Negative Breast Cancer Research Articles

Pigment epithelium-derived factor downregulation in oestrogen receptor positive breast cancer bone metastases is associated with menopause

Pigment epithelium-derived factor (PEDF) has a critical role in bone development and anti-tumour function in breast cancer (BC). As the expression and role of PEDF in BC bone metastases is unknown, we aimed to characterise PEDF in primary and metastatic BC. Subcellular PEDF localisation was semi-quantitatively analysed via immunohistochemistry in patient-matched, archived formalin-fixed paraffin-embedded primary BC and liver, lung, and decalcified bone metastases specimens. PEDF localisation was evaluated in 23 metastatic BC patients diagnosed with ER+, human epidermal growth factor receptor-2 (HER2) negative BC or TNBC. Cytoplasmic (p = 0.019) and membrane (p = 0.048) PEDF was lower in bone metastases compared to primary ER+/HER2- BC. In contrast, nuclear PEDF scores were higher in metastases compared to primary TNBC (p = 0.027), and increased membrane PEDF in metastatic tissue had improved disease-free interval (p = 0.016). Nuclear PEDF was decreased in bone metastases compared to primary ER+//HER2- BC in post-menopausal patients (p = 0.029). These novel findings indicate PEDF plays a role in clinical BC metastasis. Significantly lower PEDF levels in the post-menopausal compared to pre-menopausal setting suggests future PEDF research may have greater clinical importance in the post-menopausal ER+/HER2- BC population.

Human clinical trial using diagnostic ultrasound and microbubbles to enhance neoadjuvant chemotherapy in HER2- negative breast cancer.

In vivo and in vitro experiments have demonstrated that diagnostic ultrasound combined with microbubbles (USMB) can enhance tumor chemotherapy, but few clinical studies have explored the effect of USMB in human HER2-negative breast cancer. We aimed to compare USMB combined with neoadjuvant chemotherapy (NAC) with NAC alone in the treatment of human HER2-negative breast cancer. Patients (n=10) enrolled in the study were treated with TAC (taxane - (docetaxel), anthracycline - (epirubicin or doxorubicin liposomes), and cyclophosphamide) and ultrasound using a commercial clinical ultrasound scanner for 20min after each chemotherapy session, followed by intermittent injections of SonoVue® to induce sonoporation and enhance therapeutic efficacy. Contrast-enhanced ultrasound (CEUS) was used to record tumor perfusion before and after ultrasound treatment. After completion of chemotherapy, the maximum tumor diameter of patients in the combined treatment group (n=10) was significantly smaller than that in the control group (n=16) (p=0.017). Although the combined treatment group had higher overall response and clinical benefit rates than those in the control group, there was no statistically significant difference in RECIST between the combined treatment group and the control groups (p=0.590). More patients in the combination therapy group achieved pathologic complete response than in the control group (p=0.014). For combined treatment, CEUS revealed that the peak intensity, mean transit time, and area under the curve were higher after treatment than before treatment (p<0.001, p<0.001, p=0.003, respectively). Combined therapy did not cause additional toxicity or increase side effects. USMB and chemotherapy can be combined in a clinical setting using commercially available equipment, without additional toxicity, and may improve the efficacy of NAC in HER2-negative breast cancer.

Unique ESR1 and ESR2 estrogen receptor gene variants associated with altered risk of triple-negative breast cancer: A case-control study

BackgroundWe previously reported on the association between ESR1 and ESR2 gene variants and heightened risk of breast cancer (BC). Here we investigated the association of common ESR1 and ESR2 gene variants with triple negative BC (TNBC). MethodsThis retrospective case-control study involved 488 BC patients (130 TNBC, 358 non-TNBC patients). ESR1 (rs2234693, rs9340799, rs3020314, rs3798577) and ESR2 (rs928554, rs944459, rs4986938, rs1256049, rs1256030, rs1271572) genotyping was done by real-time PCR. ResultsWhile minor allele frequencies (MAF) of ESR1 variants were comparable between TNBC and non-TNBC subjects, significantly higher ESR2 rs1256049 MAF was seen in TNBC patients. Significantly higher frequency of ESR1 rs3798577 T/C and C/C genotypes were noted in TNBC cases, and significant differences were seen in ESR2 rs928554, rs1256049, and rs1271572 genotype distribution. Increased TNBC risk was associated with ESR1 rs3798577 T/C and C/C genotypes according to codominant and dominant models, while positive association of ESR2 rs928554 with TNBC was seen according to codominant and recessive models, and positive association of ESR2 rs1256049 with TNBC was seen according to codominant and dominant models. Positive interactions were noted between ESR2 rs1271572-ESR1 rs3020314, ESR2 rs1271572-ESR1 rs9340799, and ESR2 rs1271572-ESR1 rs2234693, ESR2 rs4986938-ESR1 rs2234693, and ESR2 rs928554-ESR1 rs9340799. Haplotype analysis confirmed the positive association of ESR1 CATT with TNBC, while ACGGCTC and ACGGTT ESR2 haplotypes were positively associated with TNBC. ConclusionResults of this study confirmed the association of unique ESR1 and ESR2 genetic variants with altered risk of TNBC. This suggests possible diagnostic and prognostic role of these variants with TNBC independent of their association with BC.

Clinical Outcomes of Metastatic Breast Cancer in Patients Having Imaging Liver Pseudocirrhosis with or without Evident Varices.

Pseudocirrhosis is an imaging finding of malignancies with liver metastasis with or without clinical liver cirrhosis-related portal hypertension (pHTN). This study defined evident pHTN by the presence of esophageal or gastric varices and compared patients' outcomes of metastatic breast cancer with imaging-diagnosed pseudocirrhosis with or without varices. The medical records from patients with metastatic breast cancer and pseudocirrhosis between 2005 and 2017 were retrospectively analyzed. Survival outcomes were compared based on endoscopic evidence of esophageal or gastric varices. Among 106 patients with pseudocirrhosis, 33 (31%) had de novo stage IV disease, and 66 (62%) had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eighty-one (76%) had initial metastases in both hepatic lobes, and 32 (30%) had esophageal or gastric varices. The median overall survival (OS) was 5 and 13 months in patients with and without varices (P = .002). The median OS in patients with HER2-positive, HR-positive/HER2-negative, and triple-negative subtype was 16, 9, and 2 months, respectively (P = .001). Patients with varices usually had cirrhotic complications, including gastrointestinal bleeding, hyperbilirubinemia, hyperammonemia, and coagulopathy. Despite their challenging clinical conditions, 7 patients with varices had OS exceeding 1 year. In multivariate analysis, evident varices (P = .007) and triple-negative subtype (P = .013) were associated with poor OS. Patients with pseudocirrhosis and evident varices had a significantly shorter median OS, and were usually associated with clinical cirrhosis-related complications. To maximize OS, early identification and meticulous supportive care are warranted.

Long-term survival after sentinel lymph node biopsy or axillary lymph node dissection in pN0 breast cancer patients: a population-based study.

Findings from randomized clinical trials have shown that survival in patients with sentinel lymph node (SLN)-negative breast cancer is noninferior with SLN biopsy (SLNB) alone versus further axillary lymph node dissection (ALND). However, the long-term outcome of these two surgical approaches in pN0 breast cancer patients in real-world setting remains uncertain. We included patients diagnosed with pathologically staged T1-2N0M0 breast cancer between 2000 and 2015 in surveillance, epidemiology, and end results 18-registry database. Patients were considered to have undergone SLNB alone if they had ≤ 5 examined lymph nodes (ELNs), and ALND if they had ≥ 10 ELNs. The outcomes included overall survival (OS) and breast cancer-specific survival. Propensity score analyses by weighting and matching and multivariable Cox regression analysis were performed to minimize treatment selection bias. We included 309,430 patients (253,501 SLNB and 55,929 ALND). In the weighted cohort, ALND was associated with significantly lower OS (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.10-1.16) and BCSS (HR 1.16; 95% CI 1.10-1.22) compared with SLNB alone. Both the propensity score-matching model and multivariable Cox model demonstrated a survival benefit for SLNB when compared with ALND. Subgroup analyses for key variables did not change these findings. We found statistically significant differences in OS and BCSS between SLNB and ALND, though the magnitude of these differences was small. Our findings further support that SLNB alone should be the standard of care for patients who do not have metastatic lymph nodes identified during breast cancer surgery.

24P How far along is precision oncology with immune checkpoint inhibitors for triple-negative breast cancer? A meta analysis and position paper

The advent of immune checkpoint inhibitors (ICIs) is underway to change the landscape of triple- negative breast cancer (TNBC) treatment. In this meta-analysis and position paper, we assess the role of atezolizumab and pembrolizumab in TNBC with the lens of precision medicine.

A quantitative characterization of the spatial distribution of brain metastases from breast cancer and respective molecular subtypes.

Brain metastases (BM) remain a significant cause of morbidity and mortality in breast cancer (BC) patients. Specific factors promoting the process of BM and predilection for selected neuro-anatomical regions remain unknown, yet may have major implications for prevention or treatment. Anatomical spatial distributions of BM from BC suggest a predominance of metastases in the hindbrain and cerebellum. Systematic approaches to quantifying BM location or location-based analyses based on molecular subtypes, however, remain largely unavailable. We analyzed stereotactic Cartesian coordinates derived from 134 patients undergoing gamma- knife radiosurgery (GKRS) for treatment of 407 breast cancer BMs to quantitatively study BM spatial distribution along principal component axes and by intrinsic molecular subtype (ER, PR, Herceptin). We used kernel density estimators (KDE) to highlight clustering and distribution regions in the brain, and we used the metric of mutual information (MI) to tease out subtle differences in the BM distributions associated with different molecular subtypes of BC. BM location maps according to vascular and anatomical distributions using Cartesian coordinates to aid in systematic classification of tumor locations were additionally developed. We corroborated that BC BMs show a consistent propensity to arise posteriorly and caudally, and that Her2+ tumors are relatively more likely to arise medially rather than laterally. To compare the distributions among varying BC molecular subtypes, the mutual information metric reveal that the ER-PR-Her2+ and ER-PR-Her2- subtypes show the smallest amount of mutual information and are most molecularly distinct. The kernel density contour plots show a propensity for triple negative BC to arise in more superiorly or cranially situated BMs. We present a novel and shareable workflow for characterizing and comparing spatial distributions of BM which may aid in identifying therapeutic or diagnostic targets and interactions with the tumor microenvironment. Further characterization of these patterns with larger multi-institutional data-sets may have major impacts on treatment or management of cancer patients.

Relationship between Aldehyde Dehydrogenase, PD-L1 and Tumor-Infiltrating Lymphocytes with Pathologic Response and Survival in Breast Cancer.

Simple SummaryAldehyde dehydrogenase 1A1 (ALDH1A1) can be used to identify breast cancer stem cells (CSC). Interaction between CSC and the tumor microenvironment might be related to the treatment response, relapse and death. The aim of this retrospective, historical cohort study was to analyze the relationship between ALDH1A1, programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), assessed through immunohistochemistry, in triple negative (TN) and human epidermal growth factor receptor 2-positive (HER2+) breast cancer tumors, and its association with clinicopathological characteristics and survival. In this study, tumors with positive ALDH1A1 expression also presented positive PD-L1 expression, higher infiltration of lymphocytes and achieved higher response to treatment. It is crucial to understand the possible implication of these biomarkers on neoadjuvant treatment response in certain subtypes of breast cancer as well as its prognostic role in early and locally advanced breast tumors, as they might be possible targets for promising treatments as immunotherapy.Aldehyde dehydrogenase 1A1 (ALDH1A1) is a cancer stem cell (CSC) marker related to clinical outcomes in breast cancer (BC). The aim of this study was to analyze the relationship between ALDH1A1, programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in triple negative (TN) and human epidermal growth factor receptor 2-positive (HER2+) BC tumors, and its association with clinicopathological characteristics and outcomes. A retrospective, historical cohort study of patients diagnosed with early or locally advanced BC treated with neoadjuvant chemotherapy was conducted. ALDH1A1, PD-L1 expression and TILs were assessed using immunohistochemistry. A total of 75 patients were analyzed (42.7% TN, 57.3% HER2+ tumors). ALDH1A1+ was related to HTILs (p = 0.005) and PD-L1+ tumors (p = 0.004). ALDH1A1+ tumors presented higher CD3+ (p = 0.008), CD4+ (p = 0.005), CD8+ (p = 0.003) and CD20+ (p = 0.006) TILs. ALDH1A1+ (p = 0.018), PD-L1+ (p = 0.004) and HTILs (p < 0.001) were related to smaller tumors. ALDH1A1+ was related to pathologic complete response (pCR) (p = 0.048). At the end of the follow-up (54.4 [38.3–87.6] months), 47 patients (62.7%) remained disease-free, and 20 (26.7%) had died. HTILs were related to improved disease-free survival (p = 0.027). ALDH1A1+ was related to PD-L1+ and HITLs, that might be related to higher pCR rates with neoadjuvant therapy.

Emerging Targeted Therapies for Early Breast Cancer.

Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in the United States (US). Most patients are diagnosed with early-stage disease; however, there is still a need to prevent recurrences that often present as incurable metastatic disease. The treatment landscape of early-stage breast cancer is evolving rapidly. The immune checkpoint inhibitor pembrolizumab is approved in combination with neoadjuvant chemotherapy for the treatment of high-risk triple-negative breast cancer (TNBC). The cyclin-dependent kinase (CDK) 4 and 6 inhibitor abemaciclib is approved for adjuvant treatment of patients with high-risk hormone receptor (HR)-positive disease. Whileadjuvant olaparib has shown significant improvement in outcomes for patients with pathogenic/likely pathogenic BRCA1/2 mutations and high-risk human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and is approved in this setting. For the HER2-positive subtype, the post-neoadjuvant therapy can be tailored based on the response to neoadjuvantchemotherapy and HER2-targeted agents. In this narrative review, we summarize the most recent approvals for early-stage breast cancer as well as frequently encountered clinical challenges utilizing these medications.

168P Long-term survival of a randomised, open-label, phase II study comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel given as neoadjuvant treatment in patients with operable triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE)

The GENEVIEVE study (NCT01779479) compared the pathological complete response (pCR) rate in patients with operable triple-negative (TNBC) or luminal B/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) treated with either cabazitaxel or weekly paclitaxel. Primary analyses showed no short-term effect of cabazitaxel in TNBC or luminal B/HER2- primary BC, while there seemed to be no differences in drug exposure and patient compliance between the two arms (Kümmel et al. Eur J Cancer 2017).

307P Incidence of neurological symptoms in brain metastases from breast cancer and its impact on prognosis: An analysis of 968 patients with brain metastases

Considering the rising detection of asymptomatic brain metastases (BM) during screening and staging procedures over the last decades, we aimed to evaluate the incidence, clinical characteristics and the prognostic value of neurological symptoms in BM from breast cancer. Patients with newly diagnosed BM from breast cancer (BC) were identified from the Vienna Brain Metastasis Registry. Patients were grouped into the three main subtypes: hormone receptor-positive/HER2 (human epidermal growth factor receptor 2)-negative breast cancer (HR BC), HER2 overexpressing BC (HER2 BC) and triple-negative BC (TN BC). A retrospective chart review and statistical outcome analyses were performed. 968 patients with BM from breast cancer (34.4% HR BC; 28.9% HER2 BC; 21.8% TN BC; 14.9% unknown receptor status) were included in the analysis. 81.6% (790/968) of the patients presented with neurological symptoms at BM diagnosis including focal deficits (695/790;88.0%), signs of increased intracranial pressure (388/790;49.1%), epileptic seizures (126/790;15.9%) and neuropsychological symptoms (133/790;16.8%). Patients with HER2 BC (66/280;23.6%) were significantly more often diagnosed with BM in absence of neurological symptoms during screening procedures compared to HR BC (62/333;18.6%) and TN BC (31/211;14.7%; chi-square test; p=0.043). Among all BC subtypes, asymptomatic patients presented with a significant longer median overall survival (OS) from diagnosis of BM compared to symptomatic patients (p<0.05; log-rank test; HR BC 20 vs. 9 months; HER2 BC 20 vs. 11 months; TN 11 vs. 5 months). In multivariate analysis, the breast cancer-specific Graded Prognostic Assessment (Breast-GPA: HR:1.4; 95% CI, 1.27-1.49; p<0.001) and the presence of neurological symptoms (HR:1.6; 95% CI, 1.35-1.95; p<0.001) presented as independently associated with survival prognosis from time of BM diagnosis respectively. Neurological symptoms are independently associated with overall survival in patients with BM from breast cancer. Our results highlight the need to incorporate neurological symptoms into the prognostic assessment of patients with BM from breast cancer.

Characterization of genetic predisposition to molecular subtypes of breast cancer in Brazilian patients.

Introduction BRCA1 and BRCA2 germline pathogenic variants (GPVs) account for most of the 5-10% of breast cancer (BC) that is attributable to inherited genetic variants. BRCA1 GPVs are associated with the triple negative subtype, whereas BRCA2 GPVs are likely to result in higher grade, estrogen-receptor positive BCs. The contribution of other genes of high and moderate risk for BC has not been well defined and risk estimates to specific BC subtypes is lacking, especially for an admixed population like Brazilian.ObjectiveThe aim of this study is to evaluate the value of a multigene panel in detecting germline mutations in cancer-predisposing genes for Brazilian BC patients and its relation with molecular subtypes and the predominant molecular ancestry.Patients and methodsA total of 321 unrelated BC patients who fulfilled NCCN criteria for BRCA1/2 testing between 2016-2018 were investigated with a 94-genes panel. Molecular subtypes were retrieved from medical records and ancestry-specific variants were obtained from off-target reads obtained from the sequencing data.ResultsWe detected 83 GPVs in 81 patients (positivity rate of 25.2%). Among GPVs, 47% (39/83) were identified in high-risk BC genes (BRCA1/2, PALB2 and TP53) and 18% (15/83) in moderate-penetrance genes (ATM, CHEK2 and RAD51C). The remainder of the GPVs (35% - 29/83), were identified in lower-risk genes. As for the molecular subtypes, triple negative BC had a mutation frequency of 31.6% (25/79), with predominance in BRCA1 (12.6%; 10/79). Among the luminal subtypes, except Luminal B HER2-positive, 18.7% (29/155) had GPV with BRCA1/2 genes contributing 7.1% (11/155) and non-BRCA1/2 genes, 12.9% (20/155). For Luminal B HER2-positive subtype, 40% (16/40) had GPVs, with a predominance of ATM gene (15% - 6/40) and BRCA2 with only 2.5% (1/40). Finally, HER2-enriched subtype presented a mutation rate of 30.8% (4/13) with contribution of BRCA2 of 7.5% (1/13) and non-BRCA1/2 of 23% (3/13). Variants of uncertain significance (VUS) were identified in 77.6% (249/321) of the patients and the number of VUS was increased in patients with Asian and Native American ancestry.ConclusionThe multigene panel contributed to identify GPVs in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.6% (BRCA1/2) to 25.2% and, considering only the most clinically relevant BC predisposing genes, to 16.2%. These results indicate that women with clinical criteria for hereditary BC may benefit from a multigene panel testing, as it allows identifying GPVs in genes that directly impact the clinical management of these patients and family members.

Assessment of Oncologists’ Perspectives on Omission of Sentinel Lymph Node Biopsy in Women 70 Years and Older With Early-Stage Hormone Receptor–Positive Breast Cancer

Randomized clinical trial data have demonstrated that omission of surgical axillary evaluation does not affect overall survival in women 70 years and older with early-stage (clinical tumor category 1 [cT1] with node-negative [N0] disease) hormone receptor (HR)-positive and erb-B2 receptor tyrosine kinase 2 (ERBB2; formerly HER2)-negative breast cancer. Therefore, the Choosing Wisely initiative has recommended against routine use of sentinel lymph node biopsy (SLNB) in this population; however, retrospective data have revealed that more than 80% of patients eligible for SLNB omission still undergo the procedure. Multidisciplinary factors involved in these patterns remain unclear. To describe surgical, medical, and radiation oncologists' perspectives on omission of SLNB in women 70 years and older with cT1N0 HR-positive, ERBB2-negative breast cancer. This qualitative study used in-depth semi-structured interviews to explore the factors involved in oncologists' perspectives on providing care to older women who were eligible for SLNB omission. Purposive snowball sampling was used to recruit a sample of surgical, medical, and radiation oncologists representing a wide range of practice types and number of years in practice in the US and Canada. A total of 29 oncologists who finished training and were actively treating patients with breast cancer were interviewed. Interviews were conducted between March 1, 2020, and January 17, 2021. Recordings from semi-structured interviews were transcribed and deidentified. Thematic analysis was used to identify emergent themes. Among 29 physicians (16 women [55.2%] and 13 men [44.8%]) who participated in interviews, 16 were surgical oncologists, 6 were medical oncologists, and 7 were radiation oncologists. Data on race and ethnicity were not collected. Participants had a range of experience (median [range] years in practice, 12.0 [0.5-30.0]) and practice types (14 academic [48.3%], 7 community [24.1%], and 8 hybrid [27.6%]). Interviews revealed that the decision to omit SLNB was based on nuanced patient- and disease-level factors. Wide variation was observed in oncologists' perspectives on SLNB omission recommendations and supporting data. In addition, participants' statements suggested that the multidisciplinary nature of cancer care may increase oncologists' anxiety regarding SLNB omission. In this study, findings from interviews revealed that oncologists' perspectives may have implications for the largely unsuccessful deimplementation of SLNB in women 70 years and older with cT1N0 HR-positive, ERBB2-negative breast cancer. Interventions aimed at educating physicians, improving patient-physician communication, and facilitating preoperative multidisciplinary conversations may help to successfully decrease SLNB rates in this patient population.

The nuclear receptor TLX (NR2E1) inhibits growth and progression of triple- negative breast cancer

Development of targeted therapies will be a critical step towards reducing the mortality associated with triple-negative breast cancer (TNBC). To achieve this, we searched for targets that met three criteria: (1) pharmacologically targetable, (2) expressed in TNBC, and (3) expression is prognostic in TNBC patients. Since nuclear receptors have a well-defined ligand-binding domain and are thus highly amenable to small-molecule intervention, we focused on this class of protein. Our analysis identified TLX (NR2E1) as a candidate. Specifically, elevated tumoral TLX expression was associated with prolonged recurrence-free survival and overall survival for breast cancer patients with either estrogen receptor alpha (ERα)-negative or basal-like tumors. Using two TNBC cell lines, we found that stable overexpression of TLX impairs in vitro proliferation. RNA-Seq analysis revealed that TLX reduced the expression of genes implicated in epithelial-mesenchymal transition (EMT), a cellular program known to drive metastatic progression. Indeed, TLX overexpression significantly decreased cell migration and invasion, and robustly decreased the metastatic capacity of TNBC cells in murine models. We identify SERPINB2 as a likely mediator of these effects. Taken together, our work indicates that TLX impedes the progression of TNBC. Several ligands have been shown to regulate the transcriptional activity of TLX, providing a framework for the future development of this receptor for therapeutic intervention.

Knockdown of CKAP2 Inhibits Proliferation, Migration, and Aggregate Formation in Aggressive Breast Cancer.

Simple SummaryCancer is a complex disease where cells grow and divide in an uncontrolled manner. It is well established that its development and progression involve major alterations in the activity of mitotic regulators. In order to improve our understanding of the contribution of cell-cycle progression defects to the development of disease, the aim of this study is to identify genes relevant to the proper progression of mitosis that are deregulated in breast cancer. Our findings identified CKAP2 as an important mitotic regulator in BC tumors. Moreover, in vitro experiments showed that gene silencing of CKAP2 blocked cell growth, cell migration, and formation of cell aggregates. These results demonstrated the important role of CKAP2 in breast cancer tumor formation.Loss of mitotic regulation is commonly observed in cancer and is a major cause of whole-chromosome aneuploidy. The identification of genes that play a role in the proper progression of mitosis can help us to understand the development and evolution of this disease. Here, we generated a list of proteins implicated in mitosis that we used to probe a patient-derived breast cancer (BC) continuum gene-expression dataset generated by our group by human transcriptome analysis of breast lesions of varying aggressiveness (from normal to invasive). We identified cytoskeleton-associated protein 2 (CKAP2) as an important mitotic regulator in invasive BC. The results showed that CKAP2 is overexpressed in invasive BC tumors when compared with normal tissues, and highly expressed in all BC subtypes. Higher expression of CKAP2 is also related to a worse prognosis in overall survival and relapse-free survival in estrogen receptor (ER)-positive and human epidermal growth factor receptor type 2 (HER2)-negative BC patients. Knockdown of CKAP2 in SKBR3 cells impaired cell proliferation and cell migration and reduced aggregate formation in a 3D culture. Our results show the important role of CKAP2 in BC tumorigenesis, and its potential utility as a prognostic marker in BC.

Breast cancer patients are at increased risk of developing uterine serous cancer: Implications for counseling - SEER analysis (402)

<b>Objectives:</b> Several studies have investigated whether patients with prior breast cancer (BC) are at increased risk for endometrial cancer/uterine serous cancer (USC). We aimed to study the relationship between previous BC and uterine serous carcinoma (USC) and analyze the effect of prior BC on the incidence and prognosis of USC patients. <b>Methods:</b> With permission of the Surveillance, Epidemiology and End Results (SEER) program of the United States National Cancer Institute, clinical-pathologic information of women diagnosed with BC and following USC were analyzed. The recorded data included age at diagnosis, stage of disease, cause of death, interval time between BC and USC diagnosis, and overall survival. Further analysis was performed according to estrogen receptor status. <b>Results:</b> The SEER database included 10021 patients with USC during the years 1975-2015. Among the patients, 698 (6.96%) had been previously diagnosed with breast cancer (BC). The incidence of USC in patients with BC history was 57 times higher than in women without BC history (p value < 0.001). The incidence of USC did not differ between ER positive and ER negative BC patients (p. value 0.94). The mean survival of USC patients with previous BC history was eight years (96 months, 95% CI: 85.7-106.2), while for USC patients with no BC history the mean survival was 10.6 years (127 months, 95% CI: 124.0-130.8), suggesting a superior survival rate for USC patients with no history of BC (p. value=0.002). Fig. 1 <b>Conclusions:</b> Our results highlight the relationship between BC and USC, suggesting an increased risk for USC among BC patients. This clinical association should be introduced to BC patients, and physicians should be alert to any EC presenting symptom in BC survivors.

Axillary Staging Is Not Justified in Postmenopausal Clinically Node-Negative Women Based on Nodal Disease Burden.

RxPONDER showed no benefit of adjuvant chemotherapy in postmenopausal women with estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer and limited nodal burden (pN1) with a recurrence score ≤ 25, suggesting that axillary staging could be omitted in cN0 patients if significant numbers of such women do not have pN2-3 disease. Here we evaluate the pN2-3 disease rate in a large cohort of postmenopausal women presenting with cN0 breast cancer. Consecutive postmenopausal patients presenting with T1-2N0 breast cancer who underwent axillary surgery from February 2006 to December 2011 were identified. Clinicopathologic characteristics associated with pN2-3 disease were examined using chi-square or Fisher's exact tests. Of 3363 postmenopausal women with cT1-2N0 breast cancer (median age 58 years, IQR 48-67 years), median tumor size was 1.3 cm (IQR 0.90-1.90cm). Post-axillary staging, 2600 (77.3%) were pN0, 643 (19.1%) were pN1, and 120 (3.6%) were pN2-3. The pN2-3 disease rate did not differ across subtypes (4.4% HER2+, 3.5% HR-/HER2-, 3.5% HR+/HER2-, p = 0.70). In the subset with HR+/HER2- tumors, on multivariable analysis, age < 65 years (odds ratio [OR] 2.38, 95% confidence interval [CI] 1.32-4.49), lymphovascular invasion (OR 5.29, 95% CI 2.72-11.2), multifocal/centric tumors (OR 3.08, 95% CI 1.79-5.32), and tumor size > 2 cm (OR 5.51, 95% CI 3.05-10.4) were significantly associated with pN2-3 nodal burden. Of 506 patients with tumors > 2 cm, 49 (9.7%) had pN2-3 disease; in the subset of 90 patients age < 65 years who had multifocal/centric tumors > 2 cm, 23 (25.6%) had pN2-3 disease. In postmenopausal women with cN0 disease, pN2-3 nodal burden is uncommon; omitting axillary staging would not miss a significant number of patients who might benefit from adjuvant chemotherapy. Information available preoperatively indicating a higher risk of nodal disease such as younger age and large, multifocal tumors should be considered in the multidisciplinary management of the axilla.

Association of vulvar lichen sclerosus with endometrial and ovarian cancer

Association of vulvar lichen sclerosus with endometrial and ovarian cancer

Clinical Utility of Genomic Assay in Node-Positive Early-Stage Breast Cancer.

Breast cancer (BC) is the most common malignancy among women in Canada. Adjuvant treatment in early BC can reduce the risk of BC recurrence. Historically, the decision for adjuvant chemotherapy for early BC was made only based on clinical and tumour characteristics. In recent years, there has been an effort toward developing genomic assays as a predictive and prognostic tool to improve precision in estimating disease recurrence, sensitivity to systemic treatment and ultimately with clinical utility for guidance regarding adjuvant systemic treatment(s). There are various commercial genomic tests available for early-stage ER+/HER-2 negative BC. This paper will review the Oncotype DX 21-gene Recurrence Score (RS), MammaPrint, EndoPredict, Prosigna®, and Breast Cancer Index (BCI) genomic assays. We will also focus on these genomic assays’ clinical application and utility in node-positive early-stage BC based on the most recent evidence and guidance recommendations.

Overview of PROTACs Targeting the Estrogen Receptor: Achievements for Biological and Drug Discovery.

Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, was designated as an Investigational New Drug by the US FDA in 2019, and a phase I trial in patients suffering from locally advanced or metastatic ER-positive/HER2- negative breast cancer was initiated. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.