3.1. Colorectal Cancer
Colorectal cancer (CRC) is the second cause of cancer death in both men and women in the world. In most cases, CRCs are sporadic. However, different hereditary CRC syndromes exist; the best known are LS (or hereditary nonpolyposis CRC) and FAP. The first one is associated with a mutation in mismatch repair (MMR) genes, or rather
MLH1,
MSH2,
MSH6 or
PMS2 [
61]. Lynch syndrome-related CRCs represent about 1%–3% of all CRC cases. FAP syndrome is caused by a germline mutation in the
APC (adenomatous polyposis coli) gene and it is responsible for nearly 1% of all CRCs [
62]. The link between CRC and a mutation in
BRCA1/BRCA2 genes is less coded; in fact, individuals affected by CRC are not normally tested either for
BRCA1 or for
BRCA2.
In 1994, the Breast Cancer Linkage Consortium (BCLC) highlighted a statistically significant increased risk of CRC in a population of
BRCA1 mutation carriers (RR = 4.11, 95% CI 2.36–7.15) [
63]. The same result was not observed in
BRCA2 mutation carriers. In subsequent years, different groups of investigators confirmed or disproved these findings. Thompson and Easton showed a 2-fold increased risk of colon cancer (RR = 2.03, 95% CI 1.45–2.85) and a decreased risk of rectal cancer (RR = 0.23, 95% CI 0.09–0.59) in
BRCA1 mutation carriers [
64]. Moreover, Brose et al. underlined a 2-fold increased risk (11%, 95% CI 8.2%–13.2%) to develop CRC in
BRCA1 carriers compared to the risk reported by Surveillance, Epidemiology, and End Results (SEER) [
65]. Phelan and his collaborators screened 7015 women carrying a
BRCA mutation and found twenty-one CRC cases, an incidence not higher than that of the general population. Nevertheless, they observed an increased risk to develop CRC in women younger than 50 years carrying a
BRCA1 pathogenic mutation. Instead, no differences with global population rates were reported in older women and in
BRCA2 mutation carriers [
66]. These findings are consistent with the results of other studies. Indeed, in a Polish population of 2398 unselected patients affected by CRC, Suchy et al. reported a mutation detection rate of about 0.42% (not higher than the rate of the control group, that was 0.48%). However, also in this trial, a major incidence of CRC in patients younger than 60 years (OR = 1.7) was underlined, though not statistically significant (
p = 0.3) [
67]. Thus, women with a
BRCA1 mutation should undergo a CRC screening test, such as a high-sensitivity fecal occult blood test or colonoscopy at a younger age. Notably, they may also be good candidates for chemoprevention programs with low-dose aspirin. Indeed, several trials highlighted a decrease in CRC incidence in subjects taking daily aspirin at the dosage of ≥75 mg/day [
68]. Particularly, Burn et al. tested 600 mg/day of aspirin in patients with Lynch syndrome and observed a reduction in CRC incidence [
69]. However, since the regular use of acetylsalicylic acid might cause severe AEs such as cerebral and gastrointestinal bleedings, the US Preventive Services Task Force recommends chemoprevention only for high-risk individuals, e.g., Lynch syndrome or FAP individuals [
70].
Mersch et al. investigated the risk of developing CRC in a group of 613
BRCA1 and 459
BRCA2 mutation carriers and found no statistically significant difference between carriers and non-carriers [
71]. Moreover, in a cohort study, Lin and colleagues observed no significantly different risk in 164
BRCA1 and 88
BRCA2 mutation carriers compared to the general population [
72]. Other studies investigated if a family history of breast cancer was associated with a higher CRC incidence. Niell and colleagues did not identify a correlation between a family history of breast cancer in a first-degree female relative and the risk of developing CRC [
73]. Conversely, Slattery and Kerber reported a low, but statistically significant, increased risk for CRC in patients with a positive family history for breast cancer [
74]. Of note, several hereditary syndromes could be involved and could explain the association. Peutz–Jeghers syndrome, Cowden syndrome and Muir–Torre syndrome are just some examples of inherited conditions with a spectrum of diseases in which both cancers (breast cancer and CRC) are accounted. Furthermore,
APC polymorphism I1307K, as reported by Woodage et al. and Redston and colleagues, might be associated with low penetrance to breast cancer susceptibility [
75,
76].
In summary, some family-based studies and prospective cohort studies suggested a possible greater risk among early-onset CRCs in
BRCA1 mutation carriers. These results seem to be confirmed by a systematic review and meta-analysis underlining a 1.49-fold higher risk of CRC in
BRCA1 mutation carriers [
77]. Nevertheless, more studies are needed to investigate the real linkage.
In recent years, also in the context of CRC, new and old drugs demonstrated efficacy in HRD conditions. In their case report, Lin et al. described a complete pathological response in a young man affected by rectal cancer carrying a
BRCA2 pathogenic mutation with a platinum-based neoadjuvant chemotherapy [
78]. The authors also reported a high tumor mutational burden (TMB), investigated by next-generation sequencing (NGS), without microsatellite instability (MSI), in their patient. Therefore, based on previous evidence for other cancers, they speculated also a possible rationale for the use of checkpoint inhibitors [
78,
79,
80]. In their study involving 6396 CRC tumor samples, Naseem et al. recently detected
BRCA1 and
BRCA2 mutations in 1.1% and 2.8% of tumors, respectively. Interestingly, they found a higher frequency of
BRCA1 and
BRCA2 mutations in MSI-high (MSI-H) patients and found that those mutations were independently associated with higher TMB. Therefore, Naseem et al. also came to the conclusion that
BRCA1 and
BRCA2 mutations might potentially be predictive biomarkers for checkpoint inhibitors in CRC [
81]. Notably, Harpaz and collaborators found a statistically significantly higher incidence of
BRCA mutations and a higher TMB in CRCs with mucinous histology, compared to adenocarcinomas, suggesting that this association might lead to the use of histopathologic characterization, besides other tests, to identify patients who may be good candidates for immunotherapy [
82].
As previously mentioned, PARPi are novel therapeutic agents. They currently play a very important role mostly in the treatment of ovarian cancer. Earlier studies investigated the role of ABT-888 (veliparib) in a CRC cell line pretreated with DNA-damaging chemotherapy agents, such as irinotecan and oxaliplatin [
83], reporting a synergistic effect. ABT-888 showed a synergistic effect also in combination with radiation [
84]. Based on these results, a phase II open-label study evaluating the action of veliparib in combination with temozolomide in metastatic CRC patients successfully met its primary endpoint with a disease control rate (DCR) of 24% and two confirmed partial responses [
85]. However, PARPi demonstrated their efficacy also when a mutation occurred in the so-called BRCAness genes, such as in
ATM. Wang et al. highlighted that CRC cell lines with an
ATM-inactivating mutation had an increased sensitivity to olaparib [
86].
Based on previous studies on myeloid malignancy [
87], Leichman et al. tested a PARPi in microsatellite-stable (MSS) and -unstable (MSI) CRC patients in a phase II clinical trial. No differences between the two groups were observed. Therefore, the authors reported that microsatellite status is not a predictive marker of response to PARPi [
88]. Certainly, more studies are needed, and for the time being, PARPi are not approved for the treatment of CRC.
3.2. Gastric Cancer
Gastric cancer (GC) is a heterogeneous disease, mostly sporadic, but hereditary in a small percentage of cases (1%–3%). Familial intestinal GC (FIGC) and hereditary diffuse GC (HDGC, ORPHA: 26106) are the principal hereditary GC conditions. HDGC syndrome is caused by a mutation in
CDH1, the gene encoding for the E-cadherin protein, and it is characterized by an association between signet ring cell/diffuse GC and lobular breast cancer [
89]. GC is also a key component of other hereditary cancer syndromes such as Lynch Syndrome, Li–Fraumeni syndrome (ORPHA:524, gene
TP53) and Peutz–Jeghers Syndrome. Furthermore, GC is accounted in hereditary breast/ovarian cancer syndrome (HBOCS).
The BCLC reported a 6-fold increased risk of GC among first-degree relatives of both
BRCA genes mutation carriers [
28,
63]. Brose et al. estimated a 4-fold higher lifetime risk to develop GC in
BRCA1 mutation carriers [
65]. Tulinius and colleagues investigated the risk of developing GC in 995 women and found a 2-fold greater risk in the
BRCA2 mutation-positive cohort [
90]. Conversely, van Asperen and collaborators highlighted no statistically significant higher risk of developing GC in
BRCA2 families in the Dutch population [
91]. Some authors explained the contradictory results, arguing that breast and ovarian cancers have an earlier onset in
BRCA1/BRCA2 mutation carriers, therefore patients might not have time to develop GC afterwards. Notably, in their population-based study, Bermejo and colleagues found a major incidence of GC in males. Particularly, in 23 families with ovarian, breast and gastric cancers, they reported 23 GC cases in males and only 1 case in females [
92]. Previously, also BCLC suggested a sex-related increased incidence of GC in males [
28].
As mentioned above, an impairment in the proteins involved in HR causes a higher susceptibility to PARPi. A phase II study reported a significant improvement in OS with the combination of olaparib plus paclitaxel in Asian patients with advanced GC, especially in
ATM mutation carriers [
93]. A subsequent phase III trial (GOLD trial) did not confirm these results, showing an OS of 8.8 months (95% CI 7.4–9.6) in the olaparib group vs. 6.9 months (95% CI 6.3–7.9) in the placebo group. Moreover, among the
ATM mutation carriers, the OS was 12 months (95% CI 7.8–18.1) in the experimental arm vs. 10 months (95% CI 6.4–13.3) in the standard arm [
94].
Several other combination therapies were investigated. A phase II basket study demonstrated the tolerability and the reasonable efficacy (ORR 10%) of the association between olaparib and durvalumab, an anti PD-L1 monoclonal antibody, in patients with relapsed GC [
95]. Currently, a study evaluating the combination of olaparib and ramucirumab (an angiogenesis inhibitor) is ongoing [
96].
3.3. Cholangiocarcinoma and Hepatocellular Carcinoma
Cholangiocarcinoma (CCA) is the second most common hepatic neoplasm after hepatocellular carcinoma. In recent years, with the purpose of improving CCA treatment, Nakamura et al. found in a series of CCA several somatic alterations in potentially targetable genes, such as kinases
FGFR1,
FGFR2,
FGFR3,
AKT3,
BRAF,
PIK3CA,
EGFR and
ALK and oncogenes
MDM2,
CCND3,
CCND1,
IDH1 and
IDH2, but also in the tumor suppressor proteins BRCA1 and BRCA2 [
97]. Moreover, Churi and his collaborators also highlighted targetable somatic mutations in
MSH2,
MLH1,
ATM,
BAP1,
MSH6,
BRCA1 and
BRCA2 in 74 CCA cases [
98]. The role of
BRCA1 and
BRCA2 in the pathogenesis of CCA was primarily suggested by BCLC. In 1999, they described a relative risk (RR) of developing CCA of about 4.97 (95% CI 1.50–16.52) among
BRCA2 mutation carriers [
28]. Encouraged by these results, Golan and other authors identified 18 cases of CCA with genetic alterations in
BRCA1 and
BRCA2 genes: five of those were germline, thirteen were somatic mutations. Thirteen CCA patients were treated with a platinum-based chemotherapy and four patients received PARPi. Notably, one of the patients treated with PARPi experienced a progression-free survival of 42.6 months [
99]. Cheng et al. also described a good response with olaparib monotherapy in a patient affected by intrahepatic CCA [
100]. Recently, Spizzo et al. analyzed 1288 CCA samples and detected
BRCA1 and
BRCA2 mutations in 46 cases, at 3.6% (0.6%
BRCA1 and 3%
BRCA2). They also underscored that these mutations were associated with a high mutational burden and suggested a potential rationale for the combination of PARPi with immunotherapies [
101]. More evidence for the use of PARPi in CCA comes from pre-clinical experiences. Indeed, Fehling et al. highlighted a synergistic action of BET inhibitors (JQ1) with PARPi in CCA cell lines [
102]. Another pre-clinical study suggested a potential role of olaparib in sensitizing CCA cells to radiation [
103], as reported above for CRC. Moving from the benchside to the bedside, clinical trials are currently ongoing. For instance, a phase II trial is evaluating olaparib in patients with metastatic CCA and aberrant DNA repair genes (
BRCA1,
BRCA2,
ATM,
RAD51 and others) [
104]. The results of this trial, which are expected in 2021, and those from other trials are needed to clarify, firstly, the real role of
BRCA1 and
BRCA2 mutations in CCA, and secondly, the potential role for PARPi use either in monotherapy or in combination with other drugs.
Regarding hepatocellular carcinoma (HCC), evidence about its link with
BRCA1 and
BRCA2 mutations is extremely limited. In a recent study, Lin J. and colleagues analyzed a population of 357 patients with primary liver cancers: 214 HCC, 122 CCA and 21 mixed HCC and CCA. They found a mutation in
BRCA1 or
BRCA2 genes only in five HCC patients. However, they reported an ATM mutation rate of 6.07%, higher than that of CCA. Clearly, because of the scarce data available, the real role of BRCA proteins in the pathogenesis of HCC cannot be postulated [
105].