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The potential of circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy decision making in locally advanced rectal cancer (LARC)
Jeanne Tie, Joshua Cohen, Yuxuan Wang, Lu Li, Isaac Kinde, Hany Elsaleh, et al.
Editorial comment from Dr Cremolini
The potential interest of the quantitative and qualitative evaluation of cfDNA in liquid biopsy is a field of interest in many solid malignancies. With regard to colorectal cancer, the potential application of liquid biopsy has been mainly focused on the early identification of mechanisms of acquired resistance to anti-EGFRs, but in spite of interesting and promising proof-of-concept findings, their way toward clinical practice has been halted by the lack of high levels of evidence. These works, commented in the poster discussion session, highlight another potential application of cfDNA in colorectal cancer, focusing on its prognostic impact in locally advanced rectal cancer and in patients undergoing radical resection of their liver metastases. The detection of cfDNA after neoadjuvant chemoradiotherapy or after rectal surgery predicts relapse with high specificity, independently of the exposure to adjuvant chemotherapy and the histopathological complete response. Similarly, the detection of cfDNA after liver metastases’ surgical resection predicts both relapse free and overall survival. These findings continue and corroborate previous results achieved by Tie et al. (Sci Transl Med 2016), evidencing the ability of cfDNA in unveiling the minimal residual disease following resection of stage II colorectal cancer. A currently ongoing clinical trial in stage II resected patients (where tools able to estimate the risk of relapse are extremely needed) incorporates results of cfDNA as decision drivers to administer or not adjuvant chemotherapy.
The optimal approach to adjuvant chemotherapy for rectal cancer is keenly debated. Routine practice and clinical guidelines vary widely. After pre-operative chemoradiation (CRT), a pathologic complete response (pCR) or nodal involvement (pN+) are prognostic markers that can guide clinical decision-making, but markers that better define the patients (pts) that are likely or unlikely to benefit from chemotherapy are urgently needed. We investigated the potential role of ctDNA as a biomarker to guide therapy.
We conducted a prospective, multi-centre study in pts with LARC (T3/T4 and/or N+) planned for CRT and curative resection. Serial plasma samples were collected pre-CRT, post-CRT, and 4-10 weeks after surgery. Somatic mutations in individual pts’ tumor were identified via sequencing of 15 genes commonly mutated in colorectal cancers. We then designed personalized assays to quantify ctDNA in plasma samples. Pts received adjuvant therapy at clinician discretion.
200 pts were enrolled between Apr-2012 and Dec-2015. Median age was 62 years (range 28-86), 67% were male and 159 pts had pre-CRT and post-op ctDNA samples available for analysis. Of these, 122 (77%) pts had detectable ctDNA prior to therapy. After surgery, 19 pts had detectable ctDNA and 11 of these 19 (58%) have recurred during a median follow up of 22 months. Recurrence occurred in only 12 of 140 (8.6%) with negative ctDNA (HR 12, p < 0.001). One hundred and two (64%) pts received adjuvant chemotherapy. Post-op ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy (chemo: HR 10, p < 0.001; no chemo: HR 16, p < 0.001). Thirty-four pts (21%) achieved a pCR, 43 (27%) had pN+ disease. pCR (vs non-pCR) was associated with a trend for lower recurrence risk (HR 0.31, p = 0.089) and pN+ (vs pN0) with a higher recurrence risk (HR 4.2, p < 0.001). ctDNA detection remained predictive of recurrence among pts with a pCR (HR 14, p = 0.014) or with pN+ disease (HR 11, p < 0.001).
Post-op ctDNA analysis stratifies pts with LARC into very high and low risk groups. ctDNA analysis remains strongly predictive of recurrence among pts with both lower risk (pCR) and higher risk (pN+) disease.
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