Breast Cancer

Targeted Therapy and Tumor Markers

Selecting the best treatment for breast cancer depends on the results of testing for tumor markers, particularly estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Because the growth of ER+/PR+ tumors is driven by estrogen, these tumors are more likely to respond to targeted treatment with drugs that lower the amount of estrogen in the body or block its action. Treatment with these targeted drugs – called antiestrogen drugs – is known as hormone (endocrine) therapy. HER2+ tumors are more likely to respond to treatment that targets the excess HER2. This treatment is known as anti-HER2 therapy.

ER+/PR+ breast cancer

Hormone therapy may be used for ER+/PR+ breast cancer of any stage. For early-stage ER+/PR+ breast cancer, hormone therapy is given after surgery and may be given after the completion of chemotherapy, depending on a woman’s individual risk of recurrence. For metastatic ER+/PR+ breast cancer, hormone therapy may be given as primary treatment, and often, multiple hormone therapy drugs are used before (or after) chemotherapy is given.

Hormone therapy drugs are primarily classified as selective estrogen-receptor modulators (SERMs) or aromatase inhibitors (AIs), and other hormone therapy drugs are also available (Table 1). These drugs work in different ways and each has different side effects. The primary difference among hormone therapy drugs is whether they can be used for women who are premenopausal or postmenopausal. You and your doctor will consider several additional factors when choosing the best type of hormone therapy.

Table 1. Types of hormone therapy for breast cancer

Type Menopause status Action Notes
SERMs*
  tamoxifen (Nolvadex)
 
  toremifene (Fareston)
 
Premenopausal and postmenopausal
 
Postmenopausal women with advanced ER+/PR+ cancers or cancers with unknown ER/PR status
 
Temporarily block estrogen receptors on breast cancer cells, preventing estrogen from binding to them
 
Has been traditional adjuvant hormone therapy for more than 30 years
AIs
  anastrozole (Arimidex)
  exemestane (Aromasin)
  letrozole (Femara)
Postmenopausal Prevent the body from making estrogen by blocking the enzyme aromatase Associated with fewer serious side effects than tamoxifen
fulvestrant (Faslodex)
Postmenopausal Blocks estrogen receptors on breast cancer cells (preventing estrogen from binding to them) and eliminates estrogen receptors on the tumor Approved only for advanced breast cancers that have stopped responding to tamoxifen or toremifene
Luteinizing hormone-releasing hormone analogs
  goserelin (Zoladex)
Premenopausal Eliminates production of estrogens in the ovaries Used for the palliative (symptom-relieving) treatment of advanced breast cancer in premenopausal and perimenopausal women
Progestins
  megastrol acetate (Megace)
Premenopausal and postmenopausal Modifies the action of other hormones in the body; also have a damaging effect on tumor cells Used for the palliative treatment of advanced breast cancer

SERMs = selective estrogen-receptor modulators; AIs = aromatase inhibitors

SERMs

Tamoxifen (Nolvadex) has been used for several decades, and studies have shown that treatment with tamoxifen for five years after surgery for early-stage breast cancer reduces the chances of recurrence by nearly half. (Recent reports suggest that continuing adjuvant tamoxifen for 10 years might be even slightly more effective.) Tamoxifen is also used as part of treatment for advanced (metastatic) breast cancer. Both premenopausal and postmenopausal women can take tamoxifen. Another SERM, toremifene (Fareston), is used only for postmenopausal women with advanced ER+/PR+ breast cancer. Another, raloxifene (Evista), is used to reduce the risk for women at high risk but not used to treat breast cancer.

Side effects often occur with tamoxifen and toremifene, such as hot flashes, irritability and fluctuations in emotions. Serious side effects are rare but can include an increased risk of uterine cancer or blood clots in the leg. For most women, however, the benefits outweigh the risks.

AIs

AIs represent a newer class of hormone therapy drugs and are recommended only for women who are postmenopausal at the time therapy is being considered. Several clinical trials have shown that AIs offer a significant survival benefit compared with tamoxifen. Trials have also shown that AIs substantially reduce the risk of breast cancer recurrence when given in one of several ways: as the only hormone therapy for five years; as sequential treatment (after two to three years of treatment with tamoxifen); or as extended treatment (for five years after the traditional five years of treatment with tamoxifen).

On the basis of these studies, it’s recommended that treatment with an AI be considered for postmenopausal women with ER+/PR+ breast cancer. The use of tamoxifen alone is recommended only for women who do not wish to take an AI or who cannot take an AI because of potential side effects.

Several clinical trials are being done to answer whether one AI is more effective than another as well as the long-term side effects and the optimum length of treatment.

Other hormone therapies

Other hormone therapies are appropriate in specific situations. Some hormone therapy drugs are used only for advanced breast cancer. For example, fulvestrant (Faslodex) is approved for postmenopausal women with advanced breast cancer that no longer responds to tamoxifen or toremifene, and progestins are used for premenopausal or postmenopausal women with advanced breast cancer, primarily to relieve symptoms. High-dose estrogens and synthetic androgens (similar to male hormones) may also be used to manage symptoms related to advanced breast cancer, but they are used less often than SERMs and AIs.

Removal or suppression of the ovaries (by surgery or radiation therapy) is another type of hormone therapy because it substantially reduces the production of estrogens in premenopausal women. Luteinizing hormone-releasing hormone (LHRH) analogs are drugs that provide an equivalent alternative to surgical removal of the ovaries in premenopausal women.

ER-/PR- breast cancer

Hormone therapy is not effective for ER-/PR- breast cancers. For these tumors, chemotherapy is used alone or in combination with anti-HER2 therapy if the tumor is HER2+.

HER2+ breast cancer

Targeted therapy agents are those that block a specific cell function that is unique to cancer cells. They can have an impact on survival and quality of life for many people and are usually used in combination with other drugs (Table 2).

About 20 percent of breast cancer tumors make extra copies of the HER2 gene, which promotes cell division. Targeted therapy drugs made for HER2+ breast cancer are known as anti-HER2 agents. One such agent, trastuzumab (Herceptin), was the first targeted therapy developed for any cancer. It’s used for both early-stage breast cancer as adjuvant therapy or for advanced breast cancer. Newer anti-HER2 agents include lapatinib (Tykerb) and pertuzumab (Perjeta). In 2013, the FDA approved a drug called ado-trastuzumab emtansine (Kadcyla), which is a combination of trastuzumab and a chemotherapy drug and can be used to treat late-stage (metastatic) HER2+ breast cancer.

For postmenopausal women with metastatic ER+ or PR+ and HER2- tumors, another treatment is a combination therapy with the targeted drug palbociclib (Ibrance) and the aromatase inhibitor letrozole (Femara). Another treatment is the targeted therapy drug everolimus (Afinitor) used in combination with the aromatase inhibitor exemestane (Aromasin).

Table 2. Approved anti-HER2 therapy drugs for HER2+ tumors

Targeted therapy agent Type of breast cancer Approved/recommended treatment
ado-trastuzumab emtansine (Kadcyla) HER2+, metastatic For women previously treated with trastuzumab and a taxane, separately or in combination
everolimus (Afinitor) ER+/PR+, HER2-, metastatic In combination with exemestane (Aromasin) for postmenopausal women who have already been treated with letrozole or anastrozole
lapatinib (Tykerb) ER+/PR+, HER2+ In combination with letrozole for postmenopausal women
HER2+, metastatic In combination with capecitabine (Xeloda) after treatment with an anthracycline, a taxane and trastuzumab
palbociclib (Ibrance) ER+, HER2-, metastatic In combination with letrozole for postmenopausal women as a first hormone-based therapy
pertuzumab (Perjeta) HER2+, metastatic In combination with trastuzumab and docetaxel in individuals who have not been treated with anti-HER2 therapy or chemotherapy
HER2+, early stage/ neoadjuvant In combination with trastuzumab and docetaxel prior to surgery for locally advanced, inflammatory or early-stage breast cancers (either larger than 2 centimeters or have spread to lymph nodes)
trastuzumab (Herceptin) HER2+, ER+/PR+ or HER2+ ER-/PR- As part of a regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel

In combination with chemotherapy regimen of docetaxel and carboplatin

As a single agent following chemotherapy that includes an anthracycline
HER2+, metastatic In combination with paclitaxel as first-line treatment, with other chemotherapy drugs, or with lapatinib for later lines of therapy

As a single agent in patients who have received one or more chemotherapy regimens

HER2- breast cancer

Anti-HER2 drugs are not effective for HER2- breast cancer, and treatment thus depends on the presence or absence of ER and PR on the tumor. As noted earlier, hormone therapy, with or without chemotherapy, can be used for HER2-, ER+/PR+ breast cancer. Treatment options are limited, however, for tumors that are negative for ER, PR and HER2 because these tumors, referred to as “triple negative,” are not likely to respond to either anti-HER2 or hormone therapy. The only currently approved treatment option (beyond surgery) for triple-negative breast cancer is chemotherapy. Although it may respond to chemotherapy, the prognosis is good only when a complete pathologic response (no evidence of disease) is achieved after a full course of chemotherapy.

These challenges have led researchers to focus on new ways to treat this type of breast cancer. One class of targeted drugs being studied for metastatic triple-negative breast cancer is poly (ADP-ribose) polymerase (PARP) inhibitors. Triple-negative breast cancer is associated with defects in DNA repair, and PARP is an enzyme involved in the repair of DNA. Adding a PARP inhibitor to a chemotherapy agent that damages DNA could enhance the effect of the chemotherapy and may lower the chance the cancer will become resistant.

In some studies, PARP inhibitors have also been effective for metastatic hereditary breast cancer, or breast cancer with identified mutations in the BRCA1 or BRCA2 gene. Like triple-negative breast cancer, hereditary breast cancer is associated with defects in DNA repair. PARP inhibitors are still under investigation, however, and can be used only in clinical trials.

Other studies have shown that some chemotherapy drugs may lead to slightly better outcomes for women with triple-negative breast cancer than for other types. Two such drugs are ixabepilone (Ixempra), given in combination with capecitabine, and eribulin (Halaven). More research is needed to better define the effectiveness of these drugs.

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