Role of intratumoral NK cells in triple-negative breast cancer in the FinXX trial and Mayo Clinic cohort.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 510-510
Author(s):  
Saranya Chumsri ◽  
Jodi M Carter ◽  
Yaohua Ma ◽  
Douglas Hinerfeld ◽  
Heather Ann Brauer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Adjuvant Chemotherapy ◽  
Nk Cells ◽  
Triple Negative Breast Cancer ◽  
Gene Expression Analysis ◽  
Triple Negative ◽  
Cd56 Expression ◽  
Improved Outcome

510 Background: Several studies have established the critical role of preexisting immune response in triple negative breast cancer (TNBC). Most studies evaluated the tumor infiltrating lymphocytes in stroma. However, limited data are available with regards to the importance of specific subtypes and spatial distribution of these immune infiltrates. Methods: NanoString IO360 gene expression analysis and Digital Spatial Profiling (DSP) were used. DSP was used to quantify 39 immune-related proteins in stromal and tumor-enriched segments from 44 TNBC samples from the FinXX trial (NCT00114816) and 335 samples from the Mayo Clinic (MC) cohort of centrally reviewed TNBC (Leon-Ferre BCRT 2018). In FinXX trial, 22 patients with recurrence and 22 patients without recurrence were included. In MC cohort, 217/335 patients received adjuvant chemotherapy while 118 patients had surgery only without adjuvant chemotherapy. Regions were segmented based on pancytokeratin staining. The general linear model was used for statistical analysis of differential expression with recurrence free survival (RFS) as a categorical variable (recur yes or no). Kaplan-Meier estimates and Cox regression models were also used for analysis. Results: In the FinXX trial, using global gene expression analysis with IO360, there was no signature significantly associated with RFS. However, using DSP, high protein expression of CD56 in the tumor-enriched segments was associated with significant improvement in RFS (HR 0.26, 95%CI 0.09-0.78, p 0.01). Nevertheless, CD56 expression in the stroma (HR 0.66, 95%CI 0.29-1.53, p 0.33) and all segments (HR 0.53, 95%CI 0.23-1.25, p 0.14) was not significantly associated with improved outcome. We further validated these findings in the MC TNBC cohort where intratumoral CD56 expression was associated with a significant improvement in RFS (HR 0.23, p 0.002) but not stromal CD56 (p 0.79). Interestingly, when evaluating the MC TNBC cohort according to receipt of chemotherapy, intratumoral CD56 was associated with improved outcome only in patients who received chemotherapy (p 0.02 vs. 0.07). In both cohorts, higher expressions of intratumoral PD-L1, HLA-DR, and CD8 were associated with improved outcome. Conclusions: Using an in-depth analysis with spatially defined context, we identify that intratumoral CD56-positive NK cells are associated with improved outcome in TNBC. Our study highlights the potential role of NK cells in TNBC and future implications for biomarkers and therapeutic targets.Support: W81XWH-15-1-0292, P50CA116201-9, P50CA015083. Clinical trial information: NCT00114816 .

scholarly journals An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Erica M. Stringer-Reasor ◽  
Jori E. May ◽  
Eva Olariu ◽  
Valerie Caterinicchia ◽  
Yufeng Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Repair ◽  
Pilot Study ◽  
Expression Analysis ◽  
Triple Negative Breast Cancer ◽  
Gene Expression Analysis ◽  
Triple Negative ◽  
Egfr Inhibition ◽  
Link Type

Abstract Background Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Methods A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. Results Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. Trial registration ClinicalTrials.gov, NCT02158507. Registered on 12 September 2014

scholarly journals The role of capecitabine-based neoadjuvant and adjuvant chemotherapy in early-stage triple-negative breast cancer: a systematic review and meta-analysis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xingfa Huo ◽  
Jinming Li ◽  
Fuxing Zhao ◽  
Dengfeng Ren ◽  
Raees Ahmad ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Adjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Randomized Clinical Trials ◽  
Triple Negative ◽  
Early Stage ◽  
Meta Analysis ◽  
Disease Free Survival

Abstract Background The role of capecitabine in neoadjuvant and adjuvant chemotherapy for early-stage triple-negative breast cancer (TNBC) is highly controversial. Our meta-analysis was designed to further elucidate the effects of capecitabine on survival in early-stage TNBC patients and its safety. Methods PubMed, Embase, and papers presented at several main conferences were searched up to December 19, 2019, to investigate capecitabine-based versus capecitabine-free neoadjuvant and adjuvant chemotherapy in TNBC patients. Heterogeneity was assessed using I2 test, combined with hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) computed for disease-free survival (DFS), overall survival (OS), and over grade 3 adverse events (AEs). Results A total of 9 randomized clinical trials and 3842 TNBC patients were included. Overall, the combined capecitabine regimens in neoadjuvant and adjuvant chemotherapy showed significantly improved DFS (HR = 0.75; 95% CI, 0.65–0.86; P < 0.001) and OS (HR = 0.63; 95% CI, 0.53–0.77; P < 0.001). In subgroup analysis, there were improvements in DFS in the groups with addition of capecitabine (HR = 0.64; 95% CI, 0.53–0.78; P < 0.001), adjuvant chemotherapy (HR = 0.73; 95% CI, 0.63–0.85; P < 0.001), and lymph node positivity (HR = 0.62; 95% CI, 0.44–0.86; P = 0.005). Capecitabine regimens were related to higher risks of diarrhea (OR = 2.88, 95% CI 2.23–3.74, P < 0.001), stomatitis (OR = 2.01, 95% CI 1.53–2.64, P < 0.001) and hand–foot syndrome (OR = 8.67, 95% CI 6.70–11.22, P < 0.001). Conclusion This meta-analysis showed that neoadjuvant and adjuvant chemotherapy combined with capecitabine significantly improved both DFS and OS in early-stage TNBC patients with tolerable AEs. There were benefits to DFS in the groups with the addition of capecitabine, adjuvant chemotherapy, and lymph node positivity.

scholarly journals Evaluation of Gene Expression Data From Cybrids and Tumours Highlights Elevated NDRG1-Driven Proliferation in Triple-Negative Breast Cancer

2020 ◽  
Vol 14 ◽  
pp. 117822342093444
Author(s):  
Akanksha Mishra ◽  
Maria Bonello ◽  
Adam Byron ◽  
Simon P Langdon ◽  
Andrew H Sims
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Gene Expression Data ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Donor Cell ◽  
Expression Data ◽  
Donor Cells

Background: Triple-negative breast cancer is an aggressive type of breast cancer with high risk of recurrence. It is still poorly understood and lacks any targeted therapy, which makes it difficult to treat. Thus, it is important to understand the underlying mechanisms and pathways that are dysregulated in triple-negative breast cancer. Methods: To investigate the role of mitochondria in triple-negative breast cancer progression, we analysed previously reported gene expression data from triple-negative breast cancer cybrids with SUM-159 as the nuclear donor cell and SUM-159 or A1N4 (c-SUM-159, c-A1N4) as the mitochondrial donor cells and with 143B as the nuclear donor cell and MCF-10A or MDA-MB-231 (c-MCF-10A, c-MDA-MB-231) as the mitochondrial donor cells. The role of potential biomarkers in cell proliferation and migration was examined in SUM-159 and MDA-MB-231 cells using sulforhodamine B and wound healing assays. Results: Rank product analysis of cybrid gene expression data identified 149 genes which were significantly up-regulated in the cybrids with mitochondria from the cancer cell line. Analysis of previously reported breast tumour gene expression datasets confirmed 9 of the 149 genes were amplified, up-regulated, or down-regulated in more than 10% of the patients. The genes included NDRG1, PVT1, and EXT1, which are co-located in cytoband 8q24, which is frequently amplified in breast cancer. NDRG1 showed the largest down-regulation in the cybrids with benign mitochondria and was associated with poor prognosis in a breast cancer clinical dataset. Knockdown of NDRG1 expression significantly decreased proliferation of SUM-159 triple-negative breast cancer cells. Conclusions: These results indicate that mitochondria-regulated nuclear gene expression helps breast cancer cells survive and proliferate, consistent with previous work focusing on an Src gene signature which is mitochondria regulated and drives malignancy in breast cancer cybrids. This is the first study to show that mitochondria in triple-negative breast cancer mediate significant up-regulation of a number of genes, and silencing of NDRG1 leads to significant reduction in proliferation.

scholarly journals An Open Label, Pilot Study of Veliparib and Lapatinib in Patients with Metastatic, Triple Negative Breast Cancer

2020 ◽  
Author(s):  
Erica M. Stringer-Reasor ◽  
Jori E. May ◽  
Eva Olariu ◽  
Valerie Caterinicchia ◽  
Yufeng Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Repair ◽  
Pilot Study ◽  
Expression Analysis ◽  
Triple Negative Breast Cancer ◽  
Gene Expression Analysis ◽  
Triple Negative ◽  
Egfr Inhibition ◽  
Metastatic Setting

Abstract Background: Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (g BRCA1/2 ) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple negative breast cancer (TNBC) with intact DNA repair, we previously showed an induced synthetic lethality with combined EGFR inhibition and PARPi. We report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Methods: A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline and taxane therapy. Patients with g BRCA1/2 mutations were excluded. Results: Twenty patients were enrolled of which 17 were evaluable for response. Median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Gene expression analysis suggest baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions: Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed.

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