BRCA Mutation in Ovarian Cancer

The word BRCA on an ovarian cancer report can mean either of two things, and they are not interchangeable.

Germline testing looks for a change you were born with. NCI notes that inherited variants sit in every cell of the body. So the sample is blood or saliva. A germline result speaks about you and about your blood relatives.

Somatic testing looks at the tumor itself. It finds changes the cancer picked up along the way. It says nothing about your relatives.

Both can qualify you for the same drug. Only one has meaning for your sister. So the first question about any BRCA result is which test produced it.

Read the report header. If the sample was blood or saliva, it is germline. If it was a tissue block from surgery or biopsy, it is tumor testing.

NCI's clinician summary states that about 20% of ovarian cancers are familial. Most of those trace back to BRCA1 or BRCA2. Several other genes are involved as well.

NCI's fact sheet gives the background rate for comparison. Harmful BRCA variants turn up in 0.2% to 0.3% of the general population, roughly 1 in 400. Among people of Ashkenazi Jewish descent it is about 2%.

This is the most immediate consequence, and it is a specific drug.

The FDA approved olaparib, sold as Lynparza, for maintenance treatment. The wording is exact. It covers adults with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. They must be in complete or partial response to first-line platinum-based chemotherapy.

Read that indication closely, because every clause is doing work:

• Germline or somatic — either test can open the door
• Advanced epithelial ovarian, fallopian tube, or primary peritoneal — these three are treated as one disease
• In complete or partial response — the drug starts after chemotherapy has worked, not instead of it
• First-line platinum-based — the timing is tied to the first course of treatment

The evidence came from SOLO-1. It randomized 391 patients, 260 to olaparib and 131 to placebo. The hazard ratio for progression-free survival was 0.30, with a p-value below 0.0001. Median progression-free survival was not reached in the olaparib group. In the placebo group it was 13.8 months.

The label's usual amount is 300 mg by mouth twice a day, taken as two 150 mg tablets, with or without food. It is printed here so the tablets in your hand make sense, but go by your own prescription: doses get lowered for low blood counts, kidney function and interacting medicines, and yours may differ.

The FDA approved a companion test alongside it, BRACAnalysis CDx, for identifying germline BRCA-mutated patients.

BRCA1 and BRCA2 are DNA repair genes. A tumor that has lost one of them repairs certain damage badly. Platinum chemotherapy works by damaging DNA. So the flaw becomes a weakness the drug can use.

NCI's summary reports what that means in the clinic. Case-control studies suggest better responses to chemotherapy in women with BRCA1 and BRCA2 variants. The comparison group is patients with sporadic epithelial ovarian cancer.

That is worth hearing at diagnosis, because a BRCA result often arrives in the same week as a difficult stage.

If the finding is germline, it travels. NCI's fact sheet gives the lifetime risks for women who inherit a harmful variant:

• Ovarian cancer with BRCA1 — 39% to 58%
• Ovarian cancer with BRCA2 — 13% to 29%
• General population ovarian cancer risk — about 1.1%
• Breast cancer with either — over 60%, against about 13% in the general population

Men carry these variants too, and pass them on. NCI puts male breast cancer risk by age 70 at 0.2% to 1.2% with BRCA1. With BRCA2 it is 1.8% to 7.1%. The general male figure is about 0.1%.

Ask who in your family should be tested. Ask for the exact variant name in writing. Relatives are usually tested for that one specific change. That test is cheaper and faster than a full panel.

For relatives who test positive, this becomes the central decision.

NCI's summary states that prophylactic oophorectomy may be considered after age 35, once childbearing is complete. It also gives the size of the benefit. The surgery was linked to a drop in ovarian cancer risk exceeding 90%. The relative risk was 0.04, with a 95% confidence interval of 0.01 to 0.16.

That is a large benefit. It is also surgery that cannot be undone, and it brings on menopause at once. NCI notes it carries potential complications. This is a real decision, not an obvious one.

1. Confirm in writing whether the test was germline, somatic, or both
2. If only tumor testing was done, ask whether germline testing is still indicated
3. Ask for a referral to a genetic counselor, and ask when the appointment is
4. Ask whether you meet the olaparib indication, and if not, which clause you fail
5. Get the exact variant nomenclature, including the gene and the change, for relatives
6. Ask whether a variant of uncertain significance was reported, and what that means for the plan

A variant of uncertain significance is a change whose effect is not yet known. It is not a positive result. It should not drive surgery or drug decisions.

These signs relate to olaparib and the other PARP inhibitors, which is what a BRCA result most often leads to here.

• Call 911 or go to an emergency department if you have chest pain or tightness, sudden shortness of breath, rapid breathing, a fast or pounding heartbeat, or you cough up blood. Those can mean a clot has reached the lungs.
• Contact your cancer team immediately, whatever the hour, if a fever of 100.4°F (38°C) or higher turns up, with or without chills or a sore throat. That is the threshold in NCI's guidance on infection during cancer treatment, and because PARP maintenance follows platinum chemotherapy and keeps blood counts under watch, it is handled as an emergency rather than a same-day call. Go to an emergency department if you cannot get through to them quickly.
• Call your care team the same day if one leg becomes painful, tender, red or swollen, which can be a clot. Call the same day for a new or worsening cough, wheezing or breathlessness.
• Call your care team within a day or two if you notice unusual bruising or bleeding, blood in your urine or stool, pale skin, or tiredness and weakness that keep getting worse. Those point to the blood counts, which are checked regularly on these drugs.

What Are PARP Inhibitors? explains the drug class in detail. HRD-Positive Ovarian Cancer covers the broader repair-defect category. BRCA Gene Mutations Explained covers the inherited side, and Ovarian Cancer Treatment by Stage covers the rest of the plan.

• National Cancer Institute — BRCA Gene Changes: Cancer Risk and Genetic Testing
• NCI PDQ — Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment (Health Professional Version)
• U.S. Food and Drug Administration — FDA approved olaparib (LYNPARZA) for maintenance treatment of BRCA-mutated advanced ovarian cancer
• MedlinePlus — Olaparib
• NCI — Infection and Neutropenia during Cancer Treatment