Metastatic breast cancer is an incurable disease that is challenging to treat, but new major developments in treatment options are giving patients cause for hope for more time.
Overall survival can mean more life for people diagnosed with cancer. Ahead, we’ll explain what overall survival means, why it’s so difficult to achieve in clinical trials, and how it relates to treatment discussions patients should consider having with their care team.
Advanced-stage breast cancer is the number one cause of cancer deaths among women between the ages of 20 and 59.  This type of breast cancer, which doctors refer to as metastatic or stage 4 breast cancer, occurs when cancerous growth spreads from the breast tissue into other parts of the body.  Although most people are more familiar with early breast cancer, especially because of “Pink” Breast Cancer Awareness Month campaigns, stage 4 breast cancer is different. It can be resistant to treatment, and unlike early-stage cancers, there is no cure.  Most common cases of metastatic breast cancer appear in the lungs, liver, bones, or brain. Even when it spreads to these areas, the cancer is still breast cancer — which means it still requires breast cancer treatment. Such challenging odds used to mean that metastatic breast cancer diagnoses offered a grim future, one often full of rigorous courses of chemotherapy and medications that had not been proven to significantly prolong patients’ lives. 
Now, we’ve entered a new age of treatment. In major clinical trials, patients taking KISQALI® (ribociclib), a CDK4/6 inhibitor, in combination with endocrine therapy had a statistically significant improvement in overall survival.  In other words, adding Kisqali to their endocrine treatment extended the lives of metastatic breast cancer patients compared to endocrine therapy alone, even for patients with more aggressive types of the disease, such as younger patients or people whose cancer had spread. This discovery is changing the way doctors look at the future of cancer care. Not only that, it’s also giving metastatic breast cancer patients hope for more life to live.
A Standard Like None Other
Since metastatic breast cancer remains a terminal condition, clinicians studying the effectiveness of treatments have to measure how well those treatments work compared to other treatments and for how long through clinical trials. Most clinical trials use shorter-term efficacy measures like progression-free survival (PFS) as their primary endpoint. Overall survival takes longer to measure, because it follows the patient for the remainder of their life. PFS, however, follows a patient until their disease progresses (gets worse), which can be much sooner than the end of their life. 
When it comes to cancer treatments, evaluating overall survival can tell you how much a medicine prolonged most patients’ lives. Not only that, overall survival data demonstrates the effectiveness of treatment, and most oncologists consider overall survival the “gold standard” for judging any treatments they might prescribe. That is because overall survival data tells us which treatments are most likely to give patients more time to live their lives.
PFS and similar “surrogate endpoints” are alternative measures used to gauge the efficacy of cancer treatments. There are benefits to using these, such as determining if a treatment is effective in a shorter period of time, ultimately making new treatments available to doctors and patients quickly.
However, sometimes shorter-term efficacy measures like PFS can be ambiguous, since it is only a prediction if a treatment will help a patient live longer. For this reason, clinical trials are designed to include primary endpoints like PFS to help new treatments get approved more quickly, but also to include secondary endpoints, such as overall survival, to determine and confirm whether the treatment extends a person’s life. When investigators analyze the results, they look for statistical significance, which is a measure of reliability for the study results. Only those treatments that show a statistically significant overall survival benefit are those that can be considered proven to extend the lives of patients. In other words, overall survival is an indispensable metric, and it’s an essential data point for consideration when figuring out which treatment option is best for the individual.
Tracking Overall Survival
Demonstrating a treatment’s ability to extend overall survival is no simple task, even for the most rigorous of clinical trials. One reason is because measuring overall survival, especially for the most effective treatments, can take a long time to achieve. Overall survival calculates the number of months—even years—that patients survive after receiving a particular treatment.  Researchers studying progression-free survival are looking to predict whether the treatment is effective in delaying time to progression; not if it will help people live longer overall.
Other treatments can pose complications for showing overall survival benefit, too. One such factor is the complexity of cancer treatment itself. During the course of their care, patients with metastatic breast cancer usually undergo subsequent rounds of treatment, often with other medications or therapies. Doctors try to choose the best course of treatment for their patients, and these additional treatments impact how long a patient lives, so proving that one treatment in particular is what helped a patient live longer is difficult.
Innovating In Treatment
As of the fall of 2020, only one CDK4/6 inhibitor, Kisqali, has demonstrated statistically significant benefit in overall survival in 2 phase 3 clinical trials.  Statistical significance indicates the reliability of clinical trial results (in other words, did a study achieve its endpoint).
What does this mean? After 3 ½ years, 70% of patients who received this medicine in addition to hormone therapy were still alive, compared to 46% who only received hormone therapy.  Kisqali is the only CDK4/6 inhibitor that has been proven to prolong the lives of patients with HR+/HER2- advanced breast cancer in 2 phase 3 clinical trials. [9, 12]
Hope for More Life
After years of clinical trials, new metastatic breast cancer treatment options have entered the market, offering patients better survival benefits than ever before.
The biggest way this treatment and others change the way we think about cancer therapies is that they do away with the “save the best for last” way of thinking. Many oncology practitioners once believed that hormone therapy, followed by a more aggressive treatment if the initial therapy failed, was the most effective course for treating metastatic breast cancer. [12, 13] But when it comes to cancer treatment, time is of the essence. Now that the latest trials have proven Kisqali combination therapy as an initial treatment for HR+/HER2- metastatic disease can extend life, there is no reason to delay and wait to use it as a second or third option following disease progression. Researchers and clinicians alike now consider this combination to be the new standard of care. [12, 13]
If patients have been diagnosed with metastatic breast cancer, they don’t have to be alone. In addition to your care team, the internet brings a myriad of resources to your fingertips, including information from the Metastatic Breast Cancer Network and Breastcancer.org. Reach out to friends and family for support, and build new connections through online support groups with other breast cancer patients. Most importantly, talk to your doctor about the latest breakthroughs in breast cancer treatment, especially ones that offer longer overall survival rates than previous therapies. Your care team will help you make an informed decision about which course of treatment is right for you.
KISQALI® (ribociclib) is a prescription medicine used in combination with:
- an aromatase inhibitor to treat pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic), as the first endocrine-based therapy; or
- fulvestrant to treat postmenopausal women with HR-positive, HER2-negative metastatic breast cancer as the first endocrine-based therapy or with disease progression following endocrine therapy
It is not known if KISQALI is safe and effective in children.
IMPORTANT SAFETY INFORMATION
What is the most important information I should know about KISQALI?
KISQALI may cause serious side effects, including:
Lung problems. KISQALI may cause severe or life-threatening inflammation of the lungs during treatment that may lead to death. Tell your health care provider right away if you have any new or worsening symptoms, including:
- trouble breathing or shortness of breath
- cough with or without mucus
- chest pain
Severe skin reactions. Tell your health care provider or get medical help right away if you get severe rash or rash that keeps getting worse; reddened skin; flu-like symptoms; skin pain/burning; blistering of the lips, eyes, or mouth; or blisters on the skin or skin peeling, with or without fever.
Heart rhythm problems (QT prolongation). KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Your health care provider should check your heart and do blood tests before and during treatment with KISQALI. Tell your health care provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you feel dizzy or faint.
Liver problems (hepatobiliary toxicity). KISQALI can cause serious liver problems. Your health care provider should do blood tests to check your liver before and during treatment with KISQALI. Tell your health care provider right away if you get any of the following signs and symptoms of liver problems:
- yellowing of your skin or the whites of your eyes (jaundice)
- dark or brown (tea-colored) urine
- feeling very tired
- loss of appetite
- pain on the right side of your stomach area (abdomen)
- bleeding or bruising more easily than normal
Low white blood cell counts (neutropenia). Low white blood cell counts are very common when taking KISQALI and may result in infections that may be severe. Your health care provider should check your white blood cell counts before and during treatment with KISQALI. Tell your health care provider right away if you have signs and symptoms of low white blood cell counts or infections such as fever and chills.
Your health care provider may tell you to decrease your dose, temporarily stop, or completely stop taking KISQALI if you develop certain serious side effects during treatment with KISQALI.
What should I tell my health care provider before taking KISQALI?
Before you take KISQALI, tell your health care provider if you:
- have any heart problems, including heart failure, irregular heartbeats, and QT prolongation
- have ever had a heart attack
- have a slow heartbeat (bradycardia)
- have problems with the amount of potassium, calcium, phosphorus, or magnesium in your blood
- have fever, chills, or any other signs or symptoms of infection
- have liver problems
- have any other medical conditions
- are pregnant, or plan to become pregnant. KISQALI can harm your unborn baby
- If you are able to become pregnant, your health care provider should do a pregnancy test before you start treatment with KISQALI.
- Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI.
- Talk to your health care provider about birth control methods that may be right for you during this time.
- If you become pregnant or think you are pregnant, tell your health care provider right away.
- are breastfeeding or plan to breastfeed. It is not known if KISQALI passes into your breast milk. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI
Tell your health care provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. KISQALI and other medicines may affect each other, causing side effects. Know the medicines you take. Keep a list of them to show your health care provider or pharmacist when you get a new medicine.
What should I avoid while taking KISQALI?
Avoid eating grapefruit and avoid drinking grapefruit juice during treatment with KISQALI since these may increase the amount of KISQALI in your blood.
The most common side effects of KISQALI include:
- hair loss
KISQALI may cause fertility problems if you are male and take KISQALI. This may affect your ability to father a child. Talk to your health care provider if this is a concern for you.
Tell your health care provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of KISQALI. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.
- U.S. Food and Drug Administration. Step 3: Clinical Research. Accessed September 15, 2020.
- The American Cancer Society. Understanding Advanced and Metastatic Cancer. Accessed September 15, 2020.
- The American Cancer Society. Treatment of Stage IV (Metastatic) Breast Cancer. Accessed September 15, 2020.
- National Cancer Institute: Overall Survival. NCI Dictionary of Cancer Terms. Accessed September 15, 2020.
- National Cancer Institute: Progression-Free Survival. NCI Dictionary of Cancer Terms. Accessed September 15, 2020.
- National Cancer Institute. Endpoint. NCI Dictionary of Cancer Terms. Accessed September 15, 2020.
- Susan G. Komen. CDK4/6 Inhibitors for Treatment of Metastatic Breast Cancer. Accessed September 15, 2020.
- American Cancer Society. Hormone Therapy for Breast Cancer. Accessed September 15, 2020.
- American Cancer Society. Breast Cancer Facts & Figures 2019-2020. Accessed September 15, 2020.
- Susan G. Komen. Treatments for Metastatic Breast Cancer. Accessed September 15, 2020.
- Metastatic Breast Cancer Network. Metastatic Breast Cancer: A Fact A Day — 31 days of October. Accessed September 15, 2020.
- Im S, Lu Y, Bardia A, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. The New England Journal of Medicine. 2019. Accessed September 15, 2020.
- Slamon D J, Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. The New England Journal of Medicine. 2019. Accessed September 15, 2020.