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CRCs can often be sporadic; however, hereditary cancer syndromes are also common in this entity. Sporadic CRC is the most common form, accounting for ∼65% to 85% of cases. Well-defined hereditary cancer syndromes that increase a person’s predisposition for CRC include Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer), accounting for 3% to 8% of cases, familial adenomatous polyposis, accounting for ∼1%, and MUTYH-associated polyposis, accounting for < 1% of cases.
We present the case of a young man who presented with locally advanced rectal cancer and was found to have a germline BRCA1 pathogenic variant. Knowledge of this variant allowed us to add oxaliplatin treatment in the neoadjuvant setting. A complete pathologic response was noted at surgery. A detailed account of this and other reported cases and studies highlighting the possible association of BRCA1/2 and CRC is presented. The patient provided written informed consent to report his case.
A 33-year-old previously healthy white man described a 3- to 4-month history of painless, intermittent bright red blood from the rectum. He had attributed it to hemorrhoids and had not sought help initially. However, owing to the persistence of the symptoms and the insistence of his family, he underwent a complete gastrointestinal evaluation. A colonoscopy showed 2 polypoid masses in the rectum, which were biopsied. A multilobulated large lesion and a semipedunculated polyp were located ∼7.5 cm and ∼7 cm from the anal verge, respectively. The pathologic features of the larger lesion were consistent with moderately differentiated adenocarcinoma with gland formation and focal gland fusion forming more solid areas. Mismatch repair immunohistochemistry showed normal expression of MLH1, MSH2, MSH6, and PMS2. Magnetic resonance imaging of the pelvis showed the larger lesion measuring 3 × 2.2 cm and infiltrating into the mesorectal fat (cT3) but did not involve the mesorectal fascia. The smaller lesion had some heterogeneously increased T2 signal and measured 1.5 × 0.7 cm. Small adjacent lymph nodes were suspicious for nodal involvement (cN1; Figure 1). The computed tomography findings of the chest were negative. The initial clinical TNM classification was stage IIIB (T3N1M0).
The patient reported a strong family history of cancer. His mother had died at 47 years of age of breast cancer and reportedly had a BRCA1 mutation (data not available for review). His maternal grandmother had developed breast cancer at 40 years old and again at 60 years and also had a BRCA1 mutation (c.4302C>T, Q1395X). His sister was tested and found to have the same pathogenic BRCA1 variant. However, the present patient had not been tested previously. He also reported a history of colon cancer on his paternal side. His paternal grandmother had had colon cancer at age 40 years and again at age 70 years, with an unknown BRCA status. His paternal great-grandfather had had colon cancer in his 50s, also with unknown BRCA status. Parental consanguinity was denied.
He was evaluated by medical genetics and underwent colon cancer next generation sequencing panel testing with a commercial panel (Invitae Laboratory) and targeted variant analysis for familial BRCA1 mutation (Myriad Genetics, Inc). The findings were heterozygous for the familial, germline, pathogenic BRCA1 variant, c.4183C>T, p.Gln1395*. No other identifiable germline mutations were found in the other genes tested, including APC, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, GREM1, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD, STK11, and TP53 genes.
Given his young age at presentation with rectal cancer, next generation sequencing was also pursued (FoundationOne), which also identified the known BRCA1 Q1395* alteration. Additionally, it detected an APC K1165* and R232*, an IGF2 amplification, and a TP53 R209fs*6. The tumor mutation burden was described as intermediate (9 mutations/MB).
He was evaluated by medical oncology, radiation oncology, and colorectal surgery, and the standard of care with concurrent chemoradiation with capecitabine as the radiosensitizer was started. He received 5040 cGy in 28 fractions using intensity-modulated radiotherapy, with capecitabine given at the standard dose of 825 mg/m2 twice daily on the days of radiation. However, on confirmation of the BRCA1 mutation, the treatment plan was modified to allow for inclusion of platinum-based chemotherapy (oxaliplatin) in the neoadjuvant setting. He tolerated treatment well. On conclusion of the concurrent chemoradiation, he underwent 2 cycles of chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin (mFOLFOX6 [leucovorin, 5-FU, oxaliplatin] standard dosing: 5-FU, 400 mg/m2 bolus; leucovorin, 400 mg/m2; oxaliplatin, 85 mg/m2 on day 1 and 5-FU, 2400 mg/m2 infusion for 46 hours) before surgical resection. This treatment modality was personalized for our patient because of his known BRCA status, tumor mutation burden, and known sensitivity of platinum-based chemotherapy in BRCA-mutant tumors. At ∼8 weeks from the start date of chemoradiation, he underwent robotic low anterior resection (total mesorectal excision) with a side-to-end coloanal anastomosis and diverting loop ileostomy. The pathologic findings from the surgical specimen showed a complete pathologic response. No residual tumor was observed. Also, the findings from the 26 excised lymph nodes were negative for malignancy.
He subsequently completed the remainder of the chemotherapy (6 more cycles of mFOLFOX6 with the same dosing) in the adjuvant setting with 5-FU and oxaliplatin. At the last follow-up examination, he continued to have no evidence of disease recurrence.
BRCA1/2 mutations are typically associated with an increased risk of breast, ovarian, pancreas, and prostate cancer. The association of CRC with BRCA1/2 mutations is unclear. Individuals with CRC are not typically tested for BRCA1/2, and inquiries of family histories have tended to focus more on Lynch syndrome-related tumors. However, additional studies with the increasing use of panel testing have seemed to reveal a possible, although modest, association (Table 1).
Table 1Review of Studies With an Association Between BRCA and Colorectal Cancer
15 of 1260 patients (0.7%) who were referred because of hereditary colon cancer syndromes were noted to have BRCA1/2 mutations. Similarly, another study reported 1% BRCA1/2 mutations in a series of 1058 patients.
Another study of 7015 women with BRCA1/2 mutations found 21 patients with CRC (16 had BRCA1 and 5 had BRCA2). The risk was particularly high for young women (age, 30-49 years; hazard ratio, 3.81; 95% confidence interval, 1.77-7.23).
It has been a rare, but recurring, theme each time a large study has performed unselected panel testing in patients with CRC.
We would argue that these studies have been more than hypothesis generating regarding the association of BRCA1/2 mutations and the risk of CRCs. For young individuals with CRC, in particular, focusing on testing for CRC genes and non-CRC genes would seem important, because the incidence of CRC in younger persons appears to be increasing. Siegel et al,
in a landmark study in 2017, first reported systematically the increasing incidence of CRC. For rectal cancer, in particular, it appeared that the risk was especially increased.
To the best of our knowledge, the BRCA1 mutation c.4183C>T, p.Gln1395* found our patient has not been described in the reviewed studies in which mutation data were available. He had a complete pathologic response after neoadjuvant radiation with capecitabine as a radiosensitizer and 2 cycles of 5-FU– and oxaliplatin-based chemotherapy. Damage to DNA by radiation and/or chemotherapy, in particular, platinum agents, produces double strand breaks. These are recognized and repaired by a coordinated response that involves the products of many tumor suppressor genes, including BRCA1 and BRCA2. Alterations or mutations in these genes lead to impaired recognition of DNA damage and inefficient repair mechanisms that can enhance cell death. We hypothesized that the addition of a platinum agent before surgery, given his BRCA status and the sensitivity of these tumors to DNA damage from radiation, might be responsible for such an excellent response.
Complete pathologic responses do occur in patients with rectal cancer after chemoradiation but have not been the outcomes for most cases. At present, a paradigm shift is occurring in how rectal cancer is being treated, with therapy moving to upfront approaches (total neoadjuvant therapy). Numerous trials are incorporating 3 to 4 months of chemotherapy upfront, followed by chemoradiation. Additionally, it seems that the lengthening interval from finishing chemoradiation to surgery (typically now 8-12 weeks) has shown increased rates of a pathologic complete response without increasing the risk of tumor progression or surgical complications.
Several ongoing clinical trials, trials in development at the Mayo Clinic, and clinical practices at our institution and other institutions such as the Memorial Sloan Kettering Cancer Center are adopting this paradigm shift (ClinicalTrials.gov identifiers, NCT02887313, NCT02921256, NCT02000050, and NCT01515787).
These trials are also incorporating neoadjuvant rectal score as a composite surrogate variable of disease-free survival and overall survival (better than the pathologic complete response) in patients with rectal cancer. Cercek et al
recently reported the results of a total neoadjuvant therapy approach in locally advanced rectal cancer. They reported an improvement in the delivery of planned treatment and an increase in the complete response rate (both pathologic and clinical) with this approach.
Our observation has its limitations, including that it is a case report. However, the observation is hypothesis generating. The review of the reported data highlight the studies that have shown that the BRCA1/2 genes are a rare, but recurring, theme noted when panel testing has been pursued in patients with CRC.
Our patient's case and review of the reported data have illustrated that genetic factors beyond the well-recognized familial CRC syndromes could be responsible for the development of CRC (eg, BRCA1/2). This might be especially more important for individuals with young-onset CRC, which has been increasingly recognized. In our patient, it is possible that the inherited mutation in BRCA1 and its effect in the homologous recombination pathway could have led to the development of his CRC.
The significance of the BRCA1 mutation on the clinical management of CRC at present remains unknown. Although BRCA1/2 mutation testing is not routinely performed for patients with CRC, the testing should be considered, especially for young individuals with CRC and those with a family history suggestive of BRCA1/2 mutations.
The authors declare that they have no competing interests.