Triple-Negative Breast Cancer’s Response to Carboplatin Before Surgery Seems Affected By BRCA1/2 Mutation Status

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Triple-negative breast cancer is:

  • estrogen-receptor-negative
  • progesterone-receptor-negative
  • HER2-negative

About 15% to 20% of breast cancers are triple-negative. Triple-negative cancers can be more aggressive, harder to treat, and more likely to come back than cancers that are hormone-receptor-positive and/or HER2-positive. Hormonal therapy and the targeted therapies Herceptin (chemical name: trastuzumab), Tykerb (chemical name: lapatinib), Perjeta (chemical name: pertuzumab), and Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine) don't work on triple-negative breast cancer.

Because triple-negative breast cancer can be more aggressive and there are a limited number of treatment choices, doctors are looking for new ways to treat it, especially early-stage, triple-negative disease.

Results from the GeparSixto study presented in 2015 suggested that adding carboplatin to the standard chemotherapy regimen would improve outcomes for women diagnosed with triple-negative disease.

Researchers wondered if having a BRCA1 or BRCA2 mutation affected how the cancer responded to the chemotherapy regimens in the GeparSixto study. So they did another analysis of the data and found that women with a BRCA1 or BRCA2 mutation responded better to chemotherapy before surgery without carboplatin, while women without a BRCA1 or BRCA2 mutation had better outcomes when carboplatin was added to the chemotherapy regimen.

The research was published online on July 13, 2017 by the journal JAMA Oncology. Read “Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial.”

Treatment given before surgery to weaken or shrink the cancer is called neoadjuvant treatment. Neoadjuvant treatment often is recommended when the breast cancer is large, aggressive, and/or has spread beyond the breast to surrounding tissue.

Carboplatin is the only platinum-based chemotherapy medicine approved by the U.S. Food and Drug Administration (FDA) to treat breast cancer. Platinum-based chemotherapy weakens or destroys breast cancer cells by damaging the genetic material in the cells and making it hard for cells to repair any genetic damage.

Many inherited cases of breast cancer are associated with two gene mutations: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two).

The average woman in the United States has about a 1 in 8, or about 12%, risk of developing breast cancer in her lifetime. Women who have a BRCA1 or BRCA2 mutation (or both) can have up to an 80% risk of being diagnosed with breast cancer during their lifetimes. Breast cancers associated with an abnormal BRCA1 or BRCA2 gene tend to develop in younger women and occur more often in both breasts than cancers in women without these genetic mutations.

Women with an abnormal BRCA1 or BRCA2 gene also have an increased risk of developing ovarian, colon, and pancreatic cancers, as well as melanoma.

In the GeparSixto study, 315 women diagnosed with triple-negative breast cancer were randomly assigned to receive either:

  • standard neoadjuvant chemotherapy
  • standard neoadjuvant chemotherapy plus carboplatin

Early results from the GeparSixto study found that adding carboplatin to the standard neoadjuvant chemotherapy for triple-negative disease improves pathologic complete response rates.

The women had breast cancer surgery after chemotherapy was completed. A pathologist examined the tissue that was removed to see if there were signs of cancer cell activity. One way doctors judge the effectiveness of treatment given before surgery is to look at the tissue removed during surgery to see if any cancer cells are present. If no cancer cells are there, doctors call it a “pathologic complete response.” This is abbreviated as pCR. Many doctors believe that a pathologic complete response to neoadjuvant treatment means the cancer is less likely to come back.

Overall pCR rates were:

  • 56.8% for women treated with standard neoadjuvant chemotherapy plus carboplatin
  • 41.4% for women treated with standard neoadjuvant chemotherapy alone

After about 3 years of follow-up, overall disease-free survival rates were:

  • 85.5% for women treated with standard neoadjuvant chemotherapy plus carboplatin
  • 76.1% for women treated with standard neoadjuvant chemotherapy alone

These differences were statistically significant, which means that they were likely due to the difference in treatment and not just because of chance.

In the secondary analysis of GeparSixto data, the researchers looked at information from 291 women in the study:

  • 43 women had a BRCA1 mutation (14.8%)
  • 7 women had a BRCA2 mutation (2.4%)
  • 23 of the 50 women (46%) with a BRCA1 or BRCA2 mutation were diagnosed with breast cancer when they were younger than 40
  • only 42 of the 241 women (17.4%) without a BRCA1/2 mutation were diagnosed with breast cancer when they were younger than 40

The researchers then compared pCR rates and disease-free survival rates between women with the mutations and women without the mutations.

For women treated with standard neoadjuvant chemotherapy alone, pCR rates were:

  • 66.7% for women with a BRCA1 or BRCA2 mutation
  • 36.4% for women without a BRCA1/2 mutation

For women treated with standard neoadjuvant chemotherapy plus carboplatin, pCR rates were:

  • 65.4% for women with a BRCA1 or BRCA2 mutation
  • 55% for women without a BRCA1/2 mutation

So, adding carboplatin didn’t increase pCR rates in women with a BRCA1 or BRCA2 mutation. The overall increase in pCR rates with carboplatin seems to be due to the better pCR rate in women without a BRCA1/2 mutation.

For women treated with standard neoadjuvant chemotherapy alone, disease-free survival rates were:

  • 82.5% for women with a BRCA1 or BRCA2 mutation
  • 73.5% for women without a BRCA1/2 mutation

For women treated with standard neoadjuvant chemotherapy plus carboplatin, disease-free survival rates were:

  • 86.3% for women with a BRCA1 or BRCA2 mutation
  • 85.3% for women without a BRCA1/2 mutation

The researchers pointed out that women diagnosed with triple-negative breast cancer without a BRCA1/2 mutation may benefit from the addition of carboplatin to neoadjuvant chemotherapy, while women with a BRCA1 or BRCA2 mutation may be able to have a less intense neoadjuvant chemotherapy regimen, but more research is needed to figure out the optimal regimen.

If you’ve been diagnosed with triple-negative breast cancer, these results are very encouraging. Still, it’s important to know that not having a pathologic complete response to chemotherapy before surgery doesn’t mean you won’t do well. Most women don’t have a pathologic complete response to neoadjuvant chemotherapy.

It’s also important to know that while this study alone won’t change the standard chemotherapy regimen before surgery for triple-negative breast cancer, it does suggest that changes will be coming as larger studies are done.

If you’ve been diagnosed with triple-negative breast cancer, you and your doctor will develop a treatment plan that will likely include chemotherapy and possibly targeted therapy medicines. No matter which treatments are recommended for you, you may want to talk to your doctor about:

  • why each treatment is recommended (including any combinations)
  • treatment timing and sequence
  • the expected benefits, risks, and side effects of each treatment

If you’ll be getting neoadjuvant chemotherapy and don’t have a BRCA1 or BRCA2 mutation and carboplatin isn’t part of the regimen, you may want to talk to your doctor about clinical trials with carboplatin that make sense for your unique situation.

For more information, visit the Breastcancer.org pages on Triple-Negative Breast Cancer.


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