Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia.
Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia; Basil Hetzel Institute, Woodville, Australia; University of Sydney, Sydney, Australia.
Clin Colorectal Cancer. 2019 Jun;18(2):141-148. doi: 10.1016/j.clcc.2018.12.002. Epub 2019 Jan 3.
For metastatic colorectal cancer, previous reports have described differences in biology and outcome, including response to biologic agents, based on whether the primary tumor is right- or left-sided. We explored the molecular markers from the AGITG MAX trial.
The AGITG MAX trial was a randomized study comparing capecitabine versus capecitabine + bevacizumab versus capecitabine + bevacizumab + mitomycin C as first-line therapy in advanced colorectal cancer. Patients were classified as having right-sided (caecum to transverse colon) or left-sided (descending colon to rectum) disease according to anatomic location. Baseline characteristics and previously described molecular profiles were compared by side of primary tumor. Survival outcomes were analyzed by the Kaplan-Meier approach and proportional hazards regression modeling.
Among the 471 patients, the location of primary tumor was known in 440 patients (93%). Molecular profile was known in 298 patients (63%). Twenty-eight percent had right-sided primary tumors. Major differences between right and left are as follows: female 49% versus 33% (P < .01), BRAF mutant 16% versus 3.5% (P ≤ .001), and phosphatase and tensin homolog (PTEN) loss 27.6% versus 53% (P = .01). There were no differences in RAS mutation, PIK3CA mutation, or high versus low expression of assessed angiogenic markers. Right-sided primary lesion predicted a poor outcome for median overall survival: right-sided disease 13.2 months versus left-sided disease 20 months (P = .001; hazard ratio [HR] = 0.67; 95% confidence interval [CI], 0.53-0.85), but not for progression-free survival (HR 0.96; 95% CI, 0.78-1.20). The relative treatment effect did not differ significantly according to location of primary tumor: right primary tumor HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.82 (95% CI, 0.54-1.22), and left primary HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.51 (95% CI, 0.4-0.63) (interaction P = .10).
There are more negative prognostic factors in patients with right-sided primary tumors, in particular high BRAF mutations, and these patients have inferior overall survival compared to those with a left-sided primary tumor. There was no suggestion that side of primary site had any impact on bevacizumab effect on progression-free survival.
对于转移性结直肠癌，既往的报告描述了生物学和预后的差异，包括对生物制剂的反应，这取决于原发肿瘤是右侧还是左侧。我们研究了 AGITG MAX 试验中的分子标志物。
AGITG MAX 试验是一项随机研究，比较卡培他滨与卡培他滨+贝伐珠单抗与卡培他滨+贝伐珠单抗+丝裂霉素 C 作为晚期结直肠癌的一线治疗。根据解剖位置，将患者分为右侧（盲肠至横结肠）或左侧（降结肠至直肠）疾病。通过原发肿瘤侧比较基线特征和先前描述的分子特征。采用 Kaplan-Meier 法和比例风险回归模型分析生存结果。
在 471 例患者中，440 例（93%）患者的原发肿瘤位置已知。298 例（63%）患者的分子特征已知。28%的患者为右侧原发性肿瘤。右侧和左侧之间存在以下主要差异：女性 49%对 33%（P<.01），BRAF 突变 16%对 3.5%（P≤.001），磷酸酶和张力蛋白同源物（PTEN）缺失 27.6%对 53%（P=.01）。RAS 突变、PIK3CA 突变或评估的血管生成标志物的高表达与低表达之间无差异。右侧原发性病变对中位总生存期的不良预后预测：右侧疾病 13.2 个月，左侧疾病 20 个月（P=.001；危险比[HR]0.67；95%置信区间[CI]0.53-0.85），但对无进展生存期无影响（HR 0.96；95% CI 0.78-1.20）。根据原发肿瘤的位置，治疗效果的相对差异并不显著：右侧原发肿瘤 HR（贝伐珠单抗组与卡培他滨单药组）为 0.82（95% CI 0.54-1.22），左侧原发肿瘤 HR（贝伐珠单抗组与卡培他滨单药组）为 0.51（95% CI 0.4-0.63）（交互 P=.10）。
右侧原发性肿瘤患者有更多的负预后因素，尤其是高 BRAF 突变，与左侧原发性肿瘤患者相比，这些患者的总生存期较差。没有迹象表明原发肿瘤侧对贝伐珠单抗在无进展生存期方面的影响有任何影响。
