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Some Triple-Negative Breast Cancers Are More Aggressive Than Others

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Not all triple-negative breast cancers are the same, with certain subtypes being much more aggressive than others, according to a study done by researchers at the Cleveland Clinic.

The study was published on April 12, 2021, by the journal JAMA Network Open. Read the abstract of “Clinical and Demographic Factors, Treatment Patterns, and Overall Survival Associated With Rare Triple-Negative Breast Carcinomas in the US.”

About triple-negative breast cancer
About the study
What this means for you

About triple-negative breast cancer

Triple-negative breast cancer is breast cancer that is:

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

This means that the growth of the cancer isn’t driven by the hormones estrogen or progesterone, or by the HER2 protein. So, triple-negative breast cancer doesn’t respond to hormonal therapy medicines or medicines that target HER2 protein receptors. About 15% of breast cancers are triple-negative.

Triple-negative breast cancers tend to be:

  • considered more aggressive than hormone-receptor-positive or HER2-positive breast cancer, mainly because there are few targeted therapy medicines that treat triple-negative breast cancer; studies suggest that triple-negative breast cancer is more likely to spread beyond the breast and more likely to come back after treatment (recur) than other types of breast cancer
  • higher grade than other types of breast cancer; the higher the grade, the less the cancer cells resemble healthy cells; on a scale of 1 to 3, triple-negative breast cancers are often grade 3

Triple-negative breast cancers currently are considered a single type of cancer and usually treated with chemotherapy. Still, research has shown there are different subtypes of triple-negative breast cancer, based on the clinical, pathological, and molecular characteristics of the cancer.

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About the study

In this study, the researchers looked at three rare subtypes of breast cancer to see how many were triple-negative, as well as how the different subtypes responded to treatment.

The subtypes were:

  • Medullary carcinoma: This subtype is called “medullary” carcinoma because the tumor is a soft, fleshy mass that looks like a part of the brain called the medulla. Medullary carcinoma cells are usually high-grade in their appearance and low-grade in their behavior. In other words, they look like aggressive, highly abnormal cancer cells, but they don’t act like them. Medullary carcinoma doesn’t grow quickly and usually doesn’t spread outside the breast to the lymph nodes.
  • Adenoid cystic carcinoma: The cells of adenoid cystic breast cancer look like cancer cells that are more commonly found in the salivary glands and saliva. In general, adenoid cystic carcinomas are low-grade and slow growing. Adenoid cystic breast cancers are often triple-negative.
  • Metaplastic breast cancer: The cells of metaplastic breast cancer look abnormal, but they still look like milk duct cells. Metaplastic breast cancers also contain cells that look like the soft and connective tissues of the breast. It’s thought that the ductal cells have gone through a change in form (metaplasia) to become completely different cells, but it’s not known how or why this happens. Metaplastic breast cancers are usually high grade, larger at diagnosis, and are considered more likely to recur and spread outside the breast. Metaplastic breast cancers are often triple-negative.

The study included information from 8,479 people diagnosed with one of the three rare breast cancer subtypes between 2010 and 2016. All the information came from the National Cancer Database, a collection of cancer information collected from more than 1,500 Commission on Cancer-accredited facilities in the United States. The database is sponsored by the American College of Surgeons and the American Cancer Society.

Of the people in the study:

  • 99.48% were women
  • 79% were white
  • 16% were Black
  • the average age was about 63
  • 255 (3%) were diagnosed with medullary carcinoma
  • 1,357 (16%) were diagnosed with adenoid cystic carcinoma
  • 6,867 (81%) were diagnosed with metaplastic breast cancer

The average follow-up times were:

  • about 6.75 years for people with medullary carcinoma
  • about 4.6 years for people with adenoid cystic carcinoma
  • about 3.72 years for people with metaplastic breast cancer

Treatment included:

  • surgery to remove the tumor in 99.6% of people with medullary carcinoma, 97.2% of people with adenoid cystic carcinoma, and 93.7% of people with metaplastic breast cancer
  • chemotherapy in 74.5% of people with medullary carcinoma, 12.9% of people with adenoid cystic carcinoma, and 68.6% of people with metaplastic breast cancer
  • hormonal therapy in 21.2% of people with medullary carcinoma, 11.2% of people with adenoid cystic carcinoma, and 13.1% of people with metaplastic breast cancer
  • radiation therapy in 61.2% of people with medullary carcinoma, 52.4% of people with adenoid cystic carcinoma, and 49.7% of people with metaplastic breast cancer
  • immunotherapy in 2.4% of people with medullary carcinoma, 0.2% of people with adenoid cystic carcinoma, and 2.8% of people with metaplastic breast cancer

The percentage of adenoid cystic carcinomas and metaplastic breast cancers that were triple-negative were similar:

  • 653 (48.1%) of adenoid cystic carcinomas were triple-negative
  • 3,637 (53.0%) of metaplastic breast cancers were triple-negative
  • 57 (22.4%) of medullary carcinomas were triple-negative

Still, 5-year overall survival rates were better for people with adenoid cystic carcinoma compared to people with metaplastic breast cancer and best for people with medullary carcinoma. Five-year overall survival rates were:

  • 91.7% for people with medullary carcinoma
  • 88.4% for people with adenoid cystic carcinoma
  • 63.1% for people with metaplastic breast cancer

“…it appears that triple-negative adenoid cystic carcinomas have 5-year survival rates that rival hormone receptor-positive disease,” Lola Fayanju, M.D., of Duke University, who was not involved in the study, said in a news report. “By examining outcomes among less common histological subtypes, the authors highlight the importance of more individualized investigation for 'orphan' breast cancers such as metaplastic carcinoma, for whom good outcomes — particularly for triple-negative cases — remain elusive.”

Metaplastic breast cancer also had the highest percentage of people diagnosed with stage III or stage IV disease. Triple-negative metaplastic breast cancer was more likely than the other rare subtypes to spread to the lungs or bones.

For each rare subtype, being triple-negative was not linked with worse overall survival compared to being hormone-receptor-positive or HER2-positive.

“This analysis is one of the largest studies investigating and updating the demographic and clinical characteristics and [overall survival] of patients with rare triple-negative breast cancers,” the researchers wrote. “Most of the patients were White and presented with stage I or stage II tumors that were poorly differentiated. Patients with metaplastic breast triple-negative breast cancer were more than twice as likely to present with metastasis to the lungs and 1.75 times as likely to present with metastasis to the bone. For each rare breast cancer subtype, triple-negative [immunohistochemistry] was not associated [with] decreased [overall survival] compared with other [immunohistochemistry] combinations.”

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What this means for you

If you’ve been diagnosed with triple-negative breast cancer, this study offers some encouraging and interesting information. The results strongly suggest that triple-negative breast cancers are not all the same and that certain subtypes have better survival rates than hormone-receptor-positive breast cancer.

Determining the subtype of triple-negative breast cancer is not universally done. Still, many cancer centers do this type of testing. You may want to ask your doctor about this study, as well as whether subtype testing has been done as part of your pathology report and what it means for your prognosis and treatment.

Armed with the most complete information you can get, you and your doctor can make the best decisions for your unique situation.

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Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser

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