The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo

ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.     

PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors have been developed recently and have shown efficacy in breast cancer as a single agent or in combination with anti‐HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established an Src inhibitor saracatinib‐resistant breast cancer cell line (SKBR‐3/SI) for the first time and by evaluating mRNA expression profile, we found that plasminogen activator inhibitor‐1 (PAI‐1) was upregulated in saracatinib‐resistant cells compared to the parent cells. Further study demonstrated that PAI‐1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of chemokine (C‐C motif) ligand 5 (CCL5). Functional assays showed that PAI‐1 and CCL5 overexpression promoted cell proliferation and migration in breast cancer cells, while inhibition of PAI‐1 and CCL5 decreased cell proliferation and migration in saracatinib‐resistant cells. We also showed that targeting PAI‐1 or CCL5 could reverse saracatinib resistance, which deserves more attention in clinical settings.     

Anti‐cancer stem cell activity of a hedgehog inhibitor GANT61 in estrogen receptor‐positive breast cancer cells

Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)‐positive breast cancer cells. It has been suggested that the non‐canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER‐positive breast cancer cells. We studied anti‐CSC activity of a non‐canonical Hh inhibitor GANT61 in ER‐positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER‐positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti‐cell growth and anti‐CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER‐positive cell lines. E2 increased the expression levels of glioma‐associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1‐S cell cycle retardation and increased apoptosis. GANT61 decreased the E2‐induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2‐induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti‐cell growth and/or anti‐CSC activities in some ER‐positive cell lines. In conclusion, the non‐canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER‐positive breast cancer cells. GANT61 enhanced anti‐cell growth and/or anti‐CSC activities of antiestrogens in ER‐positive cell lines.     

Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.     

Crosstalk of DNA double‐strand break repair pathways in poly(ADP‐ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2‐mutated cancer

Germline mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) significantly increase cancer risk in hereditary breast and ovarian cancer syndrome (HBOC). Both genes function in the homologous recombination (HR) pathway of the DNA double‐strand break (DSB) repair process. Therefore, the DNA‐repair defect characteristic of cancer cells brings about a therapeutic advantage for poly(ADP‐ribose) polymerase (PARP) inhibitor‐induced synthetic lethality. PARP inhibitor‐based therapeutics initially cause cancer lethality but acquired resistance mechanisms have been found and need to be elucidated. In particular, it is essential to understand in detail the mechanism of DNA damage and repair to PARP inhibitor treatment. Further investigations have shown the roles of BRCA1/2 and its associations to other molecules in the DSB repair system. Notably, the repair pathway chosen in BRCA1‐deficient cells could be entirely different from that in BRCA2‐deficient cells after PARP inhibitor treatment. The present review describes synthetic lethality and acquired resistance mechanisms to PARP inhibitor through the DSB repair pathway and subsequent repair process. In addition, recent knowledge of resistance mechanisms is discussed. Our model should contribute to the development of novel therapeutic strategies.     

Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines

Background:

The ataxia telangiectasia mutated and Rad3-related kinase (ATR) has a key role in the signalling of stalled replication forks and DNA damage to cell cycle checkpoints and DNA repair. It has long been recognised as an important target for cancer therapy but inhibitors have proved elusive. As NU6027, originally developed as a CDK2 inhibitor, potentiated cisplatin in a CDK2-independent manner we postulated that it may inhibit ATR.

Methods:

Cellular ATR kinase activity was determined by CHK1 phosphorylation in human fibroblasts with inducible dominant-negative ATR-kinase dead expression and human breast cancer MCF7 cells. Cell cycle effects and chemo- and radiopotentiation by NU6027 were determined in MCF7 cells and the role of mismatch repair and p53 was determined in isogenically matched ovarian cancer A2780 cells.

Results:

NU6027 is a potent inhibitor of cellular ATR activity (IC₅₀=6.7 μ) and enhanced hydroxyurea and cisplatin cytotoxicity in an ATR-dependent manner. NU6027 attenuated G2/M arrest following DNA damage, inhibited RAD51 focus formation and increased the cytotoxicity of the major classes of DNA-damaging anticancer cytotoxic therapy but not the antimitotic, paclitaxel. In A2780 cells sensitisation to cisplatin was greatest in cells with functional p53 and mismatch repair (MMR) and sensitisation to temozolomide was greatest in p53 mutant cells with functional MMR. Importantly, NU6027 was synthetically lethal when DNA single-strand break repair is impaired either through poly(ADP-ribose) polymerase (PARP) inhibition or defects in XRCC1.

Conclusion:

NU6027 inhibits ATR, impairing G2/M arrest and homologous recombination thus increasing sensitivity to DNA-damaging agents and PARP inhibitors. It provides proof of concept data for clinical development of ATR inhibitors.     

HSP90 inhibitor AUY922 abrogates up‐regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer

mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy of mTOR kinase inhibitors. We sought to discover efficient drug combination with mTOR inhibitors by elucidating the survival feedback loops induced by mTOR inhibition in breast cancer. The feedback signaling upon treatment of mTOR inhibitor AZD8055 was determined and the combinatorial activity of AZD8055 and HSP90 inhibitor AUY922 in cell signaling and proliferation were detected. Treatment of breast cancer T47D cells with AZD8055 induced activation of AKT and phosphatidylinositol 3‐kinase (PI3K), which was accompanied with increase in expression of multiple upstream proteins including EGFR, HER2, HER3 and IRS‐1. Different RTKs were revealed to be responsible for the reactivation of AKT by AZD8055 in different breast cancer cell lines. Down‐regulation of these proteins differentially enhanced the antiproliferative activity of AZD8055. AZD8055 and AUY922 displayed synergistic effect against a panel of human breast cancer cells irrespective their genotype, which was associated with enhanced cell cycle arrest and inhibition of DNA synthesis. AUY922 destabilized multiple tested tyrosine kinases and abrogated activation of AKT induced by AZD8055. AZD8055 also inhibited up‐regulation of HSP70 and HSP27 upon AUY922 treatment. Cotreatment of these two drugs demonstrated synergistic activity against triple negative MDA‐MB‐468 xenograft without enhanced toxicity. The combination of AZD8055 and AUY922 demonstrated synergistic activity against various types of breast cancer and established a mechanistic rationale for a combination approach using catalytic mTOR kinase inhibitor and HSP90 inhibitor in the treatment of breast cancer.     

Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers

The therapeutic management of various HER2-positive malignancies involves the use of HER2-targeted antibody-drug conjugates (ADCs). The primary mechanism of action of ADCs is the release of cytotoxic chemicals, which leads to single- or double-strand DNA breaks and cell death. Since both endogenous and exogenous sources of DNA damage are unavoidable, cells have evolved DNA damage-repair mechanisms. Therefore, combining inhibitors of DNA damage repair and HER2-targeted ADCs may be a practical strategy for treating HER2-positive cancers. Effects of the HER2-targeted ADC, DS-8201, in combination with PARPi (AZD2281), a DNA damage repair inhibitor that targets poly(ADP-ribose) polymerase, and ATRi (BAY1895344), which inhibits the serine/threonine kinase ATR, were determined by assessing cell-growth inhibition, apoptosis and cell-cycle arrest, as well as using in vivo pharmacodynamic studies. Combined use of AZD2281 and BAY1895344 synergistically potentiated the inhibitory effects of DS-8201 on the growth of HER2-positive cancer cells, inducing DNA damage and apoptosis, but had no effect on HER2-negative MDA-MB-231 breast cancer cells. Our data demonstrate that DS-8201 and DNA damage repair inhibitors together have synergistic anticancer effects in NCI-N87 xenograft models, effects that may reflect upregulation of γ-H2AX protein in tumor tissues. Collectively, our results indicate that the combination of DS-8201, BAY1895344, and AZD2281 exerts significant synergistic antitumor activity, suggesting that DNA damage-repair inhibitors in combination with HER2-targeted ADCs is a potential approach for treating HER2-positive malignancies, offering a promising strategy for future clinical applications.     

Expression of CD24 is associated with HER2 expression and supports HER2‐Akt signaling in HER2‐positive breast cancer cells

Human epidermal growth factor receptor 2 (HER2)‐positive breast cancer is treated with HER2‐targeted agents, such as trastuzumab and lapatinib, that suppress signaling by phosphatidylinositol 3‐kinase (PI3K)‐Akt and MAPK pathways. However, resistance to HER2‐targeted therapy remains a major clinical problem. Overexpression of CD24 has been detected in many cancers and is associated with a poor prognosis in women with breast cancer. HER2‐positive breast tumors are predominantly positive for CD24, suggesting that the expression of the two molecules is related. To investigate the relation between HER2 and CD24, we overexpressed HER2 in breast cancer cells that were triple‐negative for the estrogen receptor, progesterone receptor and HER2. We found that expression of CD24 was increased by stable overexpression of HER2. Flow cytometry thus revealed that the percentage of CD24‐positive cells was markedly higher in the HER2‐positive fraction than in the HER2‐negative fraction. Knockdown of CD24 in breast cancer cells positive for endogenous HER2 downregulated HER2 expression, whereas knockdown of HER2 did not affect the expression of CD24. Knockdown of CD24 also suppressed the phosphorylation of Akt, which functions downstream of HER2 and PI3K to promote cell survival. Moreover, knockdown of CD24 increased the sensitivity of HER2‐positive breast cancer cells to lapatinib treatment. Our results thus indicate that CD24 supports both the expression of HER2 and the consequent activation of PI3K‐Akt signaling. Furthermore, CD24 may contribute to resistance to HER2‐targeted therapy and, therefore, is itself a potential therapeutic target in HER2‐positive breast cancer.     

Trastuzumab‐based neoadjuvant therapy in patients with HER2‐positive breast cancer

Overexpression, or gene amplification, of the human epidermal growth factor receptor 2 (HER2) is evident in 20% to 25% of breast cancers. The biologic agent trastuzumab is an HER2‐targeted monoclonal antibody that inhibits the proliferation of tumor cells and induces tumor cell death through multiple mechanisms of action. Currently, trastuzumab is approved for use in the adjuvant and metastatic settings. Trials combining trastuzumab with neoadjuvant chemotherapy suggest that patients with HER2‐positive breast cancer also may benefit from preoperative trastuzumab. For this article, the author reviewed efficacy and safety data from key studies of patients who received neoadjuvant trastuzumab‐based therapy. Studies were identified from literature searches of publication and congress databases. The results of 3 large phase 3 trials (the M. D. Anderson Cancer Center neoadjuvant trastuzumab trial, the Neoadjuvant Herceptin [NOAH] trial, and the German Breast Group/Gynecologic Oncology Study Group “GeparQuattro” trial) demonstrated that, compared with chemotherapy alone, neoadjuvant trastuzumab plus chemotherapy significantly increased pathologic complete response rates to as high as 65%. Improvements in disease‐free, overall, and event‐free survival also were reported in the NOAH trial. In addition to demonstrated efficacy, a low incidence of cardiac dysfunction suggests that neoadjuvant trastuzumab is both effective and well tolerated. Similar results have been reported in a range of phase 2 studies using different trastuzumab‐based regimens. These encouraging data led the National Comprehensive Cancer Network to recommend treating patients who have operable, locally advanced, HER2‐positive breast cancer with neoadjuvant paclitaxel plus trastuzumab followed by 5‐fluorouracil, epirubicin, and cyclophosphamide plus trastuzumab. Cancer 2010. © 2010 American Cancer Society.     

Using next‐generation sequencing to redefine BRCAness in triple‐negative breast cancer

BRCAness is considered a predictive biomarker to platinum and poly(ADP‐ribose) polymerase (PARP) inhibitors. However, recent trials showed that its predictive value was limited in triple‐negative breast cancer (TNBC) treated with platinum. Moreover, tumors with mutations of DNA damage response (DDR) genes, such as homologous recombination (HR) genes, could be sensitive to platinum and PARP inhibitors. Thus, we aim to explore the relationship between mutation status of DDR genes and BRCAness in TNBC. We sequenced 56 DDR genes in 120 TNBC and identified BRCAness by array comparative genomic hybridization. The sequencing results showed that 13, 14, and 14 patients had BRCA, non‐BRCA HR, and non‐HR DDR gene mutations, respectively. Array comparative genomic hybridization revealed that BRCA‐mutated and HR gene‐mutated TNBC shared similar BRCAness features, both having higher numbers and longer length of large‐scale structural aberration (LSA, >10 Mb) and similar altered chromosomal regions of LSA. These suggested non‐BRCA HR gene‐mutated TNBC shared similar characteristics with BRCA‐mutated TNBC, indicating non‐BRCA HR gene‐mutated TNBC sensitive to platinum and PARP inhibitors. Among tumors with mutation of non‐HR DDR genes, 3 PTEN and 1 MSH6 mutation also contained significant LSAs (BRCAness); however, they had different regions of genomic alteration to BRCA and HR gene‐mutated tumors, might explain prior findings that PTEN‐ and MSH6‐mutated cancer cells not sensitive to PARP inhibitors. Therefore, we hypothesize that the heterogeneous genomic background of BRCAness indicates different responsiveness to platinum and PARP inhibitors. Direct sequencing DDR genes in TNBC should be applied to predict their sensitivity toward platinum and PARP inhibitors.     

Lapatinib耐药性HER2阳性乳腺癌细胞株的建立及鉴定

目的:为研究HER2阳性乳腺癌细胞获得拉帕替尼耐药性的机制,建立稳定具有拉帕替尼耐药性的细胞株。方法:采用2μmol/L的拉帕替尼处理HER2阳性乳腺癌细胞BT-474,维持12个月,使细胞获得稳定耐药性。然后分别利用MTT、平板克隆和软琼脂克隆形成能力分析等方法,评价所建立耐药细胞的耐药能力。结果:所建立的耐药细胞在细胞增殖能力、平板克隆形成能力和软琼脂克隆形成能力等方面均具有耐药性。结论:建立的拉帕替尼耐药性细胞BT-474具有稳定的耐药性,为后续机制研究奠定基础。     

Depletion of DNA damage binding protein 2 sensitizes triple‐negative breast cancer cells to poly ADP‐ribose polymerase inhibition by destabilizing Rad51

Poly ADP‐ribose polymerase inhibitors (PARPi) have shown promising therapeutic efficacy in triple‐negative breast cancer (TNBC) patients. However, resistance ultimately develops, preventing a curative effect from being attained. Extensive investigations have indicated the diversity in the mechanisms underlying the PARPi sensitivity of breast cancer. In this study, we found that DNA damage binding protein 2 (DDB2), a DNA damage‐recognition factor, could protect TNBC cells from PARPi by regulating DNA double‐strand break repair through the homologous recombination pathway, whereas the depletion of DDB2 sensitizes TNBC cells to PARPi. Furthermore, we found that DDB2 was able to stabilize Rad51 by physical association and disrupting its ubiquitination pathway‐induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a promising therapeutic target for TNBC.     

Epirubicin plus low-dose trastuzumab in HER2 positive metastatic breast cancer

Purpose This phase II study, evaluated the activity and cardiotoxicity of first-line epirubicin plus low-dose trastuzumab (LD-T) in patients with HER2 positive MBC. Methods Patients received epirubicin 90 mg/sqm every 3 weeks plus weekly LD-T (2 mg/kg loading dose, then 1 mg/kg). After 6/8 cycles of epirubicin, single agent trastuzumab was continued. Cardiotoxicity was defined as signs or symptoms of congestive heart failure (CHF), or ≥15% decline in LVEF without symptoms, or <15% LVEF decline to less than 50%, without symptoms. Results Forty-five patients were enrolled. Twenty-three received prior adjuvant anthracyclines. Overall response rate was 61.4%. The median time to progression was 7.4 months and the median survival was 32.8 months. Two (4.5%) patients developed CHF. Conclusions Epirubicin plus LD-T is an active regimen, however, the relatively high rate of cardiotoxicity together with the availability of less cardiotoxic and active trastuzumab-containing combinations precludes further evaluation of this regimen. An invited commentary to this article can be found at doi:.     

ATR在浸润性乳腺癌组织中的表达和临床意义

目的:探讨共济失调毛细血管扩张突变基因Rad3相关蛋白（ATR）在浸润性乳腺癌组织中的表达及其临床意义。方法:收集289例乳腺癌改良根治术后病理标本,构建组织芯片,采用免疫组化方法检测组织中ATR的表达,并分析其与临床病理参数之间的关系。结果:ATR在乳腺癌组织中的阳性表达率为70.6%（204/289）。ATR阳性表达率在肿瘤直径>2 cm组高于≤2 cm组,在TNM分期Ⅱ-Ⅲ期组高于I期组,在孕激素受体（PR）阳性组高于PR阴性组,在人类表皮生长因子受体2（HER-2）阳性组高于HER-2阴性组,在非三阴性乳腺癌组高于三阴性乳腺癌组,差异均有统计学意义（P<0.05）;ATR的表达与患者发病年龄、月经状态、组织学分级、淋巴结转移情况、雌激素受体（ER）水平、p53状态无明显相关（P>0.05）。结论:浸润性乳腺癌组织中ATR的高表达可能与乳腺癌的进展相关。     

Disruption of the blood brain barrier by brain metastases of triple‐negative and basal‐type breast cancer but not HER2/neu‐positive breast cancer

BACKGROUND:

Generally, the blood‐brain barrier (BBB) of brain metastasis was thought to be disrupted.

METHODS:

We retrospectively performed immunohistochemical staining for glucose transporter 1 (GLUT1) and breast cancer resistance protein (BCRP) to evaluate the status of the BBB in resected brain metastases. Associations between expression of GLUT1 and/or BCRP and the immunohistochemical profiles of breast cancers, such as the statuses of hormone receptors, human epidermal growth factor receptor 2 (HER2/neu), and a basal‐type marker (cytokeratin 5/6, HER1), were also analyzed.

RESULTS:

The study included 29 breast cancer patients with brain metastasis who had undergone brain tumor resections. Among the 29 patients, there was no expression of GLUT1 and BCRP in the intratumor microvessels of 9 (32%) and 11 (38%) patients, respectively. There was no expression of both GLUT1 and BCRP in 8 patients (28%). The expression of GLUT1 was significantly associated with that of BCRP (P < .001). A positive correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of HER2/neu‐positive breast cancer (P = .012), while a negative correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of triple negative or basal‐type breast cancer (P = .014 and P = .003 for triple negative and basal‐type, respectively).

CONCLUSIONS:

Brain metastases of triple negative or basal‐type breast cancers may often disrupt the BBB, whereas brain metastases of HER2/neu‐positive breast cancer tend to preserve the BBB. Cancer 2010. © 2010 American Cancer Society.     

DNA损伤应答缺陷作为乳腺癌治疗靶点的研究进展

DNA损伤应答(DNA damage response,DDR)缺陷是近年来乳腺癌治疗研究的热门靶点之一。DDR通路负责DNA损伤后的识别、信号转导和修复,其功能异常可导致细胞的凋亡或基因组不稳定性的增加。目前进入临床研究阶段的乳腺癌DDR靶向药物主要包括多聚腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase,PARP]抑制剂、ATM抑制剂、CHEK1抑制剂、ATR抑制剂及WEE1抑制剂等。主要从DDR缺陷的概念、以DDR作为靶点的基本原理、DDR各类靶向药物的临床研究现状及其在临床应用中的难点与挑战等方面展开综述。     

Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy

Treatment of triple negative breast cancer (TNBC) has been a big challenge since it is defined. To date, platinum-based chemotherapy has played a significant role in the treatment of TNBC patients. However, some patients do not respond to platinum salts or gradually develop chemoresistance, resulting in little effect, or even some adverse effects. Here, we review numerous preclinical and clinical investigations to summarize possible mechanisms and potential predictive biomarkers of platinum in TNBC. The homologous recombination deficiency (HRD) resulting from the loss of BRCA function is the main rationale of platinum efficacy in TNBC. BRCA mutation and methylation have been demonstrated to be important potential biomarkers. Based on genome-wide effects, BRCA-like classifier can identify the functional loss of BRCA and work as the predictor. HRD score that is able to identify the “BRCAness” and predict the sensitivity of platinum is increasingly considered. Taken together, all findings suggest that HR deficiency profile encompassed by BRCA mutation and high HRD score could predict response to platinum, even to other DNA-damage inducing agents. p53 family members and molecular subtypes of TNBC are also important alternative considerations for predicting platinum response based on the preclinical trials. Currently, tumor infiltrating lymphocyte level and thrombocytopenia are emerging as predictive biomarkers.