The treatment paradigm of right-sided metastatic colon cancer: harboring BRAF mutation makes the difference

Abstract

Purpose: BRAF mutations represents the main negative prognostic factor for metastatic colorectal cancer. Right-sided colon cancer (RCC) reported a higher prevalence of BRAF mutations than leftsided, hence the different response to anti-EGFR targeted therapy in first line setting. Methods: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. Results: We identified 207 advanced RCC patients: 20.3% BRAF-mutant and 79.7% BRAF wild-type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p=0.016), undifferentiated (71.4% v 44.0%, p=0.004), KRAS wt (90.5% v 38.2%, p<0.001) and MSI-H (41.7% v 16.2%, p= 0.019) tumors, with synchronous (52.4% v 31.5%, p=0.018) and peritoneal metastases ( 38.1% v 22.4%, p=0.003).Median overall survival (OS) was 16 vs 27 months in BRAF-mutant and BRAF wt (P = 0.020). In first line setting, BRAF-mutant showed a 2y OS of 80% in clinical trials, 32% in anti-VEGF, 14% in anti-EGFR and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted-therapy administered. However, survival difference was statistically significant in the anti-EGFR treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively). Conclusions: Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore, the anti-EGFR should not to be excluded in all advanced RCC but considered on a case-by-case basis.

Evaluation of Prognostic Factors for Survival in Transverse Colon Cancer

“…According to other studies on metastatic colorectal cancer (mCRC) [3,[43][44][45], TCC patients harboring BRAFV600E mutation showed a significantly worse OS than BRAF wild type. (Table 2) As we know by literature, BRAF mutation represents the main negative prognostic factor for mCRC, regardless of sidedness and other molecular factors [43,44] but this negative effect on prognosis seems to be more evident in RCC rather than LCC [3,45].…”

Incidence and prognostic factors in patents (pts) with mutant BRAF (mBRAF) metastatic colorectal cancer (mCRC) in Russia.

“…К сожалению, объемы одной статьи не позволяют оценить, насколько удаление метастазов при мутации в гене BRAF является эффективной опцией, это требует отдельного анализа. В то же время в современных работах при участии пациентов клинических исследований расширение доступа к терапии комбинацией BRAFингибиторов с антиEGFR-антителами во второй и последующих линиях позволяет достигнуть 2-летней общей выживаемости на уровне 80% [24]. Так, в рандомизированном исследовании III фазы BEACON при сравнении комбинации BRAF-ингибитора (энкорафениба), антиEGFR-антитела (цетуксимаба) с или без MEK-ингибитора (биниметиниба) и комбинации иринотекана или режима FOLFIRI с цетуксимабом во 2-3-й линии лечения больных метастатическим раком толстой кишки с мутацией в гене BRAF применение тройной или двойной комбинации таргетных препаратов привело к увеличению в 10 раз частоты объективных эффектов (26,8 и 19,5% соответственно) Применение комбинации BRAF, MEK-ингибитора и антиEGFR-антитела также привело к снижению риска смерти на 40% (ОР 0,6, 95% ДИ 0,47-0,75, р < 0,0001), что вылилось и в увеличение медианы продолжительности жизни до 9,3 мес.…”

The Role of BRAF in Metastatic Colorectal Carcinoma–Past, Present, and Future

“…The addition of panitumumab to modified FOLFOXIRI (mFOLFOXIRI), resulted in significantly higher overall response rate (ORR) as compared to mFOLFOXIRI alone (OR 21, 95% CI 1.5-293.2) [92]. Recent findings suggest that further stratifications by other predictive factors like tumor sidedness, might reveal patient subsets where the BRAF mutation status is predictive for treatment response to anti-EGFR treatment [93].…”