Negative Breast Cancer Patients Research Articles

MicroRNAs Regulating Tumor Immune Response in the Prediction of the Outcome in Patients With Breast Cancer.

MicroRNAs (miRNAs) are key regulators in immune surveillance and immune escape as well as modulators in the metastatic process of breast cancer cells. We evaluated the differential expression of plasma miR-10b, miR-19a, miR-20a, miR-126 and miR-155, which regulate immune response in breast cancer progression and we investigated their clinical relevance in the outcomes of breast cancer patients. Plasma samples were obtained from early (eBC; n = 140) and metastatic (mBC; n = 64) breast cancer patients before adjuvant or first-line chemotherapy, respectively. Plasma miRNA expression levels were assessed by qRT-PCR. We revealed a 4-miRNA panel consisted of miR-19a, miR-20a, miR-126, and miR-155 able to discriminate eBC from mBC patients with an AUC of 0.802 (p < 0.001). Survival analysis in eBC patients revealed that low miR-10b and miR-155 expression was associated with shorter disease free survival (disease free survival; p = 0.012 and p = 0.04, respectively) compared to high expression. Furthermore, miR-126 expression was associated with shorter overall survival (overall survival; p = 0.045). In multivariate analysis the number of infiltrated axillary lymph nodes and low miR-10b expression independently predicted for shorter DFS (HR: 2.538; p = 0.002 and HR: 1.943; p = 0.033, respectively) and axillary lymph nodes and low miR-126 for shorter OS (HR: 3.537; p = 0.001 and HR: 2.558; p = 0.018). In the subgroup of triple negative breast cancer (TNBC) patients, low miR-155 expression independently predicted for shorter DFS (HR: 5.056; p = 0.037). Accordingly in mBC, patients with low miR-10b expression had shorter progression free survival and OS compared to patients with high expression (p = 0.0017 and p = 0.042, respectively). In multivariate analysis, recurrent disease and low miR-10b expression independently predicted for shorter PFS (HR: 2.657; p = 0.001 and HR: 1.920; p = 0.017, respectively), whereas performance status two independently predicted for shorter OS (HR: 2.031; p = 0.03). In summary, deregulated expression of circulating miRNAs involved in tumor and immune cell interactions evaluated before adjuvant and 1st-line chemotherapy can distinguish disease status and emerge as independent predictors for outcomes of breast cancer patients.

Concurrent Down-regulation of the EAF1 and the EAF2 Genes in the Invasive Ductal Carcinoma Type of Breast Cancer

In mammals, the EAF1 and EAF2 genes build an active transcription module with other components. These genes code for factors acting as potent inhibitor of the Wnt-β catenin pathway, which might be due to their function as tumor suppressor gene. Recently, the involvement of both above-mentioned factors was described in some human tumors, but not yet in breast cancer. Breast cancer is one of the most cancer cases in Iran after colon and stomach carcinoma. We aimed therefore to investigate for the first time a possible correlation between breast cancer and the EAF1 and the EAF2 gene expression. We collected invasive ductal carcinoma tumor grading (grade 1 to 3) with marginal normal tissue from forty women diagnosed with breast cancer with the average age of 50 years old. All patients underwent triple marker test (ER/PR and Her2/neu), indeed the most of them were triple positive with few triple negative individuals. After RNA extraction, cDNA was synthesized for subsequent real-time polymerase chain reaction. The humanRPL27 gene wasusedas endogenous control. Analysis of real-time PCR results showeda significant down-regulation of EAF1 (p-value: 0.028), and of EAF2 (p-value: 0.0134) in tumor tissue samples in comparison to normal one.There was no correlation between clinical parameters and the target genes. We could find significant connection between both tumor suppressor genes in triple positive and triple negative breast cancer patients, which deserves more attention.

Axillary Reverse Mapping—Factors Affecting ARM Node Detection and Its Role in Preventing Lymphedema in Node Negative Early Breast Cancer Patients

Axillary Reverse Mapping—Factors Affecting ARM Node Detection and Its Role in Preventing Lymphedema in Node Negative Early Breast Cancer Patients

Axillary Ultrasound as Preoperative Staging in Clinical Negative Axillary Lymph Node Breast Cancer Patient

Objective: To determine the diagnostic accuracy of axillary US as a preoperative investigation by comparing it with the histology outcome of nodal status. Methods: This validation analysis was conducted in Mater Misericordia university hospital, Dublin Ireland form Feb 2007 to Feb 2015. All female patients with impalpable axillary lymph node and histology proven unifocal breast cancer between ages 18 to 75 years were included. Patients with the diagnosis of breast cancer were followed with Ultrasound imaging and results in Picture Archiving and communication system (PACS) and histology was confirmed using the patient center data base in both preoperative and postoperative course of breast cancer, including both sentinel lymph nodes and axillary lymph nodes. Results: A total of 625 patients had axillary ultrasound (US) to assess the preoperative axillary nodal status with mean age of 56±12 years. cN0 was diagnosed in 469 (75%) cases, cN1 in 136 (21.8%) cases and cN2 in 20 (3.2%) cases. After negative axillary ultrasound cN0 pathology shows positive pN2 and pN3 disease in 14 (2.9%) cases with the NPV of 97.01%. Axillary ultrasound had shown cN1 disease in 136 cases with the pathology outcome of pN2 and pN3 in 41 (30.14%) cases with the negative predictive value (NPV) of 69.85%. The overall sensitivity and specificity of the axillary US in detection of the positive node was 51.6% and 92.8% with PPV of 82.69% and NPV of 74.2%. Conclusion: Axillary US is a useful modality for screening of breast cancer patients. The negative US findings exclude the presence of advanced nodal disease. However, it cannot accurate distinguish between pN1 and pN2 or pN3 nodal disease. Keywords: Axillary ultrasound, Axillary lymph nodes, Breast cancer.

MET and FASN as Prognostic Biomarkers of Triple Negative Breast Cancer: A Systematic Evidence Landscape of Clinical Study.

BackgroundTo know the expression of Mesenchymal–Epithelial Transition factor (MET) and Fatty Acid Synthase (FASN) in Triple Negative Breast Cancer (TNBC) patients, as well as its relationship with clinical pathological characteristic and prognosis.Methodswe used immunohistochemistry staining to detect the expression of MET and FASN for those 218 TNBC patients, and analyze their relationship with the clinical pathological characteristic and prognosis.Results130 and 65 out of 218 TNBC patients were positive for MET in the cancer and adjacent tissues respectively. 142 and 30 out of 218 TNBC patients were positive for FASN in the cancer and adjacent tissues respectively. Positive expression of MET and FASN were significantly correlated with lymph node metastasis, pathological TNM, and pathological Stage. In addition, the positive expression of MET and FASN were correlated with recurrence and metastasis. The combined use of MET and FASN can better predict the survival condition.ConclusionsOur results indicated that MET and FASN showed good predictive ability for TNBC. Combined use of MET and FASN were recommended in order to make a more accurate prognosis for TNBC.

MicroRNA-26a-5p as a potential predictive factor for determining the effectiveness of trastuzumab therapy in HER-2 positive breast cancer patients.

BackgroundBreast cancer (BC) is known as the most prevalent type of cancer among women. Trastuzumab, as an anticancer drug, has been used broadly in human epidermal growth factor receptor 2 (HER-2) positive (+) BC patients. Moreover, accumulating evidence has demonstrated that microRNAs is involved in the pathogenesis BC. Hence, we aimed to investigate the effect of trastuzumab on the expression levels of microRNA-26a in HER-2 positive BC patients.MethodsThis study was conducted among HER-2 + and HER-2 Negative (−) BC patients. Serum expression of microRNA-26a was detected by real-time PCR. Then, we assessed the correlations of microRNA-26a levels with multiple clinico-pathological characteristics of BC.ResultsIn HER-2 + patients, the microRNA-26a expression significantly increased after treatment with Docetaxel/Trastuzumab in comparison to before the treatment levels (p.value = 0.01). However, this overexpression in HER-2-patients after treatment with Docetaxel was not significant compared to the levels before the treatment (p.value = 0.14). In addition, the expression of microRNA —26a has significantly increased in HER-2 + patients who were ≤48 years old and premenopausal after the treatment with Docetaxel/Trastuzumab when compared to the levels before the treatment (p.value = 0.039 vs. 0.031, respectively). Furthermore, there was a significant correlation between the expression of microRNA —26a and the tumor size, stage, estrogen receptor (ER) and progesterone receptor (PR) status in the HER-2 + group before and after the treatment (p.value = 0.043, 0.042, 0.049 and 0.034 respectively).ConclusionsTrastuzumab led to overexpression of microRNA-26a in HER-2 + BC patients. It seems that the detecting microRNA —26a expression levels, during or after the trastuzumab therapy could be a useful biomarker for monitoring the therapeutic response in HER-2 + BC patients. However, further studies on large populations of women with HER-2+ BC are needed to explore this possible novel biomarker, in more detail, within various clinical contexts.

In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy

Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.

The effects of vitamin D (Vit D) replacement on pathological complete response (PCR) in breast cancer (BC) patients receiving neoadjuvant systemic chemotherapy (NAC).

e12604 Background: Studies show that Vit D increases apoptosis by inhibiting the proliferation of BC cells. The aims of this study were to prospectively investigate the effects of Vit D replacement on PCR rates in patients receiving NAC. Methods: Breast cancer patients qualified for NAC between June 2019 and September 2020 and consent for the study were given weekly oral 50,000 IU Vit D (study group). The Control group consisted of patients who were given NAC between 2015-2020 and who did not receive Vit D replacement. Tumor characteristics and PCR compared between the study and control groups. Results: A total of 117 patients included in the study (55% in the study group). Both groups had similar patient, tumor, and treatment characteristics. PCR (ypT0/is ypN0 and ypT0/is) rates were significantly higher in the study group (28.1% vs 11.3%, p=0.025 and 37.5% vs 13.2%, p=0.003, respectively). In multivariate logistic regression analysis, estrogen receptor (ER) and HER 2 positivity, and Vit D3 replacement were identified as independent variables affecting PCR. Conclusions: Adding Vit D to NAC in breast cancer patients significantly increases PCR. This effect is more prominent in ER negative and HER2 positive breast cancer patients. Clinical trial information: NCT03986268. [Table: see text]

Systemic chemotherapy in patients with brain only metastatic breast cancer: A retrospective analysis.

1093 Background: The treatment of patients with brain only metastatic breast cancer (BO-MBC) remains very challenging. There is also very limited literature informing on appropriate treatment or natural history of this entity. Systemic chemotherapy in addition to targeted therapy and/or anti-estrogen treatment is often used, but little is known if it adds to the overall or disease free survival. In this retrospective study, we examine this, as well as other factors which may be associated with increased risk of CNS or systemic recurrence in these patients. Methods: A database search at a single institution identified 178 patients with brain metastases (BM) from breast cancer out of which 45 patients had BO-MBC between 2007-2020. We collected demographic, clinical, radiographic and other treatment data. Leptomeningeal disease (LMD) was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. We used the Brookmeyer and Crowley method. Results: The patients were followed for a median of 17.9 months; 36 out of 45 patients (80%) received local treatment for BM (surgery/radiation/both) and HER2 directed antibodies or tyrosine kinase inhibitors and/or anti-estrogen treatment, whereas 9 out of 45 patients (20%) received systemic chemotherapy in addition. There were 22 out of 45 (49%) HER2 +, 5 out of 45 (11%) HR + and 18 out of 45 (40%) triple negative breast cancer (TNBC) patients. There were 17 out of 45 patients (38%) who were deemed to have low burden of BM (defined as one to three BM and largest being ≤3 cm) whereas there were 24 out of 45 patients (53%) who had high burden of BM (defined as four or more BM or largest being &gt; 3 cm). Conclusions: Patients with BO-MBC represent a distinct entity. Despite having better survival than patients with BM and extra CNS disease these patients have a high risk of developing LMD, CNS and systemic recurrences. The addition of chemotherapy to targeted therapy and/or anti-estrogens does not decrease the rates of systemic or CNS recurrence. The ER+ subset have a lower rate of development of systemic disease, as expected due to their relatively indolent biology. The CNS and systemic recurrence seem to be higher in patients with HER2+ cancers and counterintuitively even in those with low burden of BM; albeit these were statistically insignificant.[Table: see text]

Efficacy of everolimus-containing chemotherapy in HER2 negative metastatic breast cancer patients with PI3K/AKT/mTOR mutations: A retrospective study.

e13069 Background: The PI3K/AKT/mTOR pathway is frequently altered in breast cancer. Everolimus is a selective inhibitor of mammalian target of Rapamycin (mTOR).The benefit of everolimus in metastatic breast cancer patients with PI3K/AKT/mTOR mutations remains unclear, especially in TNBC patients. Our study aimed to investigate the efficacy of the everolimus-containing chemotherapy in metastatic breast cancer patients with PI3K/AKT/mTOR mutations. Methods: 13 cases of HER2- metastatic breast cancer with PI3K/AKT/mTOR mutations treated with everolimus-containing chemotherapy were analyzed. The genetic profile in PI3K/AKT/mTOR pathway was studied. Results: Overall, 4 cases were hormone receptor (HR) positive and 9 were TNBC. 7 patients only had PIK3CA mutations, 1 patient had only PIK3R1 mutations, and 5 patients had other mutations in the pathway in addition to PIK3CA, including PTEN, PIK3CB, CTNNB1, FGFR1 and TSC2. 5 cases were treated as first or second line chemotherapy, and 8 were as third line or above. The ORR (CR+PR) was 38.5% (5/13), and DCR (CR+PR+SD) was 84.6% (11/13), including 5 cases of PR, 6 cases of SD, and 2 cases of PD. The median PFS was 5.8 months (95% CI 3.7-9.7), and the median OS was 14.3 months (95% CI 6.47-null). However, the ORR of TNBC patients was higher than that of HR-positive, which were 44.4% (4/9) and 25% (1/4), respectively ( p = 0.070). The mPFS was also longer than that of HR-positive with 5.8 months versus 1.7 months, as well as the mOS with 14.3 versus 3.8 months. We also found that the patients carrying other mutations besides PIK3CA in the PI3K/AKT/mTOR pathway had a longer PFS compared to the patients without other mutations, which was 9.7 months and 4.3 months respectively ( p = 0.272). And the DCR of the two groups were 100% and 75% respectively ( p = 0.451). Conclusions: We found that everolimus-containing chemotherapy was effective in the treatment of HER2- metastatic breast cancer with PI3K/AKT/mTOR pathway activation. TNBC patients had a trend of longer mPFS than HR+ patients. And the patients carrying other mutations besides PIK3CA in the PI3K/AKT/mTOR pathway have a trend of longer PFS and higher DCR compared to the patients without other mutations. However, trails with larger samples are needed for further verification.

Real-world Indian scenario of CDK4/6 inhibitors (palbociclib and ribociclib) with endocrine therapy in upfront hormone positive metastatic breast cancer.

e13028 Background: CDK4/6 inhibitors (CDKi), in combination with endocrine therapy (ET), has become the standard of care in the treatment of hormone positive (HR+)/ HER2 neu negative metastatic breast cancer (MBC) patients. We evaluated clinical outcomes and toxicity in MBC patients, who have received ET with two CDKi, namely palbociclib and ribociclib. Methods: This is an ambispective, single institutional analysis of de-novo HR+ MBC patients treated with CDKi (palbociclib 125 mg and ribociclib 600 mg once a day for 21 days /28 days cycle) from November 2016- October 2020 at AIIMS, New Delhi, India. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was response rate and toxicity. A total of 157 female patients were recruited in this study however the response and toxicity data were available in 120 cases. All premenopausal women received ovarian suppression or ovarian ablation. Results: A total of 120 patients were included in this study with a median age of 57 years (35-75) and 93 (77.5%) cases were postmenopausal. Twenty-three (19.1%) patients had a bone-only disease, 49 (40.9%) had bone and visceral disease and 48 (40%) had only visceral disease. In this study 91 (75.9%) patients received palbociclib and 29 (24.2%) received ribociclib. The median PFS was 18 months (4-36). Twenty four (20%) patients achieved a complete response, 69 (57.5%) patients attained partial response, 18(15%) patients had stable disease and 9 (7.5%) had disease progression. Grade 3–4 neutropenia, thrombocytopenia, and anaemia were observed in 18(15%), 8 (6.7%), and 4 (3.3%) cases respectively. None of the patients developed febrile neutropenia. Cutaneous, renal, hepatic, and gastrointestinal toxicity was observed in 1,1,3,4 cases respectively. Prolonged QTc was observed in one case. Grade 3 fatigue was observed in 7 cases. Dose interruption/delay (mean dose delay of 7 days), dose modification, and drug discontinuation were observed in 24 (20%), 12 (10%), and 10 (8.3%) of cases respectively. Conclusions: This is one of the largest real-world Indian data on CDK4/6 inhibitors on upfront HR+ MBC. Side effects are less than published literature with similar efficacy. Neutropenia was the most common side effect which was managed by brief dose interruption.

Comparison of therapy benefit from standard anti-HER2 directed approaches in metastatic breast cancer (MBC) between initially HER2-positive patients and patients initially HER2-negative with switch to HER2-positive.

1040 Background: Metaanalyses have demonstrated that 5% of initially HER2 negative breast cancer patients switch to HER2 positive during the course of the disease. Whether there is a difference in benefit from standard HER2 targeted therapies between patients initially HER2 positive and patients switching from negative to positive is unclear. We used data from the PRAEGNANT registry to compare the outcome of those patients. Methods: PRAEGNANT is a prospective advanced breast cancer registry (NCT02338167) focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis compared progression-free survival (PFS) with standard HER2 targeted therapies between patients with tumors initially HER2 negative and switched to HER2 positive and patients with tumors that were initially HER2 positive adjusted for age and hormone receptor status. Results: At the time of this analysis 4061 patients with MBC were included in the PRAEGNANT registry, 49 of which met the requirements for this analysis. Median age was 56 (IQR 48-64) years and 87.8% of the patients were hormone receptor positive. At first diagnosis 15 patients were HER2 negative and 34 patients were HER2 positive. Within a median observation time of 9 months (95%CI: 3.8, 23.7) 35 PFS events occurred. Median observation time was 9 months (95% CI: 3.8, 23.7). Initially HER2 positive patients had a longer progression-free survival (HR = 0.49, 95% CI (0.24, 1.03), p = 0.07) as compared to initially HER2 negative patients switched to HER2 positive. The 1- and 2-year-PFS rates were also higher for patients initially HER2 positive: 1-year-PFS: 52% (95% CI: 36%, 73%) versus 26 % (95% CI: 12%, 52%); 2-year-PFS: 44% (95% CI: 29%, 67%) versus 19% (95% CI: 7%, 50%). Conclusions: Median PFS and 1- and 2-year PFS rate seem to be better in patients HER2 positive at initial diagnosis receiving standard HER2 directed therapies. Although our result has to be interpreted with caution because of the small cohort and the retrospective nature of our analysis, it justifies prospective research including the group of initially HER2 negative patients switched to HER2 positive as a distinct entity. Clinical trial information: NCT02338167 .

The effect of non-oncology drugs on clinical and genomic risk in early luminal breast cancer.

e12505 Background: In women with ER-positive, HER2-negative early stage breast cancer (BC), treatment decisions for adjuvant chemotherapy are based on genomic risk and clinical risk. Recently, an effect of non-oncology medications on cancer cell lines and cancer outcome have been suggested. In this study we aimed to systematically examine the impact of non- oncology drugs on clinical risk and genomic risk (based on OncotypeDx recurrence score [RS]) in early BC. Methods: We collected data from 1385 files of ER positive HER2 negative breast cancer patients regarding their clinical risk (stage and grade), genomic risk (OncotypeDx RS) as well as data regarding medications the patients received during the month before their surgery. Statistical analysis was applied to identify the influence of various medications on OncotypeDx RS. Results: Out of the various medications we examined, we found that Levothyroxine was significantly associated with high median OncotypeDx RS (RS median = 25 ;p &lt; 0.0001) and Metformin was associated with low median OncotypeDx RS (RS median = 12 p &lt; 0.0011) in comparison to patients not receiving these medications (RS median = 17). By contrast there were no differences in the clinical risk between patients who received Metformin or Levothyroxine. Notably, Levothyroxine and metformin did not impact proliferation marker (Ki67) levels but did impact progesterone-related features, suggesting they influence genomic risk through estrogen dependent modules. Indeed, scores of other genomic tests (PAM50, Mammaprint), which are determined largely by proliferative features, were not influenced by Levothyroxine or Metformin. Finally, by using contemporary guidelines to recommend adjuvant chemotherapy based on clinical risk and genomic risk (OncotypeDx ) we show that patients (Age &gt; 50) who received Metformin treatment had 14.5% chance to be recommended adjuvant chemotherapy while patients who received Levothyroxine had 49% (p = 0.0001). Conclusions: The results of this study indicate significant impact of Metformin and Levothyroxine on clinical decisions with potential impact on early BC patients.

Impact of dendritic cell vaccines added to neoadjuvant CT on pathological complete responses in early breast cancer patients according to PD-L1 expression.

585 Background: Breast cancer (BC) in early stages exhibit a naïve and competent immune system that translates into a more prominent TIL infiltration and higher PD-L1 expression as compared to the advanced BC scenario were immunoescape and exhaustion are more prevalent. Expression of PD-L1 has been related to a better pCR when immune checkpoint inhibitors (IPI) have been added to neaodjuvant chemotherapy (NACT) in triple negative BC (TNBC). Our prior results shown dendritic cells vaccines (DCV) increased pCR in both TNBC and luminal B subtypes, with an absolute gain of 20% (p = 0.03) and a safe tolerance. Methods: Eighty-three HER2 negative BC patients with untreated stage II-III were included: 39 patients from the NCT01431196 trial that combine NACT with autologous DCV and 44 patients from a historic control group treated with the same NACT alone. NACT consists of dose dense Epirubicin plus Cyclophosphamide for 4 cycles sequenced to Docetaxel for 4 cycles. PD-L1 expression was measured in the membrane of tumoral cells with monoclonal rabbit anti PD-L1 28.8 pharmaDX (DAKO, Agilent Technologies) in FFPE samples at diagnosis. Primary endpoint was pathologic complete response (pCR) stratified by PD-L1 expression (positive or negative), while secondary endpoints were event-free survival (EFS) and overall survival (OS), also stratified by PD-L1 expression. Results: Both cohorts were well balanced in most of the features. Thirty-three percent of the tumors in the experimental group were PD-L1 positive, whereas 50% of them in the CG expressed PD-L1 (p = 0.06). Pathological CR was observed in 50% of the PD-L1 positive population, in contrast to a 2.8% in the PD-L1 negative in the NACT cohort (p &lt; 0.01) as compared to the patients assigned to the DCV group (33.4% in PD-L1 positive vs 23.1% in PD-L1 negative population; p = 0.16). Among PD-L1 positive population, more pCR were seen in the CG than in the DCV group (50% vs 33.4%; p = 0.06). Within the PD-L1 negative population, more pCR were observed in the DCV group than in the CG (23.1% vs 2.8%; p &lt; 0.05). With a median follow-up of 7 years, no significant differences were observed between the different subgroups neither in EFS (HR = 1.7; 0.42-6.8; p = 0.19) nor in OS (HR = 2.5; 0.56-11, p = 0.43). At 7 years, 20% and 14.4% of the patients relapsed according to the PD-L1 positive versus negative status respectively, and 10.78% versus 13.33% were dead. Conclusions: The benefit of DCV seems to be outstanding in the PD-L1 negative tumors that have a basal immune appropriate milieu. PD-L1 expression implies a more suppressed niche in which DCV are not able to stimulate antigen presentation and cell cytotoxic activity. PD-L1 positive population reach higher responses with both NACT±DCV than PD-L1 negative group, although the benefit seem to be higher in the NACT alone cohort. Further studies combining DVC+IPI together with NACT are needed. Clinical trial information: NCT01431196.

Retrospective analysis of HER2-low in young breast cancer patients.

e12515 Background: Traditionally, breast cancer (BC) is considered human epidermal growth factor receptor-2 (HER2) positive based on HER2 overexpression or amplification (HER2 3+ or ISH positive HER2 2+). However, an emerging subgroup of HER2 negative (HER2 1+ or 2+ and ISH negative) known as HER2-Low is associated with poor prognosis than HER2-normal (HER2 0). Currently, there is an increased interest in developing new drugs targeting HER2-Low BC to improve survival. The fact that BC in young constitutes a significant minority outside the western world but is underrepresented in clinical trials, it is worth conducting a dedicated study of HER2-low in this population to determine whether it affects their outcome. Methods: Confirmed HER2 negative BC patients aged ≤40 diagnosed in 2012-2017 were retrospectively reviewed in two centers in Alexandria, Egypt. Patients were classified as HER2-low (1+, 2+) and HER2-normal. The clinicopathological characteristics and survival outcome were determined and compared. Results: There were five hundred HER2 negative BC patients; 82% were hormone receptor-positive (HR+) vs.18% triple-negative (TNBC). Among the HER2 negative, only 31% were HER2-Low (n = 155), of which 20% was HER2-Low 1+ while 11% was HER2-Low 2+. In comparison, HER2-Low was significantly more HR+ than HER2-normal (89% vs. 79% respectively, p = 0.009). Other tumor characteristics (T-size, nodal status, Ki-67, lymphovascular invasion - LVI, extracapsular extension - ECE) were similar in HER2-Low and HER2-normal. So were the disease-free survival (DFS) and overall survival (OS). Nevertheless, sub-grouping HER2-Low into 1+ and 2+ showed significant differences in tumor characteristics between HER2-normal, HER2-Low 1+, and HER2-Low 2+, in nodal status, tumor stage, ECE, and HR status. Moreover, DFS was significantly lower in HER2-Low 2+ (63.5%) compared to HER2-normal (70%) and HER2-Low 1+ (75%); p = 0.039. Also, the OS was also significantly lower in HER2-Low 2+ compared to HER2-normal, 90% vs 96% respectively, p = 0.023. Conclusions: Our results suggest no significant difference in DFS and OS between HER2-Low and HER2-normal in young BC patients. However, subdividing HER-low into HER2-low 1+ and HER2-Low 2+ better discriminates this group; HER2-Low 2+ had significantly poor DFS and OS and this should be considered in the clinical trials.

VERU-111: An Oral Tubulin Inhibitor That Suppresses Taxane-Sensitive and Taxane-Resistant Breast Cancer

Abstract Triple negative breast cancer (TNBC) patients have poorer overall prognosis relative to patients diagnosed with other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. The microtubule inhibitor paclitaxel (Taxol, a taxane) is a frontline therapy for advanced breast cancer. We evaluated in TNBC models the preclinical safety and efficacy of a novel, potent, and orally bioavailable tubulin inhibitor, VERU-111, a tubulin inhibitor targeting the colchicine binding site. VERU-111 showed potent anti-proliferative and anti-migratory activity against several taxane-sensitive and taxane-resistant TNBC breast cancer cell lines. Based on these observations, taxane-resistant HER2+ cell lines were generated, and were also found to be responsive to VERU-111 treatment. In vivo, orally administered VERU-111 inhibited MDA-MB-231 tumor growth in a dose-dependent manner with antitumor potency similar to paclitaxel, and repressed metastases originating from the mammary fat pad or following tail vein injection. In contrast, in a MDA-MB-231 paclitaxel-resistant (TxR) subline, tumor growth was refractory to paclitaxel whereas VERU-111 significantly inhibited primary tumor growth and reduced lung and liver metastases. VERU-111 was then tested in a luciferase-labeled, multidrug resistant patient-derived xenograft (PDX) TNBC model. VERU-111 significantly inhibited HCI-10 PDX tumor growth and suppressed the expansion of axillary lymph node metastases present prior to initiation of therapy while suppressing lung, liver, bone and kidney metastases at study endpoint. Moreover, in contrast to paclitaxel, VERU-111 therapy did not cause a significant decrease in mouse body weight during treatment. Evaluation of efficacy of VERU-111 in taxane-sensitive and -resistant HER2+ xenograft models is in progress. Overall, we conclude that VERU-111 is a new generation orally bioavailable tubulin inhibitor that potently inhibits the growth of taxane-sensitive and taxane-resistant breast cancers with reduced adverse side effects relative to paclitaxel. Importantly, VERU-111 is well-tolerated in patients as evaluated in phase I/II clinical trials for advanced prostate cancer patients (NCT03752099). We propose that VERU-111 will be an effective second line therapy for patients with advanced breast cancer who progress on taxane-based therapeutic regimens.

Functional Characterization of the Orphan Nuclear Receptor TLX in Triple Negative Breast Cancer

Abstract Despite the development of various therapeutic strategies, breast cancer persists as the second leading cause of cancer-related death among women in the United States. While endocrine modulation and monoclonal antibody therapy have proved to be indispensable modes of intervention for hormone receptor (HR)-positive and HER-2 positive patients, the triple negative breast cancer (TNBC) patient population do not respond to these therapies. As TNBC is considered one of the most challenging subtypes of breast cancer to treat, there is a significant need for the development of targeted therapeutics. Due to their well-known amenability to small-molecule modulation, we investigated whether any nuclear receptors beyond those that are traditionally studied in breast cancer (e.g. ER, PR, and AR), may represent a novel target in the TNBC patient population. Analysis of clinical data revealed that expression of the orphan nuclear receptor TLX (NR2E1) was positively correlated with relapse-free survival, distant metastasis-free survival, and overall survival in both ER-negative and basal-like breast cancer patients. Therefore, we hypothesized that TLX could influence the pathophysiology of TNBC. To interrogate this hypothesis, we established TNBC cells with stable expression of TLX in order to identify direct regulatory targets, as well as the precise physiological mechanism(s) TLX may be regulating. To date, our work has revealed that TLX inhibits proliferation, slows migration, alters chemosensitivity, and impairs cell cycle progression in TNBC cells. In agreement with these findings, our work has also revealed that TLX is capable of modulating the expression of several genes that are known to regulate the processes of growth, migration, and cell cycle. Taken together, our early work supports our hypothesis, and provides valuable insight into the potential pro-survival function of TLX in TNBC. Ongoing work will continue to probe the mechanisms by which TLX impacts breast cancer biology, and establish whether the growth-inhibitory effects translate to in vivo models. As prior work has demonstrated that TLX’s transcriptional activity can be regulated by both synthetic and natural ligands, the results of our work would provide the foundational data necessary for the development of a TLX-based therapy for a patient population with limited therapeutic options and a poor prognostic outlook.

56P The impact of tumour detection method on genomic and clinical risk and chemotherapy recommendation in early hormone receptor positive breast cancer

Symptomatic breast cancers share aggressive clinico-pathological characteristics compared to screen-detected breast cancers. The decision to administer adjuvant chemotherapy for early hormone receptor positive (HR+) HER-2 negative (HER2-) breast cancer patients, is guided by both the genomic and the clinical risk of disease recurrence. We assessed the association between the method of cancer detection and genomic and clinical risk, and its effect on adjuvant chemotherapy recommendation. Patients with early HR+ HER2- breast cancer, and known OncotypeDX Breast Recurrence Score (RS) test were included. A natural language processing (NLP) algorithm was used to identify the method of cancer detection. The clinical and genomic risks of symptomatic and screen-detected tumors were compared. The NLP algorithm identified the method of detection of 401 patients, with 216 (54%) diagnosed by routine screening, and the remainder secondary to symptoms. The distribution of OncotypeDX RS varied between the groups. In the symptomatic group there were lower proportions of low RS (13 vs 23%) and higher proportions of high RS (24 vs. 13%) compared to the screen-detected group (p=.03). Symptomatic tumors were significantly more likely to have a high clinical risk (59 vs 40%; p<.0001). Based on genomic and clinical risk and current guidelines, we found that women aged 50 and under, with symptomatic cancer, had an increased probability of receiving adjuvant chemotherapy recommendation compared to women with screen-detected cancers (57 vs. 35%; p=.03). We demonstrated an association between the method of cancer detection and both genomic and clinical risk. Symptomatic breast cancer, especially in young women, remains a poor prognostic factor that should be taken into account when evaluating patient prognosis and determining adjuvant treatment plans.

P045. Should an MDT be recommending chemotherapy in the absence of a genomic assay in ER positive, HER2 negative breast cancer patients?

P045. Should an MDT be recommending chemotherapy in the absence of a genomic assay in ER positive, HER2 negative breast cancer patients?

Progression and future of CDK4/6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

With the progress of tumor molecular biology research, the clinical treatment concept of advanced breast cancer gradually tends to be accurate. Hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER-2) negative breast cancer accounts for more than 70% of all breast cancers, and it is of great significance to explore new treatment strategies to break through the bottleneck of traditional treatment faced by the patient population. Targeted therapy for this type of breast cancer started relatively late. After the first cyclin-dependent kinase (CDK) 4/6 inhibitor Palbociclib entered the clinical application for HR positive and HER-2 negative advanced breast cancer patients in 2015, the clinical treatment pattern of HR positive and HER-2 negative advanced breast cancer has been changed significantly, with a consequent breakthrough improvement in patients' survival prognosis. Based on the basic pharmacological mechanism, the author analyzes the existing research data and puts forward opinions on how to achieve precise medication in clinical practice and wider application prospects in the future.