33.28%, p=0.0001) and 2020 (40.64%, p< 0.0001). Median RS was higher in pts receiving NET than in pts who did not in 2016-2019 (p=0.0078, 0.0003, 0.0271, and < 0.0001), but was similar in 2020 (RS=16; IQR 11, 22). Conclusions: Frequency of NET administration more than doubled in 2020, but duration was shorter than in prior years, possibly due to use of NET as “bridging therapy” due to COVID19 restrictions. Black race was associated with receipt of NET in 2020, possibly reflecting disparate impact of COVID19 on Black communities. NET use in 2020 was also associated with smaller tumor size, lower Ki67, and greater likelihood of PR+ disease than in prior years. Use of RS to guide NET increased annually, beginning in 2018. Association of NET with older age, greater comorbidities, higher stage, moderate grade, and lobular histology were seen in all years. Citation Format: Della Makower, Jaeun Choi, Susan Fineberg. Impact of COVID19 on neoadjuvant endocrine therapy use in breast cancer: A National Cancer Database analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-10.

Abstract PO3-17-05: Clinical Characteristics and Outcomes of Patients Receiving Adjuvant Paclitaxel and Trastuzumab (APT regimen) for HER2-Positive Early-Stage Breast Cancer in Brazil: A Real-World Evidence

Abstract Introduction: The APT trial established adjuvant paclitaxel and trastuzumab (TH) as the standard of care for HER2-positive early-stage breast cancer with tumor size ≤ 3 cm and no more than one lymph-node micrometastasis. This single-arm phase II trial demonstrated favorable long-term outcomes, with a 3-year invasive disease-free survival (IDFS) rate of 98.7% (95% CI 97.6 – 99.8%). In an updated follow-up analysis, the 10-year IDFS and overall survival (OS) rates were 91.3% (95% CI 88.3 – 94.4%) and 94.3% (95% CI 91.8 – 98.3%), respectively. Nevertheless, outcomes observed in real-world scenarios have frequently been less favorable than those observed in clinical trials. We aimed to characterize the population receiving the APT regimen in clinical practice and evaluate if real-world outcomes align with those observed in the pivotal clinical trial. Methods: This retrospective cohort study included patients with HER2-positive early-stage breast cancer treated between 2015 and 2023 at four Brazilian cancer institutions, including public and private hospitals. Clinical and demographic data, treatment details, and outcomes were collected from electronic records. The primary endpoints were the 3-year and 7-year invasive disease-free survival (IDFS) rates. Secondary endpoints included overall survival (OS) and factors associated with IDFS. Survival analysis employed the Kaplan-Meier method, and Cox regression assessed prognostic factors. Results: A total of 133 patients treated with the APT regimen were evaluated, with a median age of 56 years (range 20–83). The majority had no special type breast carcinoma (92.4%), grade 2 (63.4%) or grade 3 (34.3%) tumors, no angiolymphatic invasion (76.3%), positive estrogen receptor (69.9%), positive progesterone receptor (55.6%), and node-negative disease (94.7%). Tumor staging distribution was as follows: T1a (12%), T1b (23.3%), T1c (49.6%), and T2 (13.5%). Most patients (95.4%) received the APT regimen as per guideline recommendations, while 3.8% received it due to contraindication to other therapies. With a median follow-up of 45.8 months, 8 patients (5.8%) experienced an invasive disease event or death from any cause: 5 (3.8%) had distant recurrence, 1 (0.8%) had local recurrence, and 2 (1.5%) died without recurrence. Notably, these events occurred in patients receiving the APT regimen according to standard indications, except for one patient with N+ disease and a contraindication to another regimen. The recurrence rate according to the T stage is presented in the Table. The 3-year IDFS rate was 100% (95% CI not applicable). All events occurred after the 3-year time point, resulting in a 7-year DFS rate of 80.8% (95% CI 62.7–90.7%). No prognostic factors related to IDFS were identified. Four patients died during the study period, yielding a 7-year OS rate of 88.0% (95% CI 61.6–96.6%). Conclusion: While the baseline characteristics of this cohort resembled those of the APT trial, the long-term outcomes observed in the real-world setting were less favorable. Further investigation is required to determine the reasons for this discrepancy, underscoring the necessity for larger real-world data studies to validate these findings. Recurrence rate according to T stage XX XX Citation Format: Giselle Carvalho, Renata Colombo Bonadio, Pedro Bergmann, Marina Nishimuni, André Rossi, Cristiano Souza, Gabriel Guimarães, Laura Testa, José Bines. Clinical Characteristics and Outcomes of Patients Receiving Adjuvant Paclitaxel and Trastuzumab (APT regimen) for HER2-Positive Early-Stage Breast Cancer in Brazil: A Real-World Evidence [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-05.

Abstract PO3-05-02: Impact of hormone receptor expression level in HR+/HER2- metastatic breast cancer in the large French ESME cohort

Abstract Background: In patients (pts) with early breast cancer (BC), the level of expression of estrogen receptor (ER) evaluated by immunohistochemistry is prognostic and predictive while progesterone receptor (PR) expression has an additional prognostic value. Allred scoring combines the percentage of positive cells and the intensity of staining. It is widely used for treatment choice for early BC. In metastatic setting, its role is less defined. Methods: The ESME database is a French National cohort of all consecutive pts who initiated a first-line treatment for metastatic BC (MBC) between January 2008 and December 2020 in one of the 18 French Comprehensive Cancer Centers (NCT03275311). For this study, we selected pts with HER2- MBC, known ER expression and intensity percentages, known PR status and who received endocrine-based therapy as first-line metastatic treatment. Primary objective was to evaluate the overall survival (OS) and first line progression-free survival (PFS1) under endocrine therapy according to ER and PR expression level. ER expression was defined using Allred score on the last available tumor sample. PR status was defined using a positive (≥10%)vs negative ( < 10%) threshold. Secondary objective was to evaluate clinical PFS1 whether de novo or recurrent MBC and according to type of first line therapy (mono- vs combined endocrine therapy). Results: In the ER+ ± PR+/HER2- population, 8269 pts had information on ER percentage and staining intensity. Median follow-up was 53.4 months (95%CI [51.9; 54.7]). Allred score distribution, OS and PFS1 are described in table 1. Median OS was 43.1 months [41.1; 45.0] for the PR- group compared with 52.3 months [50.5; 54.4] for the PR+ group. After adjustments, patients with a PR- tumour had still a worse prognosis (HR=1.20, 95%CI [1.12-1.28], p<0.001). Median PFS1 was 10.2 months[9.6; 10.8]and 14.8 months[14.2; 15.4] for pts with PR- vs PR+ tumour (HR=1.36 (1.29-1.43), p<0.001) and PR status remained significant prognostic factor independently of de novo or recurrent status and association or not with a targeted therapy. Conclusion: ER expression evaluated using the Allred scoring, as well as PR positivity, retain prognostic value in first-line MBC patients. Table 1 : OS and PFS according to Allred status, de novo status and type of endocrine therapy. * Selected variables on multivariate model include PR status, age, SBR grade, histological subtype, number of metastatic site, type of metastasis (non visceral, visceral, brain visceral), HER 2 (0 vs 1-2), metastatic-free interval, mono- vs combined endocrine therapy. Citation Format: Marie Alexandre, Florence Castan, Thibault De La Motte Rouge, Audrey Mailliez, Etienne Brain, Thomas Bachelot, Monica Arnedos, Florence Dalenc, Jean-Marc Ferrero, Vincent Massard, Isabelle Desmoulins, Marie-Ange Mouret-Reynier, Christelle Levy, Anthony Gonçalves, Anca Berghian, Aude-marie Savoye, Jean-Sébastien frenel, Lise Bosquet, Suzette Delaloge, William Jacot. Impact of hormone receptor expression level in HR+/HER2- metastatic breast cancer in the large French ESME cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-02.

Abstract PO4-02-10: Predictive Factors of Nodal Upstaging at Time of Surgery in Clinically Node Negative Patients Undergoing Neoadjuvant Chemotherapy

Abstract Introduction: Neoadjuvant chemotherapy (NAC) can be given with the intent of downstaging breast cancer or to provide prognostic information prior to any surgical intervention in both node negative (N0) and node positive patients (pts). Residual nodal disease following neoadjuvant chemotherapy generally indicates poorer overall prognosis relative to those who are node negative. Several risk factors have been postulated to predict the presence of occult lymph node metastasis: age at diagnosis, tumor size, status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor (HER-2), and BMI. NAC has been shown to eradicate axillary lymph node metastasis in up to 40% of pts. This study aims to evaluate characteristics of clinically N0 pts who underwent NAC and were upstaged to node positive status at the time of surgery. We hope to identify patient related factors that may help predict the presence of occult nodal disease as well compare pathological complete response rate (PCR) in the breast between N0 and patients who were upstaged. Methods: Data was collected through retrospective chart review of the Stroger Cook County electronic medical records system (CERNER). Pts treated at John H. Stroger Hospital from 2017-2021 with a new diagnosis of cT2-T3 invasive breast cancer who were clinically and radiologically node negative and received NAC were included. We compared demographic data, staging information, cancer characteristics and pathologic complete response rates (PCR) in the breast between those who remained node negative and those who had positive sentinel lymph nodes at the time of surgery. Pts with prior breast cancer diagnosis and those who underwent treatments at an outside institution were excluded. Statistical analysis included 2-tailed t-test and 2-tailed fisher’s (p< 0.05). Results: A total of 98 pts were identified, 62 with complete data for analysis,11 were upstaged at the time of surgery. When comparing pts who had nodal upstaging to those that remained node negative at time of surgery there was no significant difference between average BMI (28.5), age of diagnosis (58 years). Most pts (73%) were T2 at presentation, of those with nodal upstaging at time of surgery, 20% were T3 or higher, while only 5% of those who were not upstaged at surgery were greater than T3 (NS). Upstaged pts had an average tumor size of 4.16 cm while non-upstaged on average were 2.85 cm (P< 0.01). ER positive pts (ER+) and PR positive (PR+) were more likely to have nodal upstaging post op (P< 0.0012, P< 0.0013) when compared to ER negative (ER-) and PR negative (PR-) respectively. The distribution of receptor status was significantly different between groups, the most common receptor status in upstaged patients was triple positive (63%) while triple negative was most common in non-upstaged (41%). Triple positive pts were more likely to be upstaged than those with other receptor statuses (64% vs 40%, p 0.0004). There was a 100% PCR rate in the breast among non-upstaged pts compared to 10% of upstaged patients (P< 0.0001). Among all triple negative pts, 42% had PCR, of ER-/PR-/HER2+, 60% had a PCR, ER+/HER 2 negative had a 40% PCR. Conclusion: Pts with larger presenting tumor size who are node negative at presentation and have undergone chemotherapy are more likely to have occult positive nodes at the time of surgery. ER positive pts and triple positive pts are also more likely to have occult positive nodes at time of surgery. While our sample is small, our breast PCR rate is consistent with other published literature. Further investigation confirming this with larger samples and multi-institutional investigation may help to establish these relationships and elucidate a predictive model. The optimal management of these patients is worthy of further study. Citation Format: Rangel Melissa, Julia Alexieva, Alison Coogan, Elizabeth Marcus, Julie Wecsler. Predictive Factors of Nodal Upstaging at Time of Surgery in Clinically Node Negative Patients Undergoing Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-10.

Abstract PO5-26-05: Machine learning-based risk prediction for late distant recurrence in young women with estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer

Abstract Background There is a clinical unmet need to predict the risk of late recurrence in premenopausal women with estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer (BC) who completed endocrine treatment (ET). Previous studies suggest that the CTS5 model, developed using data from cohorts with postmenopausal women and predicts a likelihood of late recurrence after five years of ET, is not highly predictive in premenopausal women. We developed a machine learning-based model predicting the chance of late distant recurrence (DR) using multi-institutional cohorts of premenopausal women with ER-positive/HER2-negative BC who have had no DR for five years from the surgery. Methods The study conducted a retrospective review of patients who underwent primary surgery between 2000 and 2011 at Samsung Medical Center, Gangnam Severance Hospital, and Seoul National University Hospital. The study included premenopausal women with ER-positive/HER2-negative BC aged 45 years or younger, who were treated over two years of ET with or without ovarian function suppression and had not experienced distant recurrence for at least five years following the surgery. Patients who had received neoadjuvant chemotherapy were excluded from the study. The primary endpoint is the area under the curve (AUC) and sensitivity (Recall) of the model predicting late DR after five years from primary operation. A total of nine clinical features, including age, tumor size, the number of positive lymph nodes, nuclear grade (NG), histologic grade (HG), progesterone receptor (PR) status, chemotherapy, extension of ET, and addition of OFS, were utilized for supervised machine learning classification. Results A total of 2,555 patients were included in this study. The median age was 41 (range, 21-45) years. During a median follow-up duration of 130.3 (range, 60.0-257.6) months, 157 women (6.1%) had late DR after five years of breast cancer surgery. Age, NG, HG, tumor size, and the number of positive LNs were important clinicopathologic variables for late recurrence. The treatment variables included chemotherapy, extension of ET, and the addition of OFS. There were 1,951 patients (76.4%) who had adjuvant chemotherapy, 650 patients (25.4%) with extension of ET over 5 years, and 529 patients (20.7%) who underwent addition of OFS. To develop the model, we performed repeated 5-fold cross-validation using a Balanced Random Forest classifier. The AUC and sensitivity of the model with six features, including age, tumor size, the number of positive lymph nodes, NG, HG, and PR status, were 0.705 and 0.768, respectively. When chemotherapy was added to this model, the AUC and sensitivity of the model increased to 0.713 and 0.771, respectively. When two more treatment features, such as ET extension and addition of OFS, were added to the model, the AUC and sensitivity were 0.714 and 0.752, respectively. Conclusions Demographic and clinical characteristics of the patients in this study Table. Citation Format: Dong Seung Shin, Janghee Lee, Jong-Ho Cheun, Jun-Hee Lee, Yewon Shin, Soong June Bae, Eunhye Kang, Sunyoung Kwon, Han-Byoel Lee, Jai Min Ryu, Sung Gwe Ahn. Machine learning-based risk prediction for late distant recurrence in young women with estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-26-05.

Landscape of HER2-low breast cancer: Insights from a six-year study on prevalence and clinicopathological characteristics

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+/2+ in immunohistochemistry (IHC) and absence of ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2-low breast cancer to novel anti-HER2 antibody-drug-conjugates. Data on characteristics of HER2-low breast cancer subtype is limited. Real-world data from the Anatomic Pathology Department of Hotel-Dieu de France, spanning 2017–2023, was retrospectively collected. HER2-positive patients were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Clinicopathological characteristics between the groups were compared using a Chi-Squared test. Out of 1195 patients, we observed 341 (28.5 %) HER2-low breast cancers cases. HER2-positive breast cancer cases (n = 178; 14.9 %) were excluded. There was no significant difference in age and sex between HER2-low and HER2-zero group (p = 0.33 and 0.79, respectively). HER2-low breast cancer was associated with positive estrogen receptor status and positive progesterone receptor status (p < 0.001 and p = 0.01, respectively). Ductal adenocarcinomas were more commonly observed in HER2-low group (p < 0.001). When stratified by hormone (HR) status, 87.4 % of patients had HR-positive status and 12.6 % were HR-negative. Among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (25%vs.10 %, p = 0.04). This study showed that HER2-low is distinct from HER2-zero and is common among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Within HR-negative breast cancer, those with low HER2 expression exhibit a less aggressive profile compared to HER2-zero tumors.

Correlation between steroid receptor expression and response to progestational therapy in patients with atypical endometrial hyperplasia or cancer

BackgroundConservative management of atypical endometrial hyperplasia (AEH) or endometrial cancer (EMCA) often relies on the treatment of synthetic progestins, which show varied success and response rates. We evaluate the correlation between steroid receptor expression and response to progestin therapy in patients with AEH and EMCA. MethodsRetrospective cohort study collected data for patients with AEH or EMCA who had an endometrial sample after receiving conservative therapy utilizing either Megestrol acetate or Levonorgestrel Intrauterine device (IUD). Immunohistochemistry (IHC) was performed on pre- and post- treatment biopsy samples to assess androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR) expression. IHC scores (1–12) were calculated based on staining intensity and percentage of positive cells. Results and analysisWe identified 15 patients with AEH and EMCA between 2015 and 2023 with the majority of African American ethnicity (53 %). Fourteen patients (93 %) received Megestrol acetate, and 1 patient received Levonorgestrel IUD alone. Three patients ultimately underwent hysterectomy. Seven (46.6 %) endometrial samples had strong positivity for AR, PR and ER expression on pre-treatment biopsies, and only 3 (20 %) of them maintained strong positivity for the 3 receptors in the post-treatment. Patients who successfully responded to the treatment demonstrated a significantly greater decrease in IHC scores after the treatment compared to those who did not respond (p = 0.009). ConclusionSteroid receptor expression could be used as a possible biomarker for response to progestin therapy in patients undergoing conservative management for AEH and EMCA.

Development and Validation of MRI Radiomics Models to Differentiate HER2-Zero, -Low, and -Positive Breast Cancer.

BACKGROUND. Breast cancer HER2 expression has been redefined using a three-tiered system, with HER2-zero cancers considered ineligible for HER2-targeted therapy, HER2-low cancers considered candidates for novel HER2-targeted drugs, and HER2-positive cancers treated with traditional HER2-targeted medications. OBJECTIVE. The purpose of this study was to assess MRI radiomics models for a three-tiered classification of HER2 expression of breast cancer. METHODS. This retrospective study included 592 patients with pathologically confirmed breast cancer (mean age, 47.0 ± 18.0 [SD] years) who underwent breast MRI at either of a health system's two hospitals from April 2016 through June 2022. Three-tiered HER2 status was pathologically determined. Radiologists assessed the conventional MRI features of tumors and manually segmented the tumors on multiparametric sequences (T2-weighted images, DWI, ADC maps, and T1-weighted delayed contrast-enhanced images) to extract radiomics features. Least absolute shrinkage and selection operator analysis was used to develop two radiomics signatures, to differentiate HER2-zero cancers from HER2-low or HER2-positive cancers (task 1) as well as to differentiate HER2-low cancers from HER2-positive cancers (task 2). Patients from hospital 1 were randomly assigned to a discovery set (task 1: n = 376; task 2: n = 335) or an internal validation set (task 1: n = 161; task 2: n = 143); patients from hospital 2 formed an external validation set (task 1: n = 55; task 2: n = 50). Multivariable logistic regression analysis was used to create nomograms combining radiomics signatures with clinicopathologic and conventional MRI features. RESULTS. AUC, sensitivity, and specificity in the discovery, internal validation, and external validation sets were as follows: for task 1, 0.89, 99.4%, and 69.0%; 0.86, 98.6%, and 76.5%; and 0.78, 100.0%, and 0.0%, respectively; for task 2, 0.77, 93.8%, and 32.3%; 0.75, 92.9%, and 6.8%; and 0.77, 97.0%, and 29.4%, respectively. For task 1, no nomogram was created because no clinicopathologic or conventional MRI feature was associated with HER2 status independent of the MRI radiomics signature. For task 2, a nomogram including an MRI radiomics signature and three pathologic features (histologic grade of III, high Ki-67 index, and positive progesterone receptor status) that were independently associated with HER2-low expression had an AUC of 0.87, 0.83, and 0.80 in the three sets. CONCLUSION. MRI radiomics features were used to differentiate HER2-zero from HER2-low cancers or HER2-positives cancers as well as to differentiate HER2-low cancers from HER2-positive cancers. CLINICAL IMPACT. MRI radiomics may help select patients for novel or traditional HER2-targeted therapies, particularly those patients with ambiguous results of immunohistochemical staining results or limited access to fluorescence in situ hybridization.

Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.

Introduction: The 21-gene analysis (OncotypeDX) is validated test for pT1-3, pN0-1 with hormone receptor (HR) positive and normal expression of human epidermal growth factor receptor-2 (HER2) breast cancer (BC) to determine the aggressiveness of the disease based on the calculation of Recurrence Score (RS). Methods: In this retrospective study the authors correlated pathological characteristics and Recurrence Score (RS) by traditional statistical methods and Observed Oriented Modeling (OOM) in a realistic cohort of BC patients. Results: OncotypeDX tests were performed in 94 tumour specimens of 90 BC patients. >83% of node-negative (pN0) and >72% of node-positive (pN1) cases could avoid chemotherapy. For pN0 cases, non-parametric correlation and tests demonstrated significant association in eight types of characteristics [progesterone receptor (PR) expression, Ki-67 value, Ki-67 group, PR group, grade, estrogen receptor (ER) expression, Nottingham Prognostic Index (NPI) and Clinical Risk]. For pN1 cases, parametric correlation and tests showed significant association in six characteristic types (number of positive nodes, ER and PR expression, PR group, Ki-67 group and NPI). Based on OOM for pN0 cases, significant associations were established in three characteristics (Ki-67 group, grade and NPI group). For pN1 cases OOM found significant associations in seven characteristics (PR group, PNI, LVI, Ki-67 group, grade, NPI group and number of positive nodes). Conclusion: First in oncology, OOM was applied, which found some other significant characteristics associated with RS than traditional statistical methods. There were few patients, where no clinical associations were found between characteristics and RS contrary to statistically significant differences. Therefore, the results of these statistical analyses can be neither applied for individual cases nor able to provide the bases for screening patients, i.e., whether they need for OncotypeDX testing or not. OncotypeDX still provides a personalised approach in BC.

Hormone Receptor Status in Histologically Proven Carcinoma Breast

Abstract Background: Carcinoma breast is considered a heterogeneous disease with a varied spectrum of clinical, pathological and molecular features. The molecular classification of breast carcinoma is becoming the gold standard for its complete characterisation. Oestrogen receptor (ER) and progesterone receptor (PR) are routinely performed on all breast cancer specimens and are reliable, inexpensive and useful for therapeutic decision-making. Aim: The aim of the study was to find out the proportion of hormone receptor positivity in cases of breast cancer. Materials and Methods: This is a 1-year cross-sectional study conducted in general surgical wards of our institution. The sample size was 50. The selected patients were subjected to either of the following surgical treatments which are simple mastectomy, modified radical mastectomy or breast conservation surgery. After the surgery, the histopathological specimens were reviewed, and hormone receptor status was studied. Results: Ninety-six per cent of the study population had infiltrating ductal carcinoma and mucinous and metaplastic carcinoma constituted the remaining 4%. In this study, 35 (70%) had ER positivity and 28 (56%) had PR positivity on immunohistochemistry. Of all the factors studied, only age at first childbirth had a significant association with hormone positivity. 52.9% of women in the ER-positive group had first childbirth at or after 23 years. Only 14.3% of women with first childbirth at or after 23 years had ER negativity. Conclusion: The prevalence of hormone receptor positivity obtained in this study is more when compared to most of the studies from India and is comparable to the studies in Western literature.

Ultrasound deep learning radiomics and clinical machine learning models to predict low nuclear grade, ER, PR, and HER2 receptor status in pure ductal carcinoma in situ.

Low nuclear grade ductal carcinoma in situ (DCIS) patients can adopt proactive management strategies to avoid unnecessary surgical resection. Different personalized treatment modalities may be selected based on the expression status of molecular markers, which is also predictive of different outcomes and risks of recurrence. DCIS ultrasound findings are mostly non mass lesions, making it difficult to determine boundaries. Currently, studies have shown that models based on deep learning radiomics (DLR) have advantages in automatic recognition of tumor contours. Machine learning models based on clinical imaging features can explain the importance of imaging features. The available ultrasound data of 349 patients with pure DCIS confirmed by surgical pathology [54 low nuclear grade, 175 positive estrogen receptor (ER+), 163 positive progesterone receptor (PR+), and 81 positive human epidermal growth factor receptor 2 (HER2+)] were collected. Radiologists extracted ultrasonographic features of DCIS lesions based on the 5th Edition of Breast Imaging Reporting and Data System (BI-RADS). Patient age and BI-RADS characteristics were used to construct clinical machine learning (CML) models. The RadImageNet pretrained network was used for extracting radiomics features and as an input for DLR modeling. For training and validation datasets, 80% and 20% of the data, respectively, were used. Logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost) algorithms were performed and compared for the final classification modeling. Each task used the area under the receiver operating characteristic curve (AUC) to evaluate the effectiveness of DLR and CML models. In the training dataset, low nuclear grade, ER+, PR+, and HER2+ DCIS lesions accounted for 19.20%, 65.12%, 61.21%, and 30.19%, respectively; the validation set, they consisted of 19.30%, 62.50%, 57.14%, and 30.91%, respectively. In the DLR models we developed, the best AUC values for identifying features were 0.633 for identifying low nuclear grade, completed by the XGBoost Classifier of ResNet50; 0.618 for identifying ER, completed by the RF Classifier of InceptionV3; 0.755 for identifying PR, completed by the XGBoost Classifier of InceptionV3; and 0.713 for identifying HER2, completed by the LR Classifier of ResNet50. The CML models had better performance than DLR in predicting low nuclear grade, ER+, PR+, and HER2+ DCIS lesions. The best AUC values by classification were as follows: for low nuclear grade by RF classification, AUC: 0.719; for ER+ by XGBoost classification, AUC: 0.761; for PR+ by XGBoost classification, AUC: 0.780; and for HER2+ by RF classification, AUC: 0.723. Based on small-scale datasets, our study showed that the DLR models developed using RadImageNet pretrained network and CML models may help predict low nuclear grade, ER+, PR+, and HER2+ DCIS lesions so that patients benefit from hierarchical and personalized treatment.

Pathological implication of progesterone receptor expression in patients diagnosed with meningioma

Objectives. To assess the progesterone receptor expression in meningioma patients and to characterize the histopathological and demographic features of them. Materials and methods. A cross sectional study conducted during a period of six months from (April to October 2023) included 50 formalin fixed, paraffin embedded tissue blocks diagnosed histopathologically as meningioma. Progesterone receptor was detected using immunohistochemistry in the other section. Outcomes. The most common location of meningioma was cerebrum (56%) and the most common histopathological type was meningothelial. Regarding progesterone receptor status, negative score was presented in 44% of cases. There is a significant association between progesterone receptor status and both of grade and histopathological type of meningioma. Conclusion. High progesterone receptor positivity was linked to low grade tumors. Meningioma grade and many subtypes can be identified with the use of progesterone receptor expression, particularly in cases that are borderline.

Survival trends and patient characteristics between 2004 and 2016 for breast cancer in Japan based on the National Clinical Database-Breast Cancer Registry.

This is a prognostic report by the Japanese Breast Cancer Society on breast cancer extracted from the National Clinical Database-Breast Cancer Registry of Japan. Here, we present a summary of 457,878 breast cancer cases registered between 2004 and 2016. The median follow-up duration was 5.6years. The median age at the start of treatment was 59years (5-95%: 38-82years) and increased from 57years between 2004 and 2008 to 60years between 2013 and 2016. The proportion of patients with Stage 0-II disease increased from 74.5% to 78.3%. The number of cases with estrogen and progesterone receptor positivity increased from 74.8% to 77.9% and 60.5% to 68.1%, respectively. Regarding (neo-)adjuvant chemotherapy, the taxane (T) or taxane-cyclophosphamide (C) regimen increased by 2.4% to 8.2%, but the (fluorouracil (F)) adriamycin (A)-C-T/(F) epirubicin (E)C-T and (F)AC/(F)EC regimens decreased by 18.6% to 15.2% and 13.5% to 5.0%, respectively. Regarding (neo-)adjuvant anti-human epidermal growth factor-2 (HER2)-targeted therapy, the use of trastuzumab increased from 4.6% to 10.5%. The rate of sentinel lymph node biopsy increased from 37.1% to 60.7%, while that of axillary dissection decreased from 54.5% to 22.6%. Improvements in disease-free and overall survival were observed in patients with HER2-positive breast cancer, but there was no apparent trend in patients with hormone receptor-positive, HER2-negative, or triple-negative breast cancers.

Triple-Negative or Close-to-Triple-Negative Breast Cancer Presenting as a Thick-Walled Cystic Lesion.

Clinical and pathologic characteristics of the invasive ductal carcinoma (IDC) presenting as a thick-walled breast cyst are little known. Three female patients were included in this report. A palpable, nontender breast lump was found in all cases. While mammography showed a hyperdense mass, ultrasonography demonstrated a thick-walled cystic mass. Magnetic resonance imaging clearly showed the cystic breast lesions with ring-like or irregular rim enhancement. A grade III IDC was confirmed in all cases. All IDCs but one were estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 negative, with merely weak progesterone receptor positivity (5%) in one case. All cases underwent surgical management first and postoperative chemotherapy. Breast malignancy presenting as a thick-walled cystic mass could be a highly aggressive IDC, even triple-negative breast cancer. It is imperative for breast cancer-related practitioners to identify the potentially malignant cystic lesions timely and adopt appropriate management.

Nuclear anaplasia of positive and negative hormonal receptor (estrogen and progesterone receptor) in breast cancer cytology

Background: Breast epithelial duct cells show response to sex hormone such as estrogen and progesterone since they have receptor for estrogen and progesterone. Consequently, malignant cells from breast epithelial ductuli (Breast Ductal Carcinoma) show positivity for estrogen and progesterone receptor (ER and PR). However, when this neoplasm becomes poorly differentiated, they lost these characteristics and became ER and PR negative. On the other hand, poorly differentiated cancer cells show more nuclear enlargement that was accompanied by increase nuclear pleomorphism. This study wants to compare area of breast cancer cells nuclei and nuclear pleiomorphism in positive and negative ER and PR. Material and method: Positive and negative ER and PR breast cancer cases were collected from archive of Anatomic Pathology Department each consisting of ten to fourteen cases. Image analysis was made from each case to measure the area, diameter, and nuclear pleiomorphism. Result and discussion: There were no differences in nuclear size and pleomorphism of breast cancer cells with positive and negative ER and PR. This result show that poorly differentiated cancer cells did not accompany by increase of nuclear anaplasia. Conclusion: There is no difference of cancer cells morphology in positive and negative ER and PR. Hormonal status and anaplasia of cell nuclei can be used as independent prognostic factor to breast cancer progression.

Environmental pressures, tumor characteristics, and death rate in a female breast cancer cohort: a seven-years Bayesian survival analysis using cancer registry data from a contaminated area in Italy.

In Taranto, Southern Italy, adverse impacts on the environment and human health due to industrial installations have been studied. In the literature, few associations have been reported between environmental factors and breast cancer mortality in women. The aim of this study was to investigate the relationships between residence in areas with high environmental pressures, female breast cancer characteristics, and death rate. Data from the Taranto Cancer Registry were used, including all women with invasive breast cancer diagnosed between 01 January 2015 and 31 December 2020 and with follow-up to 31 December 2021. Bayesian mixed effects logistic and Cox regression models were fitted with the approach of integrated nested Laplace approximation, adjusting for patients and disease characteristics. A total of 10,445 person-years were observed. Variables associated with higher death rate were residence in the contaminated site of national interest (SIN) (HR 1.22, 95% CrI 1.01-1.48), pathological/clinical stage III (HR 2.77, 95% CrI 1.93-3.97) and IV (HR 17.05, 95% CrI 11.94-24.34), histological grade 3 (HR 2.50, 95% CrI 1.20-5.23), Ki-67 proliferation index of 21-50% (HR 1.42, 95% CrI 1.10-1.83) and > 50% (HR 1.81, 95% CrI 1.29-2.55), and bilateral localization (HR 1.65, 95% CrI 1.01-2.68). Variables associated with lower death rate were estrogen and/or progesterone receptor positivity (HR 0.61, 95% CrI 0.45-0.81) and HER2/neu oncogene positivity (HR 0.59, 95% CrI 0.44-0.79). The findings confirmed the independent prognostic values of different female breast cancer characteristics. Even after adjusting for patients and disease characteristics, residence in the SIN of Taranto appeared to be associated with an increased death rate.

CASE REPORT: RARE CASE OF PNEUMOCYTOMA

Pulmonary sclerosing (Pneumocytoma) is a rare benign pulmonary tumor of primitive epithelial origin. Because of the unspecific radiological features mimicking malignancies and their histological heterogeneity, the differential diagnosis with adenocarcinoma and carcinoid tumors is still challenging. We report a case of sclerosing pneumocytoma, as well as a review of the literature. Immunohistochemical findings showed intense staining of the cuboidal epithelial cells for cytokeratin-pool and TTF-1, with focal positivity for progesterone receptors. Round and spindle cells expressed positivity for vimentin, TTF-1, and focally for the progesterone receptor. Since the pre- and intraoperative diagnosis should guide surgical decision-making, obtaining a sufficient specimen size to find representative material in the cell block is of paramount importance. This overview highlights what physicians need to know regarding clinical manifestations, radiological and histological features as well as recent advances in immunohistochemistry in the diagnosis of this disease.

Thyroid Hormone Changes Correlate to Combined Breast Cancer with Primary Thyroid Cancer.

Breast cancer and thyroid cancer are two prevalent malignancies in women, and a potential association between the two diseases has been suggested. This retrospective case-control study was conducted involving 97 patients with breast cancer and thyroid cancer (BC-TC group) and 97 age-matched patients with breast cancer alone (BC group). Thyroid hormone levels, including triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH), were analyzed in healthy controls, BC patients, and BC-TC patients. BC-TC patients exhibited a higher rate of estrogen receptor (ER) and progesterone receptor (PR) positivity compared to BC patients. Serum T3 levels were significantly decreased in BC and BC-TC patients compared to healthy controls. However, there was no significant difference in T3 levels between BC and BC-TC patients. Serum TSH levels were significantly higher in BC-TC patients compared to BC patients. ER positivity, PR positivity, and serum TSH levels greater than 4.45 mU/L were independent risk factors for primary thyroid cancer in breast cancer patients.

Biomarkers for prognosis of meningioma patients: A systematic review and meta-analysis.

Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.