A pathological complete response to neoadjuvant treatment in LARC patients usually indicates a good prognosis, but the proportion is quite small. In the era of TME surgery, radiotherapy has not shown a conclusive benefit of overall survival but is associated with safety concern. Given that the local recurrence rate for TME alone is less than 10%, the benefit of neoadjuvant radiotherapy should be carefully weighed against potential negative effects . Therefore, strategies to improve tumor response and alleviate side effects can alter the present treatment algorithm by maximizing the proportion of patients eligible for less approach.
The essential goal of neoadjuvant treatment for LARC is to increase the likelihood of R0 resection and to eliminate micrometastatic lesion. The idea of neoadjuvant chemotherapy without radiation has not been assessed in resectable rectal cancer until recently because of the risk of disease progression and overtreating patients. Neoadjuvant chemotherapy without radiotherapy has been investigated for the treatment of LARC in several small trials. And promising results were observed for lower toxicity than observed in patients who received chemoradiotherapy, indicating it as a further option for patients unable or unwilling to receive radiotherapy . For example, Deng et al. showed perioperative mFOLFOX6 alone had a similar downstaging rate as fluorouracil-radiotherapy, with less toxicity and fewer postoperative complications. However, the incidence of pCR rate was only 6.6% . Consequently, the identification of a good biological marker for predicting pCR to neoadjuvant chemotherapy is urgently needed.
Chemotherapy regimen containing oxaliplatin is commonly used in the management of rectal cancer. Approximately 50% of patients benefit from treatment with oxaliplatin . Mutations of the BRCA1 (breast cancer gene 1) and BRCA2 (breast cancer gene 2) genes are considered biomarkers of genomic instability and DNA damage repair deficiency and used as predictive biomarkers of response to platinum-based agents and PARP inhibitors . The BRCA1 and BRCA2 genes confer increased susceptibility to ovarian and breast cancers. However, the risk of rectal cancers patients associated with BRCA mutations remains controversial . And the incidence of BRCA mutations in rectal cancer has not been previously reported. Accumulating evidence suggests significant effect of cisplatin or oxaliplatin in BRCA associated malignancies. The survival of patients with BRCA-associated hereditary ovarian cancers is longer than that of nonhereditary cancer patients . However, Kotsopoulos et al. reported that BRCA mutations only reflected a higher initial sensitivity of BRCA carriers to chemotherapy, but not predicted long-term survival . In breast cancer, neoadjuvant chemotherapy resulted in pathological complete response of 83% in 12 cases of BRCA1 carrier patients . And pathological complete responses to oxaliplatin or cisplatin have also been reported in pancreatic adenocarcinoma with germline BRCA2 mutations . However, case of somatic BRCA mutant rectal cancer has not been reported in the literature before. Therefore, we felt that it was critical to describe this case of a significant clinical response to neoajuvant oxaliplatin-based therapy in a LARC patient who carried a BRCA2 mutation. During the review process of the article, Aixa E. et al. also reported a case of a young man with LARC and a germline BRCA1 pathogenic variant. The patient was treated with neoadjuvant FOLFOX chemotherapy and radiotherapy, and also experienced a pCR . This is a further confirmation of our study about the association of BRCA mutation with an excellent response of oxaliplatin-based chemotherapy regimen in rectal cancer. Although the BRCA2 mutation may present in only a minority of rectal cancers, the excellent response of these group to oxaliplatin-based chemotherapy regimens indicates the BRCA status might provide an attractive predictive marker for the efficiency of oxaliplatin in the treatment of LARC.
Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. And mismatch repair-deficiency or MSI has recently been demonstrated to predict clinical benefit to immune checkpoint inhibition therapy in metastatic colorectal cancer. However, patients without MSI may also benefit from Immune checkpoint inhibition. A recent NGS study found that increased mutational load was significantly correlated with MSI yet colorectal tumors with the highest mutational burden that were distinct from MSI tumors all harbored POLE mutations . The characterization of mutational load in colorectal cancer (CRC) may serve as a better marker than MSI status in determining a hypermutant profile that could predict clinical benefit from immunotherapy . Another interesting point in our patient is high mutational burdens without MSI. Although we have notdemonstrated a direct link between high mutational burdens and BRCA somatic mutation, our observations are consistent with those recently reported for triple-negative breast cancers and serous ovarian cancer, where higher neoantigen loads observed in BRCA1/2-mutated tumors compared to DNA repair–proficient tumors [19, 20]. Considering the higher mutational load and unique mutational signature, these features provide a rationale for exploring the utility of checkpoint inhibitors in BRCA2-mutated rectal tumors. Due to the low MSI rate (15%) in colorectal cancers, BRCA mutation testing might be considered when the diagnosis of rectal cancer is found.
In conclusion, the current study demonstrated a rare occurrence of complete pathological response in a BRCA2-mutuant locally advanced rectal cancer patient treated with neoadjuvant FOLFOX chemotherapy. This case suggests an association of BRCA2 mutation with high mutation loads and an excellent response of oxaliplatin-based chemotherapy regimen for LARC. Our findings encourage further studies to analyze BRCA mutations in patients with LARC, especially for those patients unable or unwilling to receive radiotherapy.