“Amazing changes have happened in options for treatment for metastatic disease.”
Metastatic breast cancer is the most advanced stage of breast cancer (also known as stage IV), which means the cancer has spread beyond the breast to other distant parts of the body. While metastatic breast cancer can’t be cured and is more difficult to treat than early-stage breast cancer, there are many treatment options for metastatic breast cancer available, such as chemotherapy, hormonal therapy, and targeted therapy.
These treatment advances are changing the prognosis and outcomes for metastatic breast cancer patients.
“Metastatic breast cancer used to be considered a death sentence and that’s absolutely not true anymore,” says Amy Tiersten, MD, a hematologist and oncologist at the Mount Sinai Hospital in New York City. “Amazing changes have happened in options for treatment for metastatic disease.”
How Targeted Therapies for Metastatic Breast Cancer Work
Researchers have discovered certain characteristics that help cancer cells (or other cells near them) grow and thrive. This has led to the development of drugs that “target” these differences from normal cells, a class known as targeted therapy.
Targeted therapies are generally less likely than chemotherapy to harm normal, healthy cells. Many targeted drugs go after the cancer cells’ inner workings—what makes them different from normal, healthy cells—while leaving most healthy cells alone. These drugs tend to have side effects different from standard chemo drugs. Depending on the type of breast cancer, however, doctors may use targeted therapies along with chemotherapy for maximum effectiveness.
“The age of targeted therapies is really about understanding what pathways make a cancer cell proliferate more than a normal cell,” says Dr. Tiersten. “The medications that have been developed to target those specific pathways [are] absolutely incredible.”
Understanding Breast Cancer Receptors
When you look at breast cancer cells under a microscope, there are currently three possible receptors that you may find sitting on the surface: an estrogen receptor, progesterone receptor, or a growth-promoting protein called HER2/neu.
About two out of three breast cancers are hormone receptor-positive (ER-positive or PR-positive), which means their cells have estrogen or progesterone receptors. For about one in five women with breast cancer, the cancer cells have too much of HER2/neu (also called HER2) on their surface. These cancers, known as HER2-positive breast cancers, tend to grow and spread more aggressively.
“You can have some of those receptors in combination [or] one of the receptors, [but] having any of the receptors is a good thing,” says Dr. Tiersten. “Think of it as the receptor being a target, and we have targeted weapons, specific to those receptors.”
Breast cancer cells that don’t have any of these receptors are called triple-negative breast cancer.
For breast cancer cells that have receptors, doctors will recommend a targeted therapy drug depending on the type—estrogen receptor, progesterone receptor, or HER2/neu—to help stop that cell from growing.
Treating Hormone Receptor-Positive Breast Cancer with Hormone and Targeted Therapy
Hormone receptor-positive (ER-positive or PR-positive) breast cancer cells grow in response to estrogen and progesterone; they’re dependent upon these hormones for cell growth and cell division. If the cancer is hormone receptor-positive, the first course of treatment is hormone therapy using antiestrogen medications.
Antiestrogen medications (hormone therapy): “Antiestrogen medications deprive [these cells] of that estrogen and thereby starve them of what they used to grow and replicate,” says Dr. Tiersten. For hormone receptor-positive breast cancer cells, the antiestrogen hormone therapies aim to either:
- Block estrogen production. Drugs called aromatase inhibitors block the activity of an enzyme called aromatase, which the body uses to make estrogen. Examples of aromatase inhibitors approved by the FDA for metastatic breast cancer are anastrozole (Arimidex®) and letrozole (Femara®), both of which temporarily deactivates aromatase.
- Block estrogen’s effects. Selective estrogen receptor modulators (SERMs) bind to estrogen receptors to prevent estrogen from binding. SERMs approved by the FDA for treatment of metastatic breast cancer are tamoxifen (Nolvadex®) and toremifene (Fareston®). Tamoxifen has been used for more than 30 years to treat hormone receptor positive breast cancer. “Tamoxifen is one of the most well-known, gold standard [antiestrogen medications],” says Dr. Tiersten.
For women with hormone receptor-positive cancer, using targeted therapies along with hormone therapy is often helpful. Certain targeted therapy drugs can make hormone therapy even more effective, although these targeted drugs might also add to the side effects.
CDK4/6 inhibitors: CDK4 and CDK6 are enzymes that are important in cell division. CDK4/6 inhibitors are a newer class of drugs designed to interrupt the growth of cancer cells. The CDK4/6 inhibitors abemaciclib (Verzenio®), palbociclib (Ibrance®) and ribociclib (Kisqali®) are FDA-approved for breast cancer treatment. Each drug can be used in combination with antiestrogen therapy to treat hormone receptor-positive metastatic breast cancers. Abemaciclib may also be used alone without antiestrogen therapy.
mTOR inhibitors: Everolimus is a drug that targets what’s called the mTOR pathway, which is an important pathway in terms of growth and proliferation,” says Dr. Tiersten. “They’ve primarily been studied in combination with antiestrogen medications and they appear to increase the chance of response and duration of response to anti-estrogen medications,” says Dr. Tiersten. “They may reverse the emerging resistance that patients can develop to anti estrogen medications.” The medication Afinitor® is FDA-approved for metastatic breast cancer.
Treating HER2-Positive Breast Cancer with Targeted Therapy
For HER2-positive breast cancer cells, there are incredibly effective drugs that target the HER2/neu receptor, says Dr. Tiersten.
Anti-HER2 medications: These include trastuzumab (Herceptin®) or pertuzumab (Perjeta®), which are antibodies to the HER2/neu protein. Trastuzumab attaches to the HER2/neu protein, which slows or stops its growth. Trastuzumab (Herceptin®) has been used in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer that overexpresses the protein HER2/neu. Pertuzumab blocks the ability of HER2-positive breast cancer cells to receive signals that tell the cells to grow.
T-DM1: A new category of anti-HER2 medications is called T-DM1 or ado-trastuzumab emtansine. In combination with chemo, T-DM1 treats HER2-positive, locally advanced-stage or metastatic breast cancer that’s previously been treated with Herceptin and a taxane chemotherapy. T-DM1 blocks HER2-positive breast cancer cells from having the ability to receive signals telling the cells to grow. “It’s a very interesting design of a drug because it’s a very potent chemotherapy, but it attaches it to the Herceptin molecule, so it makes the chemo also very targeted and spares more normal tissue,” says Dr. Tiersten. The FDA has approved the drug Kadcyla® for the treatment of HER2-positive metastatic breast cancer.
Treating Triple-Negative Breast Cancer
Triple-negative breast cancer means that none of the common receptors—estrogen, progesterone, or HER2 / neu—are present on the breast cancer cells. For triple-negative breast cancer, the mainstay of treatment is chemotherapy, since there are no receptors on the breast cancer cell to target.
“However, there are tons of clinical trials looking at the role of newer biologic or targeted therapy to augment the effectiveness of chemotherapy or even use in lieu of chemotherapy for triple negative breast cancers,” says Dr. Tiersten.
Dr. Tiersten is a professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai. She sees patients at the Dubin Breast Center.
00:00:00,000 --> 00:00:02,234
00:00:02,234 --> 00:00:07,088
Amazing changes have happened in options
for treatment for metastatic disease
00:00:07,088 --> 00:00:12,094
compared to from when I was in training
20 years ago, to 10 years ago, to now.
00:00:12,094 --> 00:00:16,462
00:00:16,462 --> 00:00:19,921
Chemotherapy is pretty coarse cuz
you're killing cancer cells, but
00:00:19,921 --> 00:00:23,552
you're also killing some normal cells
that rapidly divide, like hair or
00:00:23,552 --> 00:00:25,480
the stomach lining or nails.
00:00:25,480 --> 00:00:30,070
The age of targeted therapies is
really about understanding what
00:00:30,070 --> 00:00:34,620
pathways make a cancer cell
proliferate more than a normal cell.
00:00:34,620 --> 00:00:39,980
And medications that have been developed
to target those specific pathways
00:00:39,980 --> 00:00:41,970
is absolutely incredible.
00:00:41,970 --> 00:00:45,690
So if you have a breast cancer cell,
there's three possible receptors,
00:00:45,690 --> 00:00:49,070
which are kind of like these filaments
that sit on the surface of the cell.
00:00:49,070 --> 00:00:53,110
There's the estrogen receptor,
progesterone receptor, and then there's
00:00:53,110 --> 00:00:58,000
a protein called HER2/neu which is over
expressed in about 20% of breast cancers.
00:00:58,000 --> 00:01:02,540
And you could have some of those receptors
in combination, none of the receptors.
00:01:02,540 --> 00:01:05,450
So having any of the receptors
is a good thing.
00:01:05,450 --> 00:01:08,710
Think of it as the receptor
being a target, and
00:01:08,710 --> 00:01:13,560
we have targeted weapons
specific to those receptors.
00:01:13,560 --> 00:01:16,420
Breast cancer cells that
are hormone receptor
00:01:16,420 --> 00:01:19,700
positive grow in response to estrogen and
00:01:19,700 --> 00:01:23,050
They're dependent upon the hormones for
cell growth and cell division.
00:01:23,050 --> 00:01:27,650
And so the anti-estrogen medications
deprive them of that estrogen and
00:01:27,650 --> 00:01:31,730
thereby starve them of what
they use to grow and replicate.
00:01:32,800 --> 00:01:35,600
So there's several different
types of anti-estrogen therapy.
00:01:35,600 --> 00:01:38,790
One of the most well known, gold standard,
been around for decades and
00:01:38,790 --> 00:01:40,440
decades is tamoxifen.
00:01:40,440 --> 00:01:44,520
Another very common anti-estrogen
medication is a category of drugs which
00:01:44,520 --> 00:01:46,160
are known as aromatase inhibitors.
00:01:46,160 --> 00:01:50,740
Some of the most exciting new targeted
therapies are the CDK 4/6 inhibitors.
00:01:50,740 --> 00:01:54,210
There's three that are available
in the United States,
00:01:54,210 --> 00:01:58,040
palbociclib, ribociclib, and abemaciclib.
00:01:58,040 --> 00:02:01,440
Those drugs inhibit
cell cycle progression.
00:02:01,440 --> 00:02:05,170
Currently they're used in hormone
receptor positive breast cancer only.
00:02:05,170 --> 00:02:08,590
One of them, abemaciclib,
also has activity by itself,
00:02:08,590 --> 00:02:13,130
not necessarily in combination
with anti-estrogen medication.
00:02:13,130 --> 00:02:15,730
There's a drug called everolimus,
00:02:15,730 --> 00:02:20,080
which is a drug that targets
what's called the mTOR pathway,
00:02:20,080 --> 00:02:24,430
which is another pathway that's important
in terms of growth and proliferation.
00:02:24,430 --> 00:02:27,940
They've primarily been studied in
combination with anti-estrogen
00:02:27,940 --> 00:02:28,680
00:02:28,680 --> 00:02:32,220
They appear to increase
the chance of response and
00:02:32,220 --> 00:02:37,660
the duration of response to
anti-estrogen medications, may reverse
00:02:37,660 --> 00:02:43,180
the emerging resistance that patients can
develop to anti-estrogen medications.
00:02:43,180 --> 00:02:44,920
For her HER2 positive breast cancer,
00:02:44,920 --> 00:02:48,670
there are incredibly effective drugs
that are targeted to that receptor.
00:02:48,670 --> 00:02:53,290
So there's trastuzumab and pertuzumab,
which are the antibodies to that protein,
00:02:53,290 --> 00:02:54,560
00:02:54,560 --> 00:02:57,520
And there's a couple of new
medications that are effective for
00:02:57,520 --> 00:02:59,950
metastatic HER2 positive breast cancer.
00:02:59,950 --> 00:03:04,000
One is a new category of
drugs which is called T-DM1.
00:03:04,000 --> 00:03:07,380
It's very interesting design of
a drug because it takes a very
00:03:07,380 --> 00:03:12,590
potent chemotherapy but
it attaches it to the herceptin molecule.
00:03:12,590 --> 00:03:17,560
So it makes the chemo also very
targeted and spares more normal tissue.
00:03:17,560 --> 00:03:21,140
Triple negative breast cancer, the main
stay of treatment is chemotherapy because
00:03:21,140 --> 00:03:25,252
we don't have the targeted
therapies to different receptors.
00:03:25,252 --> 00:03:29,542
However there's tons of clinical trials
that are looking at the role of newer
00:03:29,542 --> 00:03:35,440
biologic or targeted therapies to augment
the effectiveness of chemotherapy or
00:03:35,440 --> 00:03:37,490
even use in lieu of chemotherapy.
00:03:37,490 --> 00:03:41,111
For triple negative breast cancer,
it's a very important area of research.
00:03:41,111 --> 00:03:45,279
Hormone Therapy for Breast Cancer. National Cancer Institute. (Accessed on January 10, 2021 at https://www.cancer.gov/types/breast/breast-hormone-therapy-fact-sheet)
Systemic treatment for metastatic breast cancer: General principles. UpToDate. (Accessed on January 10, 2021 at https://www.uptodate.com/contents/systemic-treatment-for-metastatic-breast-cancer-general-principles)
Targeted Therapy for Breast Cancer. American Cancer Society. (Accessed on January 10, 2021 at https://www.cancer.org/cancer/breast-cancer/treatment/targeted-therapy-for-breast-cancer.html)