Systemic Treatments For Stage Iv Breast Cancer
Treatment often continues until the cancer starts growing again or until side effects become unacceptable. If this happens, other drugs might be tried. The types of drugs used for stage IV breast cancer depend on the hormone receptor status, the HER2 status of the cancer, and sometimes gene mutations that might be found.
Treatment Efficacy And Aes
The treatment efficacies of subsequent therapies are shown in Figure 2 and Table 3. The median PFS in group A was 4.0 months . PFS was longer in group C than in group A, but the difference was not significant . No cases of complete response or partial response were observed in group B. The ORR tended to be better in group C than in group A and had a significantly better CBR . Within the cases in which a CDK4/6 inhibitor was used as the first or second line of treatment, the ORRs were 12.5, 0, and 0% and the CBRs were 25, 9, and 16.6% in groups A, B, and C, respectively .
Table 3.
Efficacy of subsequent therapies
Fig. 2.
Progression-free survival of subsequent treatments. Group A: exemestane plus everolimus , group B: endocrine monotherapy , group C: chemotherapy . Symbols indicate censored data. The median PFS was 4.0 months in group A, 3.8 months in group B, and 6.6 months in group C. Survival rate was estimated by using the Kaplan-Meier method and compared by using the log-rank test.
Table 4 shows the AEs of subsequent therapies. The frequencies of stomatitis and hyperglycemia as nonhematological AEs were higher in group A than in the other 2 groups. In group C, there was 1 case of grade 3 renal dysfunction and 1 case of grade 3 pneumonia. No difference in the incidences of grade 3 AEs was observed between groups A and C. The frequency of treatment discontinuation because of AEs did not differ between the 3 groups.
Table 4.
Adverse events of subsequent therapies
What Are The Side Effects Of Treatment
Generally, the side effects of hormonal therapies tend to be mild and fairly well tolerated, says Brufsky. The most common side effects are menopausal symptoms , achiness in the joints and bones, and fatigue. AIs can cause some bone loss , but that can typically be well controlled with bone-modifying medications, Brufsky notes. CDK4/6 inhibitors may cause low white blood cell counts as well as some nausea and diarrhea.
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Antiangiogenic Effects Of Other Drugs
Endocrine therapy for breast cancer is mostly used in ER positive patients, and tamoxifen is the most commonly used anti-estrogen therapy. Existing data indicate that a variety of estrogen hormones, such as estradiol and progesterone, increase the expression level of VEGF in breast cancer , while tamoxifen can inhibit the secretion of VEGF and reduce the density of vascular endothelial cells in breast cancer by more than 50%, the mechanism of which is related to the regulation of the expression ratio of VEGF and sVEGFR-1 .
In addition, there is a crossover between the downstream signaling pathway of ER and VEGF signaling pathway in breast cancer , which provides a theoretical basis for clinical endocrine therapy combined with other angiogenesis inhibitors.
Research On Enhertu And Her2
The FDA approval was based on results from the DESTINY-Breast04 study, which found that Enhertu improved both progression-free survival and overall survival in people diagnosed with previously treated metastatic HER2-low breast cancer when compared with doctors choice of chemotherapy.
Progression-free survival is how long a person lives without the cancer growing. Overall survival is how long a person lives, whether or not the cancer grows.
In the DESTINY-Breast04 study, the researchers defined breast cancer as HER2-low if it received an IHC score of 1+ or an IHC score of 2+ and a negative FISH test.
The FDA announcement included a definition of HER2-low breast cancer that seems to suggest the DESTINY-Breast04 studys definition is to become the standard.
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Understanding Your Her2 Status
HER2-negative and HER2-positive breast cancers have the same symptoms. Your doctor canât tell which type you have by examining you. Instead, theyâll run a test on a small piece of your tumor. Theyâll get the sample for testing either during a biopsy or in surgery.
Your HER2 status is one of many things that affect how fast your breast cancer will grow. There are other hormone receptors that respond to hormones in your blood as well. Doctors also sometimes refer to receptors separately as estrogen receptors and progesterone receptors .
But doctors often talk about all the different receptors together. So your HER2-negative cancer will be either HR-positive/HER2-negative or HR-negative/HER2-negative. If your cancer is negative for HER2 and both types of hormone receptors, itâs called triple negative.
Knowing your breast cancerâs HER2 status — together with its hormone receptor status — tells you and your doctors about the biology of the cancer. It helps doctors decide which treatment is best to try first and what options you have if you need to try something else later.
Some breast cancer treatments work by targeting HER2. If your cancer is HER2-negative, your doctor wonât use those therapies. Theyâll suggest other options based on how advanced your cancer is and whether itâs positive for hormone receptors. They might also look at other factors, including genetic or other changes in your cancer that could affect how fast itâs likely to grow or spread.
Summary Of Treatment Options For Metastatic Breast Cancer
Hormone receptor-positive, HER2-negative breast cancer
Hormonal therapy is considered the standard initial treatment for HER2-negative metastatic breast cancer that is also hormone receptor-positive. It is often given in combination with targeted therapy. However, chemotherapy may also be given. A clinical trial may also be an option for treatment at any stage.
Hormone receptor-negative, HER2-negative breast cancer
In general, chemotherapy or targeted therapy is given for treatment of triple-negative breast cancer. A clinical trial may also be an option for treatment at any stage.
HER2-positive breast cancer that has spread to parts of the body other than the brain
In general, HER2-targeted therapy is regularly added to treatment for HER2-positive breast cancer that has spread. The drugs used depend on the treatments already given and whether the cancer is hormone receptor-positive. The treatment recommendations for first-line, second-line, and third-line or higher treatment are described below. A clinical trial may also be an option for treatment at any stage.
First-line treatment
Second-line treatment
-
For people with advanced breast cancer that has grown during or after first-line treatment with a HER2-targeted therapy, ASCO recommends trastuzumab deruxtecan as a second-line treatment.
Third-line or higher treatment
HER2-positive breast cancer that has spread to the brain
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Definition Of Hormone Sensitivity And Hormone Resistance In Metastatic Luminal Disease
What variables can be used to set the definition of hormone sensitivity and hormone resistance in luminal MBC?
Two different scenarios must be considered when establishing the possible definition of primary or secondary hormone resistance. One would be time-dependent, defining relapse after adjuvant treatment, and the other would consider time to progression during the treatment of metastatic disease. If relapse occurs within 2 years after beginning adjuvant HT, or during the first 6 months of first-line HT, experts consider that resistance or insensitivity to HT is primary or intrinsic. In turn, when the diagnosis of relapse occurs more than 2 years after starting adjuvant HT, but within 1 year of completing adjuvant therapy, or if progression occurs later than 6 months after starting HT for metastatic disease, experts consider that resistance is acquired or secondary . Regardless of the time periods, if relapse occurs during adjuvant HT, the disease is resistant to that specific hormonal strategy . The same occurs if metastatic cancer progresses within a period of less than 1 month after discontinuation of such treatment . Table 3 shows some of the definitions used in clinical practice guidelines.
Table 3 Main definitions of primary and secondary hormone resistance
Is there evidence for suggesting that a combination of several hormonal drugs can reverse hormone resistance and increase effectiveness compared to single-agent hormone therapy?
How Common Is Her2
About 4 out of 5 breast cancers donât have extra HER2. Chances are good that your HER2-negative breast cancer is positive for one or both hormone receptors. Almost 70% of breast cancers are HR-positive/HER2-negative. Only about 10% of them are HR-negative/HER2-negative or triple negative.
Cancers can change over time. If your HER2-negative cancer goes away, then comes back or spreads, your doctor may test it again to see if itâs still negative for HER2.
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What Is A 5
A relative survival rate compares women with the same type and stage of breast cancer to women in the overall population. For example, if the 5-year relative survival rate for a specific stage of breast cancer is 90%, it means that women who have that cancer are, on average, about 90% as likely as women who dont have that cancer to live for at least 5 years after being diagnosed.
Progression During Hormone Therapy
For hormone receptor-positive cancers that were being treated with hormone therapy, switching to another type of hormone therapy sometimes helps. For example, if either letrozole or anastrozole were given, using exemestane, possibly with everolimus , may be an option. Another option might be using fulvestrant or a different aromatase inhibitor, along with a CDK inhibitor. If the cancer has a PIK3CA mutation and has grown while being treated with an aromatase inhibitor, fulvestrant with alpelisib might be considered. If the cancer is no longer responding to any hormone drugs, chemotherapy immunotherapy, or PARP inhibitors might be options depending on specific features of the cancer or any gene changes that might be present.
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What Do The Test Results Mean
The results of HER2 testing will guide you and your cancer care team in making the best treatment decisions.
It is not clear if one test is more accurate than the other, but FISH is more expensive and takes longer to get the results. Often the IHC test is done first.
- If the IHC result is 0 or 1+, the cancer is considered HER2-negative. These cancers do not respond to treatment with drugs that target HER2.
- If the IHC result is 3+, the cancer is HER2-positive. These cancers are usually treated with drugs that target HER2.
- If the IHC result is 2+, the HER2 status of the tumor is not clear and is called “equivocal.” This means that the HER2 status needs to be tested with FISH to clarify the result.
Triple-negative breast tumors dont have too much HER2 and also dont have estrogen or progesterone receptors. They are HER2-, ER-, and PR-negative. Hormone therapy and drugs that target HER2 are not helpful in treating these cancers. See Triple-negative Breast Cancer to learn more.
Triple-positive breast tumors are HER2-positive, ER-positive, and PR-positive. These cancers are treated with hormone drugs as well as drugs that target HER2.
Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.
Last Revised: May 25, 2022
Factors To Consider In Selecting Chemotherapeutic Regimens
For the therapeutic options for patients who undergo the chemotherapy, several factors that affect the individual treatment should be taken into account. Since many drugs are available for breast cancer, there is no optimum treatment order applicable to all patients. The patients with metastatic breast cancer often receive numerous treatments during the course of treatment. Since metastatic breast cancer is generally considered incurable disease, participation in clinical trials is also recommended.
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Tamoxifen Fulvestrant And Ovarian Suppression
Tamoxifen emerged as a non-surgical alternative for the management of ER+ MBC in the late 1970s. A non-steroidal selective estrogen receptor modulator whose primary effect is to competitively inhibit the binding of estradiol to ERs, tamoxifen prevents the receptor from binding to the estrogen-response element on DNA. However, it also induces elevated estradiol levels via a partial agonist effect that can be suppressed to normal postmenopausal levels by gonado-tropin-releasing hormone agonists. Studies comparing tamoxifen with oopherectomy among pre-meno pausal women with MBC found no significant difference in overall response rate , duration of response, time to progression , or survival, nor was there a significant difference in outcomes when GnRH agonists were compared with oopherectomy .
Complete estrogen blockade in premenopausal women can be achieved by using combination therapy and is analogous to the principle of total androgen blockade in prostate cancer. Meta-analysis has confirmed that the combination of GnRH agonists plus tamoxifen affords a superior progression-free survival and overall survival compared with luteinizing hormone release hormone agonists alone in the treatment of premeno-pausal women with ER/PR+ MBC .
Future Directions: Molecular Subtypes And Targeted Therapy
While ER, PR, and Her2 status primarily inform the selection of therapy for MBC, recent advances in genomic analysis have provided insight into metastatic behavior of breast cancers within specific biologic subtypes. In addition to the conventional prognostic factors of size and lymph node involvement, analysis of archival specimens in women by breast cancer subtypes – such as luminal A, luminal B, luminal/Her2-enriched, non-luminal/Her2-enriched, basal-like, and triple-negative tumors – appears to show different patterns of relapse and response to treatment . ER- tumors are associated with early relapse and a higher proportion of metastatic disease involving the central nervous system, whereas ER+ tumors carry a risk of late relapse with a predilection for bone. Her2-enriched tumors demonstrate a high relapse rate in the brain, liver, and lung. Triple-negative basal-like tumors demonstrate a high and early relapse rate, with a greater incidence of brain, lung, and nodal metastases triple-negative non-basal like subtypes also demonstrate a higher rate of visceral involvement that includes a greater proportion of liver metastases . Although molecular subtype analysis is not yet a standard component of pathologic evaluation, knowledge of these subtypes in the future may add to the evaluation of women with MBC, affording both prognostic and predictive tools.
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What Is Her2 And What Does It Mean
HER2 is a protein that helps breast cancer cells grow quickly. Breast cancer cells with higher than normal levels of HER2 are called HER2-positive. These cancers tend to grow and spread faster than breast cancers that are HER2-negative, but are much more likely to respond to treatment with drugs that target the HER2 protein.
All invasive breast cancers should be tested for HER2 either on the biopsy sample or when the tumor is removed with surgery.
Paradoxical Estrogen Sensitization: Estradiol
The development of estrogen sensitization in breast cancer cells after long-term estrogen deprivation paradoxically enables treatment with low-dose estradiol that in some cases confers re-sensitization to subsequent retreatment with an AI. Women with ER/PR+ AI-resistant metastatic disease were randomly assigned to 30 mg daily of estradiol or 6 mg daily to assess CBR in the low-dose versus higher-dose group . AI resistance was defined as relapse within 2 years after adjuvant AI or prior treatment within the metastatic setting. Study participants who had been exposed to fulvestrant within the previous 12 months were excluded because of data showing in vitro antagonism of estrogen-induced apoptosis. There was no significant difference in the CBR between the two groups, and re-treatment with the last AI used in the responders showed clinical benefit in three of the seven patients re-treated.
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Definition Of Metastatic Disease Or Locoregional Recurrence Not Susceptible To Local Curative Treatment
The luminal subtype is characterized by overexpression of estrogen receptors and/or progesterone receptors . HR status is determined using immunohistochemical techniques on tumor biopsies. The tumor is considered HR positive if HR expression is detected in at least 1% of the nuclei of the invasive tumor cells. Staining in10% of the nuclei indicates unambiguous positivity for the indication of HT if staining is observed in 110% of the nuclei, the pros and cons of HT must be weighed up. Tumors without ER expression but with positive PR expression should be considered RH-positive tumors that may benefit from HT .
Is it necessary to determine the intrinsic luminal subtype using gene expression platforms for therapeutic decision-making in luminal MBC?
Can luminal A and B MBC subtypes be differentiated using immunohistochemical techniques?
What are the criteria for defining menopause?
Table 1 Definitions of menopause from clinical practice guidelines
Should metastatic disease be biopsied at the time of its appearance and should the result guide the therapeutic decision?
Table 2 shows the recommendations and conclusions of the expert group with regard to this topic.
Table 2 Recommendations and conclusions on the definition of metastatic or recurrent locoregional luminal disease not susceptible to curative local treatment
Adverse Reactionsmaintenance Recurrent Ovarian Cancer
Most common adverse reactions in 20% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: nausea , fatigue , anemia , vomiting , nasopharyngitis/upper respiratory tract infection /influenza , diarrhea , arthralgia/myalgia , dysgeusia , headache , decreased appetite , and stomatitis .
Study 19: nausea , fatigue , vomiting , diarrhea , anemia , respiratory tract infection , constipation , headache , decreased appetite , and dyspepsia .
Most common laboratory abnormalities in 25% of patients who received LYNPARZA in the maintenance setting were: increase in mean corpuscular volume , decrease in hemoglobin , decrease in leukocytes , decrease in lymphocytes , decrease in absolute neutrophil count , increase in serum creatinine , and decrease in platelets .
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Where Do These Numbers Come From
The American Cancer Society relies on information from the Surveillance, Epidemiology, and End Results Program database, maintained by the National Cancer Institute , to provide survival statistics for different types of cancer.
The SEER database tracks 5-year relative survival rates for breast cancer in the United States, based on how far the cancer has spread. The SEER database, however, does not group cancers by AJCC TNM stages . Instead, it groups cancers into localized, regional, and distant stages:
- Localized: There is no sign that the cancer has spread outside of the breast.
- Regional: The cancer has spread outside the breast to nearby structures or lymph nodes.
- Distant: The cancer has spread to distant parts of the body such as the lungs, liver, or bones.