Abstract 1943: Radiosensitization of PIK3CA wild type triple negative breast cancers with Bcl-family inhibition

2021 ◽  
Author(s):  
Andrea M. Pesch ◽  
Benjamin C. Chandler ◽  
Anna R. Michmerhuizen ◽  
Nicole Hirsh ◽  
Kari Wilder-Romans ◽  
...  
Keyword(s):  
Triple Negative ◽  
Breast Cancers ◽  
Wild Type

scholarly journals Analysis of Adaptive Olaparib Resistance Effects on Cisplatin Sensitivity in Triple Negative Breast Cancer Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Ambikai Gajan ◽  
Ashapurna Sarma ◽  
Seongho Kim ◽  
Katherine Gurdziel ◽  
Gen Sheng Wu ◽  
...  
Keyword(s):  
Cellular Response ◽  
Triple Negative ◽  
Breast Cancers ◽  
Wild Type ◽  
M Cell ◽  
Inflammatory Stress ◽  
Interstrand Crosslink ◽  
Cisplatin Sensitivity ◽  
Interstrand Crosslink Repair ◽  
Parp 1

Poly-(ADP)-ribose polymerase inhibitors (PARPi) and platinum-based drugs are promising therapies for triple negative breast cancers (TNBC) with BRCA1 or BRCA2 loss. PARPi(s) show better efficacies when combined with platinum-based therapy, however, acquisition of PARPi resistance has been linked with co-resistance to platinum-based drugs. Here, we show that TNBCs with constitutively hyperactivated PARP-1 display greater tolerances for the PARPi olaparib and cisplatin, and respond synergistically to olaparib/cisplatin combinations with increased cytotoxicity. Regardless of BRCA1 and PARP-1 activity status, upon gaining olaparib resistance (OlaR), OlaR MDA-MB-468 (BRCA1 wild-type) and SUM1315 (BRCA1 mutant) TNBC cells retain cisplatin sensitivities of their isogenic parental counterparts. OlaR TNBC cells express decreased levels of PARP-1 and Pol η, a translesion-synthesis polymerase important in platinum-induced interstrand crosslink repair. Although native RAD51 recombinase levels are unaffected, anti-RAD51 immunoreactive low molecular weight sbands are exclusively detected in OlaR cells. Despite normal BRCA1, RAD51 foci formation/recruitment to double-strand breaks are impaired in OlaR MDA-MB-468 cells, suggesting homologous-recombination impairment. RNA-seq and pathway analysis of cisplatin-affected genes revealed enrichment of G2/M cell cycle regulation and DNA repair pathways in parental and OlaR MDA-MB-468 cells whereas parental and OlaR SUM1315 cells showed enrichment of inflammatory stress response pathways associated with TNFR1/2, TWEAK and IL-17 signaling. These data show that TNBC models with wild type versus mutant BRCA1 exhibit differences in CDDP-induced cellular response pathways, however, the CDDP-induced signaling responses remain stable across the isogenic models of OlaR from the same lineage. These data also show that adaptive OlaR does not automatically promote cisplatin resistance, implicating the potential benefit of platinum-based therapy for OlaR TNBCs.

Abstract 1952: CDK4/6 inhibition radiosensitizes RB1 wild type triple negative breast cancers through impaired homologous recombination

2021 ◽  
Author(s):  
Andrea M. Pesch ◽  
Nicole Hirsh ◽  
Anna R. Michmerhuizen ◽  
Benjamin C. Chandler ◽  
Kari Wilder-Romans ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Triple Negative ◽  
Breast Cancers ◽  
Wild Type

scholarly journals Efficacy and Safety of PARP Inhibitors in Advanced or Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-analysis

2020 ◽  
Author(s):  
Xu Liu ◽  
Kan Wu ◽  
Dan Zheng ◽  
Chuanxu Luo ◽  
Yu Fan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Triple Negative ◽  
Meta Analysis ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Parp Inhibitors ◽  
Hematological Toxicity ◽  
Breast Cancers ◽  
Efficacy And Safety ◽  
Wild Type

Abstract BackgroundPoly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in metastatic triple-negative breast cancers (TNBC). We performed a systematic review and meta-analysis to evaluate the efficacy and safety of this drug in patients with advanced or metastatic TNBC.MethodsOn August 2020, we searched all published phase II/III clinical studies of PARP inhibitors in advanced/metastatic TNBC patients. Data were extracted independently by two authors and analyzed using Review Manager software version 5.3. End points included overall response rate (ORR), progression-free survival (PFS) and adverse events.ResultsTen clinical trials were identified, with a total of 1495 patients included. Pooled analyses showed that the addition of PARP inhibitors could provide a significant improvement of ORR (risk ratio [RR]=2.00, 95% confidence interval [CI]: 1.14–3.50, p=0.02) and PFS (hazard ratio [HR]=0.68, 95 %Cl: 0.59-0.77, p<0.0001) compared to chemotherapy in the whole population. In subgroup analysis, BRCA mutated patients have a higher objective response to PARP inhibitor, with a RR of 2.85 (95%CI: 1.34–6.06, p=0.007) compared to BRCA wild-type patients. However, no significant differences in ORR were observed between homologous recombination deficiency (HRD) positive and non-HRD subgroup (RR=1.82, 95%CI: 0.81–4.08, p=0.14). Hematologic toxicities were common adverse events of PARP inhibitors.ConclusionsPARP inhibitors are an effective option for the treatment of advanced or metastatic TNBC patients. BRCA mutated patients could derive more benefits from PARP inhibitors when compared to BRCA wild-type patients. In clinical application, hematological toxicity related to PARP inhibitors should be monitored regularly.

scholarly journals Triple-negative breast cancers are increased in black women regardless of age or body mass index

2009 ◽  
Vol 11 (2) ◽  
Author(s):  
Lesley A Stead ◽  
Timothy L Lash ◽  
Jerome E Sobieraj ◽  
Dorcas D Chi ◽  
Jennifer L Westrup ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Black Women ◽  
Body Mass ◽  
Triple Negative ◽  
Breast Cancers

scholarly journals Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2506
Author(s):  
Mark van Barele ◽  
Bernadette A. M. Heemskerk-Gerritsen ◽  
Yvonne V. Louwers ◽  
Mijntje B. Vastbinder ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hormone Replacement ◽  
Breast Cancers ◽  
Younger Women ◽  
Alternative Pathways ◽  
Increased Risk ◽  
History Of ◽  
Hormone Sensitive

Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

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