Personalised genetic testing in breast cancer patients and what it means.
Hereditary breast cancer – inherited germline mutations
This means the abnormally functioning genes we inherit that predict a high lifetime risk for developing breast cancer ranging from 35-80% by 80 years of age. Inherited breast cancer is rare and causes only 5% of all breast cancers. Currently the guidelines for testing high risk genes has expanded with lowered thresholds for genetic testing of the following genes: BRCA1, BRCA2, PALB2, CHD1, P53 and PTEN. We test different numbers of genes based on family history of breast and ovarian cancer or other cancers that indicate the need for syndromic testing. These other cancers include: prostate; pancreatic; colonic; stomach; thyroid; and uterine cancer amongst others. We use established algorithms on which to base referring you to a specialist geneticist.
In the last 5 years, we have tested women presenting with early breast cancer who are: <45 years of age; have a triple negative (negative for oestrogen, progesterone and HER2) breast cancer <70 years of age; and bilateral breast cancer <60 of age.
Hereditary gene testing focuses treatment recommendations on: risk-reducing breast and ovarian surgery, including high-risk breast screening and biological risk-reducing chemoprevention using drugs like Tamoxifen or Aromatase Inhibitors (AIs) for 5 years. Importantly, we should also check for hereditary genes in advanced breast cancer where the cancer has returned or spread to other body sites.
Mutations or abnormal function of the BRCA1/2 genes means that cancer cells cannot detect damages to their genetic material or DNA, and also cannot repair their damaged DNA. This is why cancers occur at such high rates in these patients. This genetic deficiency can be used as a treatment advantage when combined with drugs that block sensors of DNA damage and repair. These drugs are called PARP inhibitors and they effectively kill BRCA1/2 abnormal cancer cells where the BRCA genes aren’t functioning. The PARP inhibitors sensitise BRCA cancers to the DNA damaging effects of chemotherapy and radiotherapy.
The platinum types of chemotherapy like Carboplatin are also particularly effective in killing BRCA mutated breast cancers.
These drugs are also highly effective in treating triple negative breast cancers (no expression of oestrogen, progesterone or the HER2 gene) that carry mutations of the BRCA 1 (70%) or BRCA2 (20%) genes.
The abnormal DNA repair pathways conferred by these gene mutations can be used for treatment advantages.
The more recent testing of the PALB2 gene (Partner and Localiser of Breast Cancer 2 (BRCA2)) functions together with the BRCA2 gene and serves as an additional drug-able target for cancer treatments. All women previously undergoing BRCA testing before 2014 should be referred for retesting of BRCA1/2 and PALB2.
Women with advanced breast cancer that carried BRCA mutations were treated with PARP inhibitors in two breast cancer trials called OLYMPIAD and EMBRACA. They both showed a significant improvement in cancer-free survival.
Currently, there are many breast cancer trials evaluating PARP inhibitors either at the pre-surgery (neoadjuvant) or post-surgery (adjuvant) stages of treatments in women with BRCA abnormal genes.
Genomic gene expression signatures in early oestrogen (ER+) positive breast cancer to guide chemotherapy
A number of commercial assays are used to quantitate levels of 10 -100 different gene expressions using messenger RNA in what is known as a “transcriptome”. This is not the same as a germline mutation that occurs in hereditary breast cancers or advanced breast cancers (described above). Until now, we have relied on cancer histological grade and proliferation index (ki67), but the transcriptome profile provides us with much more prognostic/predictive information on the full spectrum of breast cancers over and above routine breast cancer staging.
The transcriptome predicts 10-year overall survival in women with early stage oestrogen positive (ER+) lymph node negative disease evaluated in the TAILORX trial. The 21-Gene OncotypeDx recurrence score identifies those women who will benefit from chemotherapy after surgery, and allows us to recommend personalised treatments.
Another trial called MINDACT has also shown that the 70 gene MammaPrint assay determines when chemotherapy is beneficial for increasing survival in addition to ER+ endocrine treatment. Young age <50 years is a key factor when interpreting the gene recurrence scores, with greater benefits of chemotherapy in younger women compared to those >50 years. This may be due to a chemotherapy-induced menopause. OncotypeDx can also be used to predict recurrence scores in lymph node positive patients, who may avoid chemotherapy without compromising cancer outcomes.
Other genomic assays such as the 12-gene EndoPredict and the PAM-50 have not been as fully evaluated in studies comparing chemotherapy versus no chemotherapy. It is possible that gene assays may also predict when to extend or prolong endocrine treatments such as Tamoxifen or aromatase inhibitors from 5 to 10 years, however there are no high-quality studies validating this at present.
Genomic sequencing in advanced breast cancer to increase drug treatments
Testing acquired or somatic mutations of 200-600 genes is based on the relatively frequent mutations that occur between the primary breast cancer and the subsequent recurrence or relapse of breast cancer. Testing can be done by sequencing genes in the cancer tissue or the circulating free cancer DNA (ctDNA), where cancer cells release their DNA into the circulation when they die. The gene testing of ctDNA correlates well with that of the cancer tissues and should be evaluated first. Levels of ctDNA can be used to predict worse cancers that are progressing, and are not responding to treatments after only two weeks.
Acquired mutations as cancers evolve or that occur after treatments have been shown in ER+ cancers to involve the oestrogen resistance gene (ESR 1) that confers resistance to aromatase inhibitors, which means these drugs cease to be effective. The commonest mutations in 40% of ER+ cancers also affect the PI3 kinase pathway that can be targeted by specific drugs.
Germline testing of BRCA1/2 selects patients who will benefit from PARP inhibitors and carboplatin chemotherapy. Triple negative cancers may also harbour mutations in the PIK3 kinase pathway that can be used as drug-able targets.
Molecular testing of breast cancer is a rapidly evolving field and is here to stay!
References:
Litton JK, Burstein HJ, Turner NC. Molecular Testing in Breast Cancer. Am Soc Clin Oncol Educ Book. 2019 Jan; 39: e1-e7. doi: 10.1200/EDBK_237715.
More information: