基因检测报告解读精选百篇（1）

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七来我认真解读了近万份基因检测报告，帮助别人的同时自己也从中学到了很多知识。现将一些基因突变扩增异常复杂的基因检测报告解读精选出来形成系列文章。

基因检测报告主要是提供关乎选择靶向药化疗药的部分生物标志物和提供预判预测ICB免疫治疗的部分生物标志物。做基因检测，要做至少检测五六百个基因的基因检测或者全外显子基因检测。现在还做医院那种只检测几十个基因的基因检测纯粹是浪费肿瘤患者最宝贵的资产--取下来的病灶组织。

靶向药化疗药的其他部分生物标志物主要是靠做免疫组化检测（不是医院给癌症定性的那简单的几个蛋白免疫组化检测）。目前国内的肿瘤相关蛋白全景检测、蛋白质谱检测、自己选定靶点蛋白的检测也已都实际可做了。

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患者是ER阳性、PR阳性、HER2阴性乳腺癌患者。

按照《指南》的粗放式治疗方案，应用抗雌激素治疗+卵巢去势治疗+CDK4/6抑制剂的方案。

但患者存在多个抗雌激素治疗、CDK4/6抑制剂的耐药突变扩增。应用《指南》的粗放式治疗方案疗效不会好。她的治疗经历也证实了这点。

性激素是HR阳性乳腺癌的主驱动因素之一，必须针对治疗；因此尽管有耐药因素，但抗雌激素治疗+卵巢去势治疗必须还要用。

患者不存在cdk4扩增、cdk6扩增、ccnd1扩增等必须要用CDK4/6抑制剂的基因突变扩增，又存在耐药因素，因此不必用CDK4/6抑制剂。

患者的靶向药治疗模式应为抗雌激素治疗+卵巢去势治疗+根据基因突变扩增情况的针对用药。

第一部分必须要针对用药的异常基因

一、FGFR1扩增

1、FGFR1扩增是内分泌治疗和CDK4/6抑制剂的耐药因素

（1）《Fibroblast growth factor receptor signaling in estrogen receptor-positive breast cancer: mechanisms and role in endocrine resistance》

FGFR1 is frequently amplified, especially in aggressive Luminal B-like tumors, and its amplification is associated with poor prognosis and treatment resistance. The co-amplification of FGFR1 with oncogenes like EIF4EBP1 and NSD3 complicates its role as a standalone oncogenic driver.

（2）《Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer》

Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.

2、FGFR1靶点的靶向药有帕唑帕尼、帕纳替尼、厄达替尼、英菲格拉替尼、培米替尼等药物。这些药物同时也都有抗血管生成的作用。

针对基因扩增用靶向药，一般遵循“IC50值越用越小”这个原则。不要一上来就用英菲格拉替尼、培米替尼这些对FGFR1靶点IC50值特别低的药，不然耐药后再用其他IC50值高的药未必有用。

3、FGFR1扩增的HR阳性乳腺癌对MTOR抑制敏感

《FGFR1 Amplification Mediates Endocrine Resistance but Retains TORC Sensitivity in Metastatic Hormone Receptor-Positive (HR+) Breast Cancer》

Purpose: While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1-amplified (FGFR1+) metastatic breast cancer (MBC) remains undefined.Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR+)/HER2- MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro.

Results: In the clinical cohort (N = 110), we identified that patients with FGFR1+ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P = 0.005), coexisting TP53 mutations (41% vs. 21%; P = 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1+ HR+/HER2- MBC. In preclinical models, estrogen receptor-positive (ER+)/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER+ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition.

Conclusions: Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER+/FGFR1+ MBC.

这尤其对有 FGFR1扩增，已经用过了某个FGFR1抑制剂，现在再用另外的FGFR1抑制剂却没什么疗效的HR阳性乳腺癌患者，有比较重要的意义。

或者既有FGFR1扩增，又有一些要用mtor抑制剂的突变扩增，因为耐受有限，不能fgfr1抑制剂和mtor抑制剂一起用的时候，要优先选择mtor抑制剂

二、IGF1R扩增

1、IGF1R的高表达和激活介导抗雌激素治疗的耐药

《IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer》

Antiestrogen resistance in estrogen receptor positive (ER+) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B, CDK10, CDK5, EIF2AK1, and MAP2K5, and the tamoxifen resistance inducers CHEK1, PAK2, RPS6KC1, TTK, and TXK. The p21-activated kinase 2, PAK2, is the strongest resistance inducer. Silencing of the tamoxifen resistance inducing genes, particularly PAK2, attenuates IGF1R-mediated resistance to tamoxifen and fulvestrant. High expression of PAK2 in ER+ metastatic breast cancer patients is correlated with unfavorable outcome after first-line tamoxifen monotherapy. Phospho-proteomics has defined PAK2 and the PAK-interacting exchange factors PIXα/β as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIXα/β modulate IGF1R signaling-driven cell scattering. Targeting PIXα/β entirely mimics the effect of PAK2 silencing on antiestrogen re-sensitization. These data indicate PAK2/PIX as an effector pathway in IGF1R-mediated antiestrogen resistance.

2、IGF1R扩增介导CDK4/6抑制剂耐药

《Abstract PD7-08: Igf1r mediates cdk4/6 inhibitor (cdk4/6i) resistance in tumor samples and in cellular models》

Conclusions: IGF1R amplification events were identified in tumor biopsy samples that reflect either intrinsic or acquired resistance to CDK4/6i-based therapy. HR+ breast cancer cells which over-express IGF1R demonstrate enrichment under palbociclib drug selection in a flow cytometry-based competition assay, which was abrogated by concurrent use of a MEK or IGF1R inhibitor. These results suggest that IGF1R may join the increasingly heterogeneous landscape of CDK4/6i resistance mediators. Further exploration of this possibility is warranted. A subset of patients with IGF1R-mediated CDK4/6i resistance could benefit from therapeutic strategies designed to downregulate MEK or IGF1R activity.

3、IGF1R的高表达和激活介导pik3ca、mtor、egfr等靶点的药物耐药

（1）《IGF1R upregulation confers resistance to isoform-specific inhibitors of PI3K in PIK3CA-driven ovarian cancer》

Genomic alterations (GA) in PIK3CA leads to the hyper-activation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway in more than 20% of ovarian cancer (OC) patients. Therefore, PI3K therapies are under clinical evaluation for this subset of patients. Evidently, in clinical trials testing the efficacy of isoform-specific inhibitors of PI3K (PI3Ki), patients having a stable disease eventually relapse, as tumors become resistant to treatment. Hence, there is an urgent clinical need to develop new therapeutic combinations to improve the efficacy of PI3Ki in PIK3CA-driven OC patients. Here we identified the molecular mechanism that limits the efficacy of the beta-sparing PI3Ki, Taselisib (GDC0032), in PIK3CA-mutated OC cell lines (IGROV1 and OAW42) that acquired resistance to GDC0032. By comparing the molecular profile of GDC0032-sensitve and -resistant OC cell lines, we found that AKT/mTOR inhibition is required for GDC0032 efficacy. In resistant cells, the sustained activation of AKT/mTOR was regulated by the upregulation of the insulin growth factor 1 receptor (IGF1R). Knockdown of IGF1R re-sensitized cells to GDC0032 in vitro, and the combination of AEW541, an IGF1R inhibitor, with GDC0032 exhibited potent anti-tumor activity in vitro and in vivo. We further demonstrated that IGF1R regulates tumor cell proliferation in IGROV1 cells, whereas in OAW42, it determines autophagy as well. Overall, our findings suggest that the dual inhibition of PI3K and IGF1R may be considered as a new therapeutic strategy in PIK3CA-driven OC.

（2）《Focal Adhesion- and IGF1R-Dependent Survival and Migratory Pathways Mediate Tumor Resistance to mTORC1/2 Inhibition》

Aberrant signaling by the mammalian target of rapamycin (mTOR) contributes to the devastating features of cancer cells. Thus, mTOR is a critical therapeutic target and catalytic inhibitors are being investigated as anti-cancer drugs. Although mTOR inhibitors initially block cell proliferation, cell viability and migration in some cancer cells are quickly restored. Despite sustained inhibition of mTORC1/2 signaling, Akt, a kinase regulating cell survival and migration, regains phosphorylation at its regulatory sites. Mechanistically, mTORC1/2 inhibition promotes reorganization of integrin/focal adhesion kinase-mediated adhesomes, induction of IGFR/IR-dependent PI3K activation, and Akt phosphorylation via an integrin/FAK/IGFR-dependent process. This resistance mechanism contributes to xenograft tumor cell growth, which is prevented with mTOR plus IGFR inhibitors, supporting this combination as a therapeutic approach for cancers.

（3）《Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer》

Seventeen of the cell lines tested were resistant to gefitinib, whereas 3 cell lines were sensitive. The three remaining cell lines showed intermediate values. Thirteen resistant cell lines were found to be positive for total-IGF-1R expression, while all the sensitive cell lines were negative, resulting in a positive predictive value (PPV) of 81 % for total-IGF-1R to predict resistance. Seven resistant cell lines exhibited high p-IGF-1R levels, whereas all 3 sensitive cell lines were negative for p-IGF-1R, resulting in a PPV of 100 % for p-IGF-1R to predict resistance. Neither a knock-down of IGF-1R expression nor an activation of the IGF1-R pathway through exogenous IGF-1 expression affected gefitinib sensitivity. In primary NSCLC tissues, IGF-1R expression was found to be significantly higher in patients with progressive disease, i.e., showing gefitinib resistance, as compared to those with a complete or partial response.

4、IGF1R抑制剂 Linsitinib 目前有原料药

Linsitinib (OSI-906)是一种选择性IGF-1R抑制剂，在无细胞试验中IC50为35 nM；对InsR抑制作用适中，IC50为75 nM，对Abl，ALK，BTK，EGFR， FGFR1/2，PKA等没有抑制活性。

（1）CAS号：867160-71-2

（2）分子量：421.49

（3）用法用量：每天两次，每次150毫克。（NCT00924989：“150 mg twice daily”）

（4）常见副作用：疲劳、恶心、呕吐、高血糖

5、如果用不上Linsitinib，可以用特拉匹韦这个IGF1R抑制剂的替代药物

《The antiviral drug telaprevir induces cell death by reducing FOXA1 expression in estrogen receptor α (ERα)-positive breast cancer cells》

Previously, we found that telaprevir (Tel), the inhibitor of hepatitis C virus NS3/4A serine protease, reduces estrogen receptor α (ERα) content at the transcriptional level without binding to the receptor, prevents ERα transcriptional activity, and inhibits basal and 17β-estradiol (E2)-dependent cell proliferation in different breast cancer (BC) cell lines. Here, we further characterize the Tel action mechanisms on ERα levels and function, identify a possible molecular target of Tel in BC cells, and evaluate Tel as an antiproliferative agent for BC treatment. Tel-dependent reduction in ERα levels and function depends on a Tel-dependent decrease in FOXA1 levels and activity. The effect of Tel is transduced by the IGF1-R/AKT/FOXA1 pathway, with the antiviral compound interacting with IGF1-R. Tel prevents the proliferation of several BC cell lines, while it does not affect the proliferation of normal nontransformed cell lines, and its antiproliferative effect is correlated with the ratio of FOXA1/IGF1-R expression. In conclusion, Tel interferes with the IGF1-R/AKT/FOXA1 pathway and induces cell death in ERα-expressing BC cells. Thus, we propose that this antiviral could be repurposed for the treatment of ERα-expressing BC.

三、ZNF217扩增升高ERBB3的表达；ERBB3高表达介导抗雌激素治疗的耐药、增强AKT的磷酸化从激活AKT/MTOR

1、《Mechanisms of Endocrine Therapy Resistance in Estrogen Receptor Positive Breast Cancer by ZNF217 and ERBB3 Signaling》

Significantly, ZNF217 directly activates the ERBB3/PI3K/AKT signaling pathway.

Together, my results suggest that Zfp217 overexpression in ER+ breast cancer cells causes endocrine therapy resistance and that growth factor induction via NRG1 induces non-canonical ER binding to the genome and a ZNF217-dependent gene expression signature. I have identified new targets that are regulated by ZNF217 and NRG1 signaling and a possible new role for ZNF217 in regulating the crosstalk between ER+ breast cancer cells and immune cells. This study unraveled new mechanisms of endocrine therapy resistance, unveiling new therapeutic options for ER+ breast cancer patients.

2、《ZNF217, a candidate breast cancer oncogene amplified at 20q13, regulates expression of the ErbB3 receptor tyrosine kinase in breast cancer cells》

On the basis of these findings, we propose that cells bearing amplified ZNF217 genes may be selected for during breast cancer evolution, at least in part due to increases in ErbB3 levels and associated Akt signaling, which would contribute to a pro-survival phenotype of ZNF217-positive breast tumors. Our findings strongly suggest that ErbB3 is one link between ZNF217 and enhanced phospho-Akt levels (Huang et al, 2005).

四、ZNF703扩增激活AKT/MTOR通路造成他莫昔芬耐药

《Luminal Breast Cancer Cell Lines Overexpressing ZNF703 Are Resistant to Tamoxifen through Activation of Akt/mTOR Signaling》

ZNF703 overexpression in MCF-7 breast cancer cells activated the Akt/mTOR signaling pathway, downregulated ERα, and reduced the antitumor effect of tamoxifen. Low-dose tamoxifen did not suppress, but rather, stimulated the growth of cells overexpressing ZNF703. ZNF703 knockdown in MDA-MB-134 and HCC1500 luminal B-type breast cancer cell lines by siRNA significantly decreased survival rates when cells were treated with tamoxifen. Furthermore, targeting ZNF703 with a mTOR inhibitor increased the inhibitory effects of tamoxifen in ZNF703-overexpressing cells.

五、SOX9扩增

1、sox9介导抗雌激素治疗的耐药

《Embryonic transcription factor SOX9 drives breast cancer endocrine resistance》

Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2–ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

2、SOX9表达越高，mtor抑制剂作用越强。

《SOX9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin》
The mTOR inhibitor rapamycin exerts an enhanced antitumoral and anti-metastatic effect on CRC cells expressing high SOX9 levels.

六、YWHAZ扩增

1、YWHAZ介导抗雌激素治疗耐药

《Reversal of endocrine resistance in breast cancer: interrelationships among 14-3-3ζ, FOXM1, and a gene signature associated with mitosis》

This study reveals that 14-3-3ζ is a key predictive marker for risk of failure on endocrine therapy and serves a pivotal role impacting growth factor signaling, and promoting cell survival and resistance to endocrine therapies. Targeting 14-3-3ζ and its coregulated proteins, such as FOXM1, should prove valuable in restoring endocrine sensitivity and reducing risk of breast cancer recurrence.

2、YWHAZ激活PI3K/AKT/MTOR通路

《YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells》

Above of all, our results suggested that YWHAH could promote the proliferation of gastric cancer cells by activating the PI3K/AKT/mTOR signaling pathway.

综上，必用药部分：

1、抗雌激素治疗+卵巢去势治疗必须要做。

2、FGFR1扩增、IGF1R扩增、ZNF217扩增、ZNF703扩增、SOX9扩增、YWHAZ扩增会介导抗雌激素治疗治疗，且IGF1R扩增、ZNF217扩增为所有扩增中扩增倍数最高，因此必须针对治疗。

3、IGF1R扩增可以用Linsitinib；用不上Linsitinib可以用替代药物特拉匹韦。

4、FGFR1扩增可以用FGFR1抑制剂、mtor抑制剂；ZNF217扩增可以用ERBB3抑制剂、AKT抑制剂、mtor抑制剂；ZNF703扩增可以用AKT抑制剂、mtor抑制剂；SOX9扩增可用mtor抑制剂；YWHAZ扩增可用mtor抑制剂。综合考虑，用mtor抑制剂。

5、mtor抑制剂目前已上市的成品药是依维莫司、西罗莫司、白蛋白型西罗莫司这些药。这些药分子量都比较大，入脑效果不好。如果患者有脑转病灶，要用分子量小的mtor抑制剂如Sapanisertib之类的药物，具体见公众号上的《pi3k/akt/mtor通路药物再整理》一文。

6、患者的必用药方案就是：抗雌激素内分泌药+卵巢去势针+Linsitinib或者特拉匹韦+mtor抑制剂。还有其他如mdm2扩增之类的基因突变扩增也应该或者说也可以用药，但考虑到耐受，未必能再增加用药了。

7、mtor抑制剂的副作用比较大，常见副作用有肺炎、高血糖、口腔溃疡等。如患者已有肺炎，最好是先治疗好肺炎至少是有控制肺炎的有力办法再用mtor抑制剂。无肺炎也要在用mtor抑制剂期间一直喝参芪补肺汤+白花蛇舌草注射液等消炎的中成药注射雾化来防治肺炎。勤测血糖。每天用碳酸氢钠水、康复新液漱口防治口腔溃疡。

8、hsp90抑制剂

（1）抑制hsp90会延缓内分泌药的耐药

《HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models》

The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.

（2）IGF1R是hsp90的客户蛋白

《HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review)》

These client proteins include receptor tyrosine kinases (HER2, EGFR, IGF-1R and MET), signaling proteins (AKT and SRC), transcription factors (HIF-1 and TP53) and cell cycle regulatory proteins (CDK4 and CDK6) (46–49).

（3）抑制hsp90可以抑制FGFR1

《Investigation of anticancer activities of STA-9090 (ganetespib) as a second generation HSP90 inhibitor in Saos-2 osteosarcoma cells》

This study has found the down-regulation of the expression levels of oncogenic genes: DKK1, TWIST1, WNT10B, WNT3A, RANK, RANKL, PTH, FGFR1, FGFR2, LTBP2, IL6, TGFβ1, MMP2 and SPARC genes, in STA-9090 treated Saso-2 cells.

（4）抑制hsp90可以抑制akt/mtor

《Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma》

P-mTOR, p70S6K, and AKT demonstrated both time- and dose-dependent decrease upon exposure to PU-H71. To determine if this effect was unique to PU-H71, we also tested other small molecule Hsp90 inhibitors. Treatment with CUDC-305 or ganetespib resulted in similar dose-dependent downregulation of PI3K signaling, confirming the dependence of these proteins on Hsp90 (Fig. 5B).

如果患者不能耐受抗雌激素内分泌药+卵巢去势针+Linsitinib或者特拉匹韦+mtor抑制剂，可以用抗雌激素内分泌药+卵巢去势针+hsp90抑制剂匹米替比 (Pimitespib)。

第二部分其他基因突变扩增

一、MDM2扩增

1、mdm2过表达介导对CDK4/6抑制剂的耐药

《Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review》

Mouse double minute 2 homolog (MDM2) is a protein that negatively regulates p53 activity, in destabilizing and inhibiting cellular senescence.53 Approximately 20%–30% of breast cancer patients show overexpression of MDM2,54 and this overexpression contributes particularly to the progression of HR-positive breast cancer.55 It is reported that CDK4/6 inhibitor-resistant cells have disrupted senescence pathways and insensitivity to the induction of senescence.56 Therefore, interruption of the senescence pathway by MDM2 in a p53-dependent manner may cause resistance to CDK4/6 inhibitors. MDM2 inhibitors activate p53 by disrupting the MDM2-p53 complex.57 A combination of palbociclib with an MDM2 inhibitor (RG7388) produced a synergistic anticancer effect in human liposarcoma.57 In addition, another MDM2 inhibitor (CGM097) has shown synergistic effects in combination with CDK4/6 inhibitors or fulvestrant, abrogating cells that are resistant to CDK4/6 inhibitors, as well as those resistant to endocrine therapy in vitro and in vivo.56 These studies highlight the importance of MDM2 in overcoming resistance to CDK4/6 inhibitors.

2、内分泌治疗联合mdm2抑制剂可治疗ER阳性乳腺癌

《MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer》

We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model.

3、mdm2抑制剂是apg115，替代药物是伊立替康这些药，具体见公众号文章《MDM2抑制剂》。

4、mtor抑制剂很多，但IGF1R抑制剂不多，关键Linsitinib 可及性也比较差。患者的mdm2扩增倍数不低，如果患者用不上IGF1R抑制剂或者IGF1R抑制剂耐药后，可以用mdm2抑制剂，采用抗雌激素内分泌药+卵巢去势针+mtor抑制剂+mdm2抑制剂的治疗策略。

5、比较有意思的是，内分泌药氟维司群也是一种mdm2抑制剂。

《Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs》

The human homologue of mouse double minute 2 (MDM2) is overexpressed in tumors and contributes to tumorigenesis through inhibition of p53 activity. We investigated the effect of the anti-estrogen fulvestrant on MDM2 expression and sensitivity of estrogen receptor positive human breast cancer cell lines to chemotherapeutics. Fulvestrant down-regulated MDM2 through increased protein turnover. Fulvestrant blocked estrogen-dependent up-regulation of MDM2 and decreased basal expression of MDM2 in the absence of estradiol. As combinations of fulvestrant with doxorubicin, etoposide or paclitaxel were synergistic, altering cell cycle distribution and increasing cell death, this provides rationale for testing combinatorial chemotherapy with fulvestrant as a novel therapeutic strategy for patients with advanced breast cancer.

二、SRSF2扩增

SRSF2表达低，HSV-1溶瘤病毒疗效才好；top1抑制剂可以抑制SRSF2的磷酸化

《Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells》

Oncolytic human herpes simplex virus type 1 (HSV-1) shows promising treatment efficacy in late-stage clinical trials. The anticancer activity of oncolytic viruses relies on deregulated pathways in cancer cells, which make them permissive to oncolysis. To identify pathways that restrict HSV-1 KM100-mediated oncolysis, this study used a pooled genome-wide short hairpin RNA library and found that depletion of the splicing factor arginine-rich splicing factor 2 (SRSF2) leads to enhanced cytotoxicity of breast cancer cells by KM100. Serine/arginine-rich (SR) proteins are a family of RNA-binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing. Further characterization showed that KM100 infection of HS578T cells under conditions of low SRSF2 leads to pronounced apoptosis without a corresponding increase in virus replication. As DNA topoisomerase I inhibitors can limit the phosphorylation of SRSF2, we combined a topoisomerase I inhibitor chemotherapeutic with KM100 and observed synergistic anticancer effect in vitro and prolonged survival of tumor-bearing mice in vivo.

TOP1抑制剂伊立替康同时也是mdm2抑制剂，又能抑制SRSF2磷酸化，因此将来患者在IGF1R靶点无药可用后，可更换靶点治疗，用伊立替康同时针对治疗mdm2和srsf2（或许还有top1）

三、CD79B扩增

针对CD79B目前有ADC药物 Polivy（polatuzumab vedotin, 泊洛妥珠单抗）。Polivy前端是靶向CD79b的单克隆抗体，后端链接细胞毒药物MMAE。药物载药比DAR为3-4。

四、BRD4扩增

1、抑制BRD4可延缓乳腺癌内分泌治疗的耐药

《BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer》

Breast cancer is the most commonly occurring malignancy in women and the second most common cause of cancer-related deaths. ER+ breast cancer constitutes approximately 70% of all breast cancer cases. The standard of care for ER+ breast cancer involves estrogen antagonists such as tamoxifen or fulvestrant in combination with CDK4/6 inhibitors such as palbociclib. However, these treatments are often not curative, with disease recurrence and metastasis being responsible for patient mortality. Overexpression of the epigenetic regulator, BRD4, has been shown to be a negative prognostic indicator in breast cancer, and BET family inhibitors such as ARV-825 and ABBV-744 have garnered interest for their potential to improve and prolong the response to current therapeutic strategies. The current work examined the potential of utilizing ARV-825 and ABBV-744 to increase the effectiveness of tamoxifen or fulvestrant plus palbociclib. ARV-825 was effective in both p53 wild-type (WT) breast tumor cells and in cells lacking functional p53 either alone or in combination with tamoxifen, while the effectiveness of ABBV-744 was limited to fulvestrant plus palbociclib in p53 WT cells. These differential effects may be related to the capacity to suppress c-Myc, a downstream target of BRD4.

2、BRD4可用替代药物氮卓斯汀

《Structure investigation, enrichment analysis and structure-based repurposing of FDA-approved drugs as inhibitors of BET-BRD4》

We report herein detailed structural insights into the ligand recognition modes guiding bromodomain selectivity, enrichment analysis and docking-based database screening for the identification of the FDA-approved drugs that have potential to be the human BRD4 inhibitors. Analysis of multiple X-ray structures prevailed that the lysine-recognition sites are highly conserved, and apparently, the dynamic ZA loop guides the specific ligand-recognition. The protein-ligand interaction profiling revealed that both BRD2 and BRD4 shared hydrophobic interaction of bound ligands with PRO-98/PRO-82, PHE-99/PHE-83, LEU-108/LEU-92 and direct H-bonding with ASN-156/ASN-140 (BRD2/BRD4), while on the other hand the water-mediated H-bonding of bound ligands with PRO-82, GLN-85, PRO-86, VAL-87, ASP-88, LEU-92, TYR-97 and MET-132, and aromatic π-π stacking with TRP-81 prevailed as unique interaction in BRD4, and were not observed in BRD2. Subsequently, through ROC curve analysis, the best enrichment was found with PDB-ID 4QZS of BRD4 structures. Finally, through docking-based database screening study, we found that several drugs have better binding affinity than the control candidate lead (+)-JQ1 (Binding affinity = -7.9 kcal/mol), a well-known BRD4 inhibitor. Among the top-ranked drugs, azelastine, a selective histamine H1 receptor antagonist, showed the best binding affinity of -9.3 kcal/mol and showed interactions with several key residues of the acetyl lysine binding pocket. Azelastine may serve as a promising template for further medicinal chemistry. These insights may serve as basis for structure-based drug design, drug repurposing and the discovery of novel BRD4 inhibitors.

第三部分 ICB免疫治疗

影响ICB免疫疗效的因素很多，基因检测报告只反映了部分内容，还要结合患者的肿瘤免疫微环境的免疫组化检测、肿瘤相关蛋白全景检测、患者一些诸如NLR、白蛋白等血液指标等综合考虑研判。

从群体数据来说，HR阳性her2阴性乳腺癌用icb免疫治疗对PFS和OS都没有益处

1、内分泌药联合icb免疫治疗临床活性与内分泌单药相当

《Phase II Study Combining Pembrolizumab with Aromatase Inhibitor in Patients with Metastatic Hormone Receptor Positive Breast Cancer》

This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2- MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3-46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone.

2、化疗联合icb免疫治疗对对PFS和OS都没有益处

《Efficacy and safety of a combination treatment of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis》

In patients with metastatic Human Epidermal Growth Factor Receptor 2 (HER2) negative breast cancer, pooled therapy showed no benefit for PFS (HR = 0.80, 95% CI: 0.50-1.28) and OS (HR = 0.87, 95% CI: 0.48-1.58).

对于患者个体来说

图片

一、TMB值高，是个ICB的有利因素

二、MDM2扩增是ICB的不利因素

A pancancer analysis of impact of MDM2/MDM4 on immune checkpoint blockade (ICB)

MDM2/MDM4 are implicated in hyperprogression after immune checkpoint blockade (ICB).

When all tumors were considered, MDM2 amp4, 6 and 8 significantly associated with shortened OS (amp4: HR 1.31; amp6: HR 1.31; amp8: 1.29, all p<0.0001)