HER2阳性结直肠癌研究进展

表皮生长因子受体2（HER2）是肿瘤发生、发展过程中的癌基因,在7%的结直肠癌患者中表达,与表皮生长因子受体单克隆抗体的耐药相关。随着CRC治疗困境的出现,以及靶向HER2为乳腺癌、胃癌患者带来生存获益,HER2在CRC中的意义及抗HER2治疗的预后价值被广泛关注,围绕HER2阳性CRC的临床研究亦不断开展。目前,CRC中HER2阳性的诊断标准已逐渐统一,HER2靶向治疗如单克隆抗体、酪氨酸激酶抑制剂、抗体-药物耦联物及HER2相关免疫治疗的单独或联合治疗策略在HER2阳性CRC中显示出较好的疗效,能为患者带来生存获益,本文就此方面的研究进展作一综述。     

HER2 as a Predictive Biomarker and Treatment Target in Colorectal Cancer

The prognosis of metastatic colorectal cancer (mCRC) is poor. Cetuximab and panitumumab, 2 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs), improve the overall survival of patients with RAS wild-type mCRC. However, not all patients with RAS wild-type mCRC will respond to anti-EGFR mAbs. Several retrospective trials suggest that human epidermal growth factor receptor 2 (HER2) amplification could be a predictive biomarker of resistance to anti-EGFR mAbs in patients with metastatic RAS and RAF wild-type mCRC. Dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab has shown promising preliminary anti-tumoral efficacy in RAS wild-type mCRC. Although these findings need to be confirmed in randomized trials, the data strongly support that HER2 is an actionable gene in CRC and provide the scientific rationale to test HER2 status on a routine basis in this disease. In this review, we discuss the predictive value of HER2 activation in CRC as well as its potential role as a treatment target.     

Clinicopathologic Characteristics of HER2-positive Metastatic Colorectal Cancer and Detection of HER2 in Plasma Circulating Tumor DNA

BackgroundTherapy targeting human epidermal growth factor receptor 2 (HER2, also known as ERBB2) is an effective approach for HER2-positive metastatic colorectal cancer (mCRC). HER2 status is typically determined using immunohistochemistry and fluorescence in situ hybridization. Circulating tumor DNA (ctDNA) enables noninvasive detection of gene mutations and copy number alterations including HER2 amplification.Materials and MethodsWe screened 351 patients with mCRC and studied the clinicopathologic characteristics of HER2-positive mCRC. HER2 expression in tumor samples measured with immunohistochemistry and fluorescence in situ hybridization was compared with HER2 copy number variation in plasma ctDNA detected by targeted sequence capture covering exons of 170 genes. We also examined the correlation between changes in tumor burden in ctDNA and antitumor response by imaging evaluation during the treatment course.ResultsPositive HER2 status was observed in 12 (3.4%) patients (7 males and 5 females), with a median age of 56 years. The HER2 concordance rate between tumor samples and ctDNA was 66.7% (20/30). Changes in tumor burden in ctDNA during the treatment course correlated with responses on imaging.ConclusionsDetection of HER2 copy number variation in ctDNA may be an alternative option for noninvasive determination of HER2 status. Tumor burden changes in ctDNA were consistent with imaging evaluation.     

晚期结直肠癌三线及三线以上治疗的研究进展

结直肠癌是消化道最常见恶性肿瘤之一,大多数结直肠癌患者就诊时已属中晚期,失去手术机会.化疗及分子靶向治疗为结直肠癌的有效治疗手段.目前,晚期结直肠癌的三线治疗尚无标准方案.全文对晚期结直肠癌的三线及三线以上治疗相关的临床研究进行了简要分析.     

Novel Targets in Advanced Colorectal Cancer

Purpose of Review

Although current guidelines suggest only testing for RAS and BRAF mutations as well as MMR deficiency in metastatic colon cancer, there are many other promising therapeutic targets that are being studied. We aim to review the recent literature and evidence behind some of these novel targets.

Recent Findings

Many of these targets such as NTRK, ROS, ALK, and HER2 are being studied in current clinical trials and hold great potential in changing the treatment landscape for metastatic colorectal cancer.

Summary

Current molecular testing algorithms may need to be expanded to allow better target discovery and for patients to benefit from more therapeutic options.

     

Prognostic Value and Molecular Landscape of HER2 Low-Expressing Metastatic Colorectal Cancer

BackgroundThe prognostic value and molecular landscape of human epidermal growth factor receptor 2 (HER2) low-expressing (HER2-L) metastatic colorectal cancer (mCRC) remain unclear.Patients and MethodsThis study enrolled patients with mCRC who had undergone surgical resection of primary tumor. Using the specimen, we evaluated HER2 expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 positivity was defined as follows: HER2 positivity (HER2-Pos) as IHC 3 + or IHC 2+/FISH positive, HER2-L as IHC 2+/FISH negative or IHC 1+, and HER2 negativity (HER2-Neg) as IHC 0+. Gene alterations were determined by next-generation sequencing.ResultsBetween 2005 and 2015, a total of 370 patients were analyzed, comprising 15 patients (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg disease. The clinicopathologic characteristics among groups had no differences. HER2-L had a significantly higher proportion of coaltered RAS mutation than HER2-Pos (P = .037). With a median follow-up of 101.8 months, HER2-L had a significantly better median overall survival than HER2-Pos (P = .029) (18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 patients harboring wild-type RAS and receiving anti-EGFR antibody therapy, HER2-L had a better median progression-free survival tendency than HER2-Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.1 in HER2-Neg (P = .036).ConclusionHER2-L mCRC showed a better prognosis than HER2-Pos mCRC, and it is similar to HER2-Neg mCRC. Hence, HER2-L mCRC might have different biologic behavior in terms of prognostic value and molecular landscape of mCRC, suggesting the possibility of implementation of HER2-guided clinical development against HER2-expressing mCRC.     

Evolving Treatment of Advanced Colorectal Cancer

Advances in colorectal cancer treatment have led to improved outcomes for patients. A number of cytotoxic agents, alone and in combination, have shown activity. The addition of the newer, so-called “targeted” agents to standard chemotherapy drugs and regimens has also modestly improved outcomes. Progress in our knowledge and understanding of molecular pathways has led to the identification of markers critical in determining response or nonresponse to some of the targeted agents. This review discusses the available therapies in metastatic colorectal cancer and describes some of the molecular markers implicated in activity and resistance to current targeted therapies.     

Dual HER2 Targeted Therapy With Pyrotinib and Trastuzumab in Refractory HER2 Positive Metastatic Colorectal Cancer: A Result From HER2-FUSCC-G Study

BackgroundDual-HER2 targeted therapy has led to a promising antitumor effect in HER2 positive cancers including gastrointestinal cancer. The present data focus on patients with HER2 positive colorectal cancer who received pyrotinib and trastuzumab after failure to standard second-line treatment.MethodsPatients diagnosed of HER2 positive refractory or metastatic colorectal cancer were enrolled to receive trastuzumab in combination with pyrotinib as third-line and beyond therapy. Trastuzumab was given as a loading dose at 8 mg/kg followed by 6mg/kg once every 3 weeks, and oral pyrotinib as 400 mg per day until progression. ORR was set as the primary endpoint. PFS and OS were set as a secondary endpoints. This trial is registered with Clinical Trial.gov, NCT04960943, and is ongoing.ResultsBetween February 2020 to December 2021, 16 patients including 14 with RAS wild-type status were enrolled in this cohort. ORR was 50.0% in the overall population, and 57.1% in RAS wild-type patients. At a median follow-up of 11.2 months, median PFS and OS were 7.53 and 16.8 months, respectively. The RAS/BRAF wild-type patients had prolonged survival (PFS: 7.53 vs. 1.63 months, P = .02; OS: NR vs.4.13 months, P = .001) compared with RAS/BRAF mutant patients. The most common treatment-emergent adverse event (TEAE) reported is diarrhea. Five (31.3%) patients reported grade 3 TEAEs, and no death was reported.ConclusionsTrastuzumab in combination with pyrotinib demonstrated encouraging antitumor activity that translated to prolonged survival benefit in HER2 positive refractory or mCRC patients who are RAS wild-type with acceptable tolerance.     

伊立替康联合卡培他滨二线治疗晚期结直肠癌

目的:观察伊立替康(开普拓,CPT-11)联合卡培他滨(希罗达)治疗一线化疗失败的晚期结直肠癌的疗效及安全性。方法:72例晚期结直肠癌患者,均为经氟脲嘧啶(5-FU)、亚叶酸钙(LV)以及奥沙利铂等药物一线化疗失败者,行CPT-11联合卡培他滨方案治疗,CPT-11180mg/m2,静脉滴注90min,第1天;卡培他滨1250mg/m2,2次/天,第1～14天口服,休息7天,21天为1个疗程,每例患者至少接受4个疗程。按照WHO实体瘤近期客观疗效评定标准进行评价。结果:72例均可评价疗效及不良反应。完全缓解(CR)为0,部分缓解(PR)16例,有效率(RR)22.2%(16/72),稳定(SD)44例,进展(PD)12例。中位疾病进展时间7.6个月(6～28个月),中位生存期12.8个月。不良反应主要为恶心、呕吐、厌食、白细胞减少、脱发和延迟性腹泻,多为Ⅰ～Ⅱ度。结论:伊立替康联合卡培他滨二线治疗晚期结直肠癌,用药方便、疗效肯定,不良反应低,可广泛用于临床。     

Prognostic and Predictive Value of HER2 Amplification in Patients With Metastatic Colorectal Cancer

Purpose

To evaluate a prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer (mCRC).

沙利度胺联合方案治疗晚期结直肠癌临床观察

目的探讨沙利度胺联合方案治疗晚期结直肠癌的疗效及安全性。方法45例经病理证实的晚期结直肠癌患者随机分为治疗组和对照组。治疗组22例接受沙利度胺联合卡培他滨和奥沙利铂治疗,对照组23例仅接受卡培他滨联合奥沙利铂治疗。3周为1周期,至少2周期化疗,评价疗效。研究无进展生存期(PFS)、客观有效率（ORR）、疾病控制率（DCR）,并观察安全性及不良反应。结果治疗组DCR为68.2%,而对照组为43.5%,差异有统计学意义（P＜0.05）, PFS 、ORR及患者生活质量两组间差异无统计学意义(P＞0.05)。结论沙利度胺联合方案治疗晚期结直肠癌可显著提高疾病控制率且耐受性良好,值得临床进一步研究。     

The Role of Liver-Directed Therapy in Metastatic Colorectal Cancer

Purpose of Review

Colorectal cancer liver metastasis is a major clinical problem, and surgical resection is the only potentially curative treatment. We seek to discuss various liver-directed therapy modalities and explore their roles in the evolving realm of treatment strategies for metastatic colorectal cancer.

Recent Findings

Clinical outcomes for patients with colorectal cancer liver metastases have improved as more patients undergo potentially curative resection and as the armamentarium of systemic treatment and liver-directed therapies continues to expand. Liver-directed therapies have been developed as adjuncts to improve resectability, employed in the adjuvant setting to potentially reduce local recurrence rates, and utilized in the palliative setting with the aim to improve overall survival.

Summary

Ongoing research is expected to validate the role of these evolving therapeutic options, and determine how best to sequence and when to apply these therapies.

     

晚期转移性结直肠癌内科治疗进展

结直肠癌的发病率在世界各国尤其是发达国家中明显上升,近20年来在我国尤其是在大城市,结直肠癌的发病率已占消化道癌的第二位。2000年,世界范围内,结直肠癌新发病例940000,其中死亡254000例。目前,由于结直肠癌的诊断手段、手术技术及支持治疗的进步,Ⅰ、Ⅱ、Ⅲ期结直肠癌患者的5年生存率明显升高,但对于已经出现转移的结直肠癌患者,5年生存率仍然很低。复发转移性结直肠癌的主要治疗手段是化疗,1996年后伊立替康、奥沙利铂与卡陪他滨相继问世,新一代药物可使中位生存时间延长到20个月,单克隆抗体与化疗联合又使中位生存时间延长到24个月左右,这在晚期实体癌的化疗史上是了不起的进步。     

The Role of Hypoxic Stop-Flow Perfusion and High Dose Chemotherapy in the Treatment of Regionally Advanced Colorectal Cancer

Abstract

The primary or secondary forms of colorectal cancers involving local structures or spreading in the abdomen or pelvic area without extra-regional metastases are identified as regionally advanced colorectal cancers (RACRC). They are unresectable and thus radiotherapy and chemotherapy are the fundamental treatment methods. However, these regimens have failed to check the diffusion of tumor satisfactorily in most forms of RACRC.

The abdominal and pelvic regions can be isolated from corporal circulation by temporary occlusion of the aorta and cava and perfused with high doses of chemotherapeutic drugs. The hypoxic abdominal or pelvic stop-flow method for delivering high-dose antiblastic agents to these body districts to avoid toxicity by chemofiltration has been suggested. This study examines the possibility of using this method to treat various forms of RACRC.