Breast cancer (BC) is the most common cancer in women, and the leading cause of death in women.1 Ovarian cancer (OC) is the gynaecological cancer with the highest mortality rate.2 Hereditary cancer accounts for 8%–10% of all tumours diagnosed. Approximately 5%–10% of BCs and 10%–15% of OCs are hereditary, and 25% have been linked to germline mutations in BRCA1/2.1
The aim of our study was to analyse the usefulness of multigene panels (MP) in patients with BC undergoing treatment with neoadjuvant chemotherapy (NCT) with clinical criteria for genetic study of hereditary cancer (Table 1).
Clinical selection criteria of genetic study.
| A single case. Irrespective of the family: |
| Woman affected by BC and OC (goal/synchronic) |
| BC ≤ 40 years |
| Bilateral BC (the first tumour ≤40) or triple negative BC ≤60 years |
| Non mucinous high grade epithelial OC or primary tubal or peritoneal tumour |
| BC in a male |
| Two or more cases First degree relative (parents, children and siblings) and second grade (grandparents, grandchildren, uncles and aunts, nephews and nieces): |
| Bilateral BC at any age +BC< 50 years |
| BC and OC |
| 2 BC < 50 years |
| Three or more cases. Direct relatives with BC and/or OC: |
| ≥ 3 BC ± OC |
BC, breast cancer; OC, Ovarian cancer.
Llort Pursals and Ramón y Cajal3.
We conducted a prospective, observational study at the Hospital Juan Ramón Jiménez, Huelva, during the years 2019−2020. Of a total of 98 women with locally advanced BC who were candidates for treatment with NCT, 19 patients (19.4%) were included (Table 2).
Patient characteristics.
| Individual | Age | Immunohistochemical | Criteria | Type of mutation | RRM | RRSO |
|---|---|---|---|---|---|---|
| 1 | 38 | Her 2 | >1 case | BRCA1 | Yes | Yes |
| 2 | 42 | Triple negative | >1 case | BRCA non-informative | No | No |
| 3 | 41 | Triple negative | Single case | BRCA non-informative | No | No |
| 4 | 48 | Triple negative | >1 case | BRCA1 | Yes | Yes |
| 5 | 53 | Luminal B1 | >1 case | BRCA1 | Yes | Yes |
| 6 | 46 | Luminal B1 | >1 case | BRCA1 | Yes | No |
| 7 | 50 | Triple negative | >1 case | BRCA non-informative | No | No |
| 8 | 48 | Luminal B2 | >1 case | BRCA non-informative | No | No |
| 9 | 28 | Triple negative | Single case | MUTHY | No | No |
| 10 | 45 | Luminal B2 | Single case | CHEK2 | No | No |
| 11 | 42 | Triple negative | >1 case | BRCA non-informative | No | No |
| 12 | 45 | Luminal B2 | Single case | BRCA non-informative | No | No |
| 13 | 51 | Luminal A | >1 case | BRCA non-informative | No | No |
| 14 | 37 | Luminal B1 | >1 case | BRCA non-informative | No | No |
| 15 | 50 | Triple negative | >1 case | BRCA non-informative | No | No |
| 16 | 32 | Triple negative | Single case | BRCA non-informative | No | No |
| 17 | 40 | Luminal A | >1 case | BRCA non-informative | No | No |
| 18 | 48 | Triple negative | Single case | BRCA non-informative | No | No |
| 19 | 50 | Luminal A | >1 case | BRCA non-informative | No | No |
RRM, reduced risk mastectomy; RRSO, bilateral risk-reducing salpingo-oophorectomy.
Multigene panels by DNA extraction from peripheral blood were performed by next-generation sequencing (NGS). Pathogenic variants (PV) or probably pathogenic variants (PPV) found were confirmed by multiplex ligation-dependent probe amplification or multiplex ligation-dependent probe amplification (MLPA). BRCA1, BRCA2, CDH1, PTEN, STK11, TP53, ATM, BRIP1, CHEK2, PALB2, MSH6, RAD51C, RAD51D, MSH2, MLH1, MUTYH and PMS2 genes were analysed. Participants signed an informed consent form, the centres' protocols on the publication of patient data were followed, and the privacy of the subjects was respected. Data analysis was carried out using SPSS® version 22 statistical software.
The median age was 45 years (IQR: 40–50). In 31.6% of the cases a PV was identified: four in BRCA1 (21.05%), one in MUTYH (5.26%) and one in CHEK2 (5.26%). Thirteen patients had non-informative (negative) BRCA. All patients with BRCA1 PV opted for surgery for their breast cancer and risk-reducing mastectomy (RRM) of the contralateral breast, and 75% also had risk-reducing salpingo-oophorectomy (RRSO) in the same surgical procedure. Risk-reducing surgery (RRS) was not performed in patients with PV in the CHEK2 and MUTYH genes because it was not indicated after reviewing the family history.
The development of NGS has improved the ability to study numerous genes at the same time while reducing costs. Hereditary breast and ovarian cancer syndrome (HBC and OCS) is linked to PV/PPV in genes with high (BRCA1/2, TP53, PALB2, PTEN) and moderate penetrance (CHEK2, CDH1, among others).4,5
In our case, the result was obtained prior to surgery, so the genetic study was useful in those carriers of PV in high-risk genes for HBC and OCS. Tumour intervention and RRS of the contralateral breast and RRSO was planned for those who wanted it. All interventions were performed in patients carrying BRCA1, as no PV were found in other high-risk genes (BRCA2, PALB2, TP53, among others). This is due to the low prevalence of these genes in the population, which is around 6% of families with hereditary cancer syndrome.5 In cases with negative (non-informative) results, RRM was not indicated. The benefit of RRS in moderate risk genes (ATM, CHEK2, etc.) is controversial and will be agreed on the basis of family history and patient preferences after a detailed explanation of the risks and benefits. It has not been demonstrated that in these cases the overall survival of the intervened patients is increased. In patients carrying PV in the CHEK2 gene, it could be offered in those cases with high familial burden or assessed in carriers of a deletion variant (del1100C) despite low familial burden. The del1100C appears to contribute to an increased risk of BC compared to other PV in this gene. A case-control study reported an OR of 2.55 (95% CI 2.10–3.10, p < .001).6 On the other hand, MUTYH is a gene associated with attenuated familial adenomatous polyposis when PV are detected in homozygosis, characterised by a high risk of colorectal cancer (CRC). 7 The increased risk of BC and CRC in the heterozygous form has not been demonstrated in several studies. In these cases, colonoscopy follow-up is recommended based on a family history of first/second-degree CRC.8
BRCA1/2 genes with VP/VPP account for approximately 20%–25% of all HBC and OCS,9 which is consistent with our findings. For this reason, in places where it is difficult to access a genetic study by NGS where the study time is expected to be prolonged, we could initially request the study of only the BRCA1/2 genes by MLPA and, in the event of obtaining a non-informative study, consider extending the rest of the genes depending on the family history. This would shorten the time of the result, reduce costs and improve the performance of the study.
To conclude, the use of Mp by NGS is a useful tool in the diagnosis of HBC and OCS, given that we found a high prevalence of PV that justifies the need to study these patients, benefiting from the intervention of the tumour and RRS in the same surgical act.
