Triple Threat

Breast medical oncologist Priyanka Sharma, MD, is searching for better, more personalized treatment for triple-negative breast cancer at The University of Kansas Cancer Center in Kansas City.

Breast cancer affects 1 in 8 women in her lifetime. Over the years, physicians have worked to identify different types of breast cancer to improve and customize treatment. Among the various types, triple-negative breast cancer is the rarest and most aggressive – affecting about 15% of breast cancer patients. It is also the least studied.

"If we look at how we define this type of cancer, we define it by what it is not. And when you define something by what it is not, it's harder to treat," says Dr. Sharma. "Once we know what it is, we can develop better treatments for those types of cancers."

A little-understood disease

Breast cancer can be classified in many ways, depending on the specific cause(s) and stage, but usually falls within 1 of 4 subtypes.

• Endocrine receptor-positive: This accounts for about 70% of all breast cancers and grows in response to estrogen or progesterone hormones.
• HER2 positive: About 15% of breast cancer cases are HER2 positive. This means that the cancer cells make too much of a protein called HER2.
• Triple-positive: A triple-positive breast cancer diagnosis means that the cancer cells test positive for estrogen or progesterone receptors, and also HER2 protein.
• Triple-negative: Women whose cancer cells test negative for estrogen receptors, progesterone receptors and HER2 are said to have triple-negative breast cancer. This means that the growth of this cancer is not supported by estrogen, progesterone or the HER2 protein.

Compared to other types of breast cancer, triple-negative breast cancer grows faster, is more likely to return after treatment and has a poorer prognosis. It more often affects women before age 40 or 50. It's also more common in African-American or Hispanic women, or women who carry a BRCA1 gene mutation.

While the approach to treatment is similar to all other forms of breast cancer – surgery, radiation, chemotherapy – targeted drugs like anti-estrogen agents and anti-HER2 drugs that work for the other 3 types of breast cancer won't work for triple-negative breast cancer.

"This cancer needs a more tailored approach than what we have available in clinics currently," says Dr. Sharma.

Searching for answers

To better understand the disease and what causes it, Dr. Sharma has spent the last 6 years gathering clinical information from a registry of about 900 triple-negative breast cancer patients. The idea, she says, is to find better, more personalized treatments for each patient. As one of the leading researchers studying this type of cancer, Dr. Sharma's research tool is unlike anything else in the world.

"This helps us study the cancer better," Dr. Sharma says. "It helps us understand why some women have a good response to regimen A, and some have a good response to regimen B."

Dr. Sharma suggests that triple-negative breast cancer most likely contains many different subtypes, each of which could be targeted with specific treatments once it is better understood. By studying the women in the registry, she hopes to tailor specific cancer treatments based on what works best for each woman.

Living proof

Leslie McGuire was one of the patients who benefited from Dr. Sharma's research. At just 30 years old, Leslie was inaccurately diagnosed with hormone-positive breast cancer, but she came to The University of Kansas Cancer Center for a second opinion. Here, she received a shocking new diagnosis of triple-negative breast cancer.

"The first thing I thought about was my son, who was 5 months old at the time," says Leslie. "I thought, 'I can't go anywhere. This baby needs a mom.'"

Through genetic testing, Leslie learned that she inherited a BRCA1 gene mutation – which is commonly associated with triple-negative breast cancer. Knowing that she and her husband wanted to expand their family, Leslie was put on a personalized treatment plan that also included fertility preservation.

"Within our first appointment, we were asked, 'Do you want to have another baby?' And while I couldn't even think beyond my appointment, it's pretty amazing that they were already thinking about life after cancer," says Leslie. "We saw the fertility specialist the next day."

Leslie and her husband met with specialists in advanced reproductive medicine and had emergency in vitro fertilization (IVF) before her first round of chemotherapy to preserve her eggs. She was given a special type of chemotherapy derived from the metal platinum that research, including research from Dr. Sharma's registry, suggested might work better for her. It was also less harmful to her ovaries. In addition, Leslie had a bilateral mastectomy with reconstruction after she completed chemotherapy. To stay optimistic, she recited the same mantra day after day.

With the help of her cancer care team, Leslie's mantra is coming true. She has been cancer-free since October 2014 and gave birth to her second child in 2016 – without the help of IVF.

"It was a surprise and a blessing because we didn't know if I could have another baby naturally," she says.

 The cure rates for women like Leslie aren't what physicians would like them to be. According to Dr. Sharma, around 70-80% of women with triple-negative breast cancer are cured, but about 30% are not.

"We want that number to be 100% someday," says Dr. Sharma.

Dr. Sharma's research is advancing that goal. Her detailed registry allows her to develop clinical trials targeted to the needs of patients in the region. Currently, she's the principal investigator for 4 clinical trials at The University of Kansas Cancer Center:

• BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer: This trial is studying a targeted drug called PI3K inhibitor in combination with chemotherapy in breast cancer to determine the highest dose and effectiveness of this combination in women with metastatic breast cancer.
  
  
• Neoadjuvant Carboplatin and Docetaxel in Triple-Negative Breast Cancer: This trial is evaluating the anticancer activity of a platinum-based drug used in combination with 2 different chemotherapy regimens for women with early-stage breast cancer.
  
  
• Cisplatin Plus Romidepsin and Nivolumab in Locally Recurrent or Metastatic Triple-Negative Breast Cancer: This study is evaluating the anticancer activity of DNA-damaging chemotherapy along with a targeted drug and immunotherapy in women with metastatic breast cancer.
  
  
• Cisplatin With or Without Veliparib in Treating Patients with Stage IV Triple-Negative and/or BRCA Mutation-Associated Breast Cancer: This NCI-sponsored national study is evaluating the safety and effectiveness of a targeted drug called a PARP inhibitor in combination with chemotherapy for women who have had a recurrence of triple-negative breast cancer and now have stage 4 disease.

About 120 new women participate in Dr. Sharma's registry every year. With their help, she's working to understand the biological differences between the different types of triple-negative breast cancer, and she's identifying markers that explain why certain cancers come back and why others don't. Her research, she says, has been well-received by women in the community as well as partnering physicians.

"We're still working on figuring out what drives this cancer," Dr. Sharma says. "I think we still have to make a lot of progress for treatment changes to arrive in clinic, and for all women to have access to more targeted drugs. Until then, I think clinical trials are the way to go."