Subtype of Metastatic Hormone-Receptor-Positive Disease May Help Guide Treatment Decisions

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Doctors are always trying to figure out which medicines best treat different types of breast cancer. The clinical characteristics of a breast cancer:

  • stage
  • tumor grade
  • tumor size
  • hormone-receptor status
  • HER2-receptor status

help guide treatment decisions for the disease.

A study suggests that the intrinsic or molecular subtype of a metastatic, hormone-receptor-positive breast cancer may help women and their doctors make treatment decisions.

The research was published in the October 2016 issue of JAMA Oncology. Read “Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib.”

There are five main intrinsic or molecular subtypes of breast cancer that are based on the genes they express:

  • Luminal A breast cancer is hormone-receptor positive (estrogen-receptor and/or progesterone-receptor positive), HER2 negative, and has low levels of the protein Ki-67, which helps control how fast cancer cells grow. Luminal A cancers are low-grade, tend to grow slowly, and have the best prognosis.
  • Luminal B breast cancer is hormone-receptor positive (estrogen-receptor and/or progesterone-receptor positive), and either HER2 positive or HER2 negative with high levels of Ki-67. Luminal B cancers generally grow slightly faster than luminal A cancers and their prognosis is slightly worse.
  • Triple-negative/basal-like breast cancer is hormone-receptor negative (estrogen-receptor and progesterone-receptor negative) and HER2 negative. This type of cancer is more common in women with BRCA1 gene mutations. Researchers aren’t sure why, but this type of cancer also is more common among younger and African-American women.
  • HER2-enriched breast cancer is hormone-receptor negative (estrogen-receptor and progesterone-receptor negative) and HER2 positive. HER2-enriched cancers tend to grow faster than luminal cancers and can have a worse prognosis, but they are often successfully treated with targeted therapies aimed at the HER2 protein, such as Herceptin (chemical name: trastuzumab), Perjeta (chemical name: pertuzumab), Tykerb (chemical name: lapatinib), and Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine).
  • Normal-like breast cancer is similar to luminal A disease: hormone-receptor positive (estrogen-receptor and/or progesterone-receptor positive), HER2 negative, and has low levels of the protein Ki-67, which helps control how fast cancer cells grow. Still, while normal-like breast cancer has a good prognosis, its prognosis is slightly worse than luminal A cancer’s prognosis

Metastatic breast cancer is breast cancer that has spread to a part of the body away from the breast, such as the bones or liver.

To do the study, the researchers analyzed 821 breast cancer tumor samples from postmenopausal women diagnosed with hormone-receptor-positive, metastatic breast cancer. The women were all part of another study, called the EGF30008 clinical trial. In the EGF30008 trial:

  • none of the women had been treated for metastatic disease before
  • the women were randomly assigned to be treated with either the hormonal therapy Femara (chemical name: letrozole) and the targeted therapy Tykerb or Femara and a placebo pill that looked just like Tykerb

The researchers classified the tumor samples as one of the five subtypes:

  • 382 cancers were luminal A
  • 244 cancers were luminal B
  • 28 cancers were basal-like
  • 61 cancers were HER2-enriched
  • 106 cancers were normal-like

Overall, 644 cancers were HER2-negative:

  • 335 were luminal A
  • 196 were luminal B
  • 16 were HER2-enriched
  • 21 were basal-like
  • 76 were normal-like

Overall, 157 cancers were HER2-positive:

  • 42 were luminal A
  • 46 were luminal B
  • 45 were HER2-enriched
  • 6 were basal-like
  • 18 were normal-like

While it might seem incorrect that 16 of the HER2-negative cancers were classified as HER2-enriched, it’s important to remember that a cancer’s intrinsic molecular subtype is based on levels of specific genes that cancer expresses. So while a cancer may have normal levels of HER2 receptors, the cancer’s genome may be expressing high levels of genes associated with HER2 and be classified as HER2-enriched.

The researchers compared the women’s progression-free survival and overall survival information with the molecular subtypes of the tumors to see how certain subtypes responded to the two treatments.

Progression-free survival is how long the women lived without the cancer growing. Overall survival is how long the women lived whether or not the cancer grew.

For the 644 HER2-negative cancers:

  • Compared to luminal A cancers, all the other subtypes had worse progression-free survival:
    • luminal B cancers had a 1.457 times higher risk of the cancer growing
    • HER2-enriched cancers had a 2.873 times higher risk of the cancer growing
    • basal-like cancers had a 2.258 times higher risk of the cancer growing
  • Median progression-free survival was:
    • 16.9 months for luminal A disease
    • 11.0 months for luminal B disease
    • 4.7 months for HER2-enriched disease
    • 4.1 months for basal-like disease
  • Similarly, compared to luminal A cancer, all the other subtypes had worse overall survival:
    • luminal B cancers had a 1.518 times higher risk of causing death
    • HER2-enriched cancers had a 2.528 higher risk of causing death
    • basal-like cancers had a 2.338 higher risk of causing death
  • Median overall survival was:
    • 45 months for luminal A disease
    • 37 months for luminal B disease
    • 16 months for HER2-enriched disease
    • 23 months for basal-like disease

For the 157 women with HER2-positive disease:

  • Compared to luminal A cancers, all the other subtypes had worse progression-free survival:
    • luminal B cancers had a 1.471 times higher risk of the cancer growing
    • HER2-enriched cancers had a 1.818 times higher risk of the cancer growing
    • basal-like cancers had a 4.799 times higher risk of the cancer growing
  • Median progression-free survival was:
    • 11.07 months for luminal A disease
    • 5.55 months for luminal B disease
    • 4.37 months for HER2-enriched disease
    • 3.58 months for basal-like disease
  • Similarly, compared to luminal A cancer, all the other subtypes had worse overall survival:
    • luminal B cancers had a 1.547 times higher risk of causing death
    • HER2-enriched cancers had a 1.913 times higher risk of causing death
    • basal-like cancers had a 2.919 times higher risk of causing death
  • Median overall survival was:
    • 32 months for luminal B disease
    • 28 months for HER2-enriched disease
    • 19 months for basal-like disease
    • Note: The researchers didn’t have enough data to calculate median overall survival for luminal A disease; this was because women diagnosed with luminal A disease were doing particularly well and not many had died

The researchers then looked to see how much Tykerb helped increase progression-free survival in each subtype. In HER2-negative disease, they found that only HER2-enriched cancers got significant benefits from Tykerb. Progression-free survival was:

  • 6.49 months for the HER2-enriched subtype of HER2-negative disease treated with Tykerb and Femara
  • 2.60 months for the HER2-enriched subtype of HER2-negative disease treated with only Femara

In HER2-positive disease, all the subtypes got more benefits from being treated with Tykerb and Femara compared to being treated with Femara alone.

“In this analysis…subtype was the most important prognostic factor for progression-free survival and overall survival beyond classical clinical-pathological factors, including HER2 status,” the researchers wrote. “The prognostic information provided by the intrinsic subtypes that further define tumor characteristics might help guide treatment decisions in metastatic breast cancer.”

If you’ve been diagnosed with hormone-receptor-positive, metastatic disease, you might want to talk to your doctor about this study. While molecular subtyping of breast cancer isn’t yet the standard of care, it is often done in clinical trials.

Molecular subtype testing is available but isn’t widely used because doctors are waiting for more studies to confirm how this information can be used to help guide treatment decisions. If you’re interested in molecular subtype testing, talk to your doctor. Together, you can figure out if this type of testing is right for your unique situation.



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