Presentation: Patient with metastatic triple-negative breast cancer

A 46-year-old woman is diagnosed with a grade 3 ER-negative, PR-negative and HER2-negative (triple negative) breast cancer. Staging investigations reveal metastases in the lungs and liver. There is no significant family history of cancer. You wish to undertake genomic testing and are considering what constitutional (germline) and/or somatic (tumour) genetic testing is available and appropriate for her.

Constitutional (germline) testing

• Women with breast cancer (primary or metastatic) or high-grade ductal carcinoma in situ are eligible for constitutional (germline) genomic testing of the BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM (truncating variants and c.7271T>G only) and CHEK2 genes (truncating variants only) if they meet at least one of the following criteria:
  • triple-negative breast cancer diagnosed <60 years;
  • breast cancer (grade 2 or higher) diagnosed <40 years;
  • bilateral breast cancer and both cancers diagnosed <50 years;
  • breast cancer diagnosed <45 years and an FDR (first-degree relative) with breast cancer <45 years;
  • Ashkenazi Jewish ancestry and breast cancer at any age; or
  • combined pathology-adjusted Manchester score ≥15 or CanRisk carrier probability of ≥10%. (These tools can be used to calculate risks. If you are not confident to do so, seek support from your local clinical genetics service.)
• Women diagnosed with breast cancer ≤30 years or HER2-positive breast cancer ≤35 years are also eligible for testing of TP53. Testing can be taken contemporaneously with testing of other genes, after appropriate pre-test counselling.
• PARP inhibitors have been licensed in Europe for the second-line treatment of metastatic triple-negative breast cancer with an underlying germline pathogenic variant in BRCA1/BRCA2, but have not yet been approved by NICE for use in the NHS. They may be available in the context of clinical trials.
• Consider a referral to clinical genetics for any woman with breast cancer (primary or metastatic) who has a personal and/or family history of endometrial, thyroid, diffuse gastric cancers or non-cancerous features, such as cleft lip/palate, macrocephaly, mucocutaneous lesions, or a history of intussusception, which may be features of an underlying syndromic cause of breast cancer predisposition.
• Women with lobular breast cancer may be eligible for CDH1 testing if they meet one of the following criteria:
  • lobular breast cancer <70 years and diffuse gastric cancer <70 years;
  • lobular breast cancer and ≥FDR/SDR has diffuse gastric cancer (≥one case occurred <70 years); or
  • two cases of lobular breast cancer <50 years, such as bilateral or multiple ipsilateral tumours.
• Patients who are considered for palliative chemotherapy with capecitabine palliative chemotherapy should undergo germline testing of the dihydropyrimidine dehydrogenase (DPYD) gene. Certain variants in the DPYD gene result in a deficiency of the enzyme dihydropyrimidine dehydrogenase and a subsequent reduction in metabolism of fluoropyrimidine chemotherapy drugs (such as 5FU and capecitabine). This results in serious and sometimes life-threatening toxicity, including diarrhoea, mucositis and skin reactions, if these chemotherapy agents are given at standard doses.

Somatic (tumour) testing

• Immunohistochemical testing of PD-L1 status of triple-negative breast cancer is available within the NHS. Expression of PD-L1 at a level of 1% or more (as assessed using the SP142 antibody assay) confers eligibility for first-line treatment of metastatic, unresectable or locally advanced disease with nab-paclitaxel and the immunotherapy agent atezolizumab.
• The immunotherapy agent pembrolizumab has been approved by the European Medicines Agency (EMA) for first-line treatment of metastatic triple-negative breast cancer with a PDL-1 combined positive score of at least 10% (using the 22C3 antibody), but is not currently approved by NICE. This treatment may be available as part of a clinical trial.
• Somatic (tumour) testing for Anti-Trop-2 to determine eligibility for sacituzumab govitecan is currently not approved in the UK (although it has been granted approval by the US Food and Drug Administration). It may be available as part of a clinical trial or with pharmaceutical company funding.
• Somatic testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for metastatic breast cancer patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.
• Somatic testing PI3KCA mutations is available if this information will aid diagnosis or influence clinical trial opportunities; PI3KCA mutation inhibitors are currently only licensed in ER-positive metastatic breast cancer.
• Other somatic testing may be available within clinical trials for metastatic breast cancer.
• All patients with solid tumours who have exhausted all standards of care testing and treatment are eligible for whole genome sequencing (WGS) to explore clinical trial options. In addition, patients with triple-negative breast cancer of any stage are currently eligible for WGS in the context of a pilot study.

• Consult the National Genomic Test Directory eligibility criteria to ensure your patient is eligible for testing. You can also refer to this spreadsheet of all available tests.
• For information on the genes that are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service signed-off panels resource.

Constitutional (germline) testing

• For germline testing of patients affected with breast cancer, the panel to request is:
  • R208 (inherited breast cancer and ovarian cancer): This tests for constitutional (germline) mutations in BRCA1, BRCA2, PALB2, ATM* and CHEK2* (*truncating variants only).
  • Women diagnosed with breast cancer <30 years, or women <35 years with triple-positive (ER+,PgR+, HER2+) breast cancer are also eligible for TP53 testing (R216) after appropriate counselling.
• Patients being considered for palliative chemotherapy with capecitabine palliative should undergo germline DPYD testing using test code M3.7.
• For constitutional DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomic Laboratory Hub for details of test request forms and where to send samples.
• A record of discussion (RoD) form is required prior to constitutional (germline) tests. If you have not completed an RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form. An RoD form is currently not required for DPYD variant testing.
• Depending on the details you provide and the test that is chosen, a range of different genomic investigation techniques will be applied to your patient’s DNA. These include (but are not restricted to):
  • Single gene sequencing or hotspot testing
  • Gene panel sequencing
  • MLPA

Somatic (tumour) testing

• Immunohistochemical assessment of PD-L1 expression can be arranged with your local pathology service.
• NTRK fusion gene analysis can be requested as test M3.5. This consists of next-generation sequencing (NGS) structural variant analysis.
• Somatic PI3KCA variant testing can be requested as test M3.6. This is performed as part of a multi-target NGS panel.
• WGS of solid tumours where the patient has exhausted all standards of care testing and treatment is requested as code M232.
• WGS for triple-negative breast cancer of any stage (pilot study) can be requested as code M234.
• WGS requires access to a fresh tumour sample and a matched blood (EDTA) sample for germline testing. An RoD must be completed for this investigation – see how to complete an RoD form. Please discuss with your local GLH before submitting samples for WGS to confirm the local test pathway details.

For clinicians

• NHS England: National Genomic Test Directory and eligibility criteria* (note that somatic (tumour) tests are listed in the directory for cancer, while constitutional (germline) tests are listed in the directory for rare and inherited disease)
• NICE: Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer
• NICE: Guidance on atezolizumab with nab-paclitaxel for untreated PD-L1-positive, locally advanced or metastatic, triple-negative breast cancer
• NICE: Guidance on entrectinib for treating NTRK fusion-positive solid tumours
• NICE: Guidance on genetic testing for patients with breast and ovarian cancer
• UK Chemotherapy Board: Personalised Medicine Approach For Fluoropyrimidine-based Therapies

For patients

• Breast Cancer Now: Atezolizumab information
• Breast Cancer Now: ‘Family history of breast cancer: managing your risk’ booklet
• Cancer Research UK: Inherited breast cancer information
• Macmillan: Inherited breast and ovarian cancer information