A new drug was recently approved by the US Food and Drug Administration (FDA) for the treatment of metastatic breast cancer – breast cancer that has spread to other areas of the body, such as the bones, liver, lungs or brain. Sacituzumab govitecan (Trodelvy), which is given by intravenous infusion, was granted accelerated approval to treat metastatic triple negative breast cancer in patients who have already been on 2 prior treatments for their disease.
Triple negative breast cancer accounts for approximately 15% of breast cancers. It is more common in younger patients, African Americans, and those with a BRCA1 gene mutation. It can be very challenging to treat since there is no specific cellular target, such as the estrogen receptor or Her2/neu protein. Patients with triple-negative breast cancer very commonly receive chemotherapy but the disease may come back or progress despite aggressive treatment.
Sacituzumab govitecan is an antibody-drug conjugate, which is an antibody that is combined with a chemotherapy drug. The antibody targets a protein (trophoblast cell surface antigen-2, or trop-2) on the surface of the cancer cell, and the chemotherapy drug causes breaks in the tumor cell DNA, which leads to cancer cell death. The FDA approval was based on a non-randomized (meaning all patients received the study drug) study of 108 patients who were experiencing disease progression despite receiving between 2 – 10 prior treatment regimens. Among the study participants, approximately 33% experienced a partial or complete tumor response to the medication. Median duration of treatment response was nearly 8 months. Severe adverse reactions included diarrhea, neutropenia (low white blood cell counts), anemia (low red blood cell counts), fatigue, nausea and vomiting. 2 patients stopped treatment due to side effects.
Any advance in the treatment of metastatic breast cancer is welcome news. It is hoped that as new drugs are developed, a longer-lasting response to therapy will be achieved.
The US Food and Drug Administration (FDA) has recently approved a new treatment for patients with metastatic breast cancer. Tucatinib (Tukysa) was approved for use in combination with 2 other agents, trastuzumab (Herceptin) and capecitabine (Xeloda) in patients with unresectable (too advanced to remove with surgery) or metastatic (spread to other areas of the body, such as bone, liver, lungs or brain) Her2/neu over-expressed breast cancer (Her2+). Tucatinib is approved for patients who have already been treated with one or more anti-Her2/neu treatments.
Tucatinib is a an oral (pill) medication known as a tyrosine kinase inhibitor. Results of the Her2CLIMB trial were presented in December at the San Antonio Breast Cancer Symposium. The study enrolled 612 patients with metastatic or unresectable Her2+ breast cancer who had received at least one other Her2+ targeted agent but were experiencing progression of disease. Unique to this study was that almost half of the participants had metastases to the brain – often these patients are excluded from clinical trials.
Some of the key findings were that in patients who received tucatinib with trastuzuab and capecitabine versus those who received trastuzumab and capecitabine alone:
Median progression free survival was 7.8 months versus 5.6 moths
Median progression free survival for patients with baseline brain metastases was 7.6 versus 5.4 months
Median overall survival was 21.9 versus 17.4 months
Confirmed objective response rate was 40.6% versus 22.8%
Serious adverse reactions occurred in 26% of patients and 6% of patients had to stop treatment due to adverse reactions. The most common side effects were diarrhea, hand-foot syndrome, nausea, fatigue, liver toxicity, mouth sores, decreased appetite, abdominal pain, headache, anemia and rash.
The approval of tucatinib provides another option for patients with aggressive breast cancer, including those who have brain metastases. However, as previously discussed, this study is a reminder of how far we have to go to achieve a reliable and long-lasting treatment response in patients with metastatic breast cancer.
https://drattai.com/wp-content/uploads/2019/12/56484315_s.jpg692692drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2020-04-20 03:56:102020-04-20 03:56:17Tucatinib Approved for Metastatic Breast Cancer
“Recurrence” simply means that the cancer has come back. Breast cancer can recur in the breast or chest area, which is called a local recurrence. This is usually treated with surgery to remove the recurrent tumor, most commonly mastectomy if lumpectomy was the original operation. Radiation therapy, chemotherapy, or hormonal therapy may also be recommended. The risk of local recurrence after lumpectomy is generally less than 10% and less than 5% after mastectomy.
Breast cancer cells can travel from the breast to the lymph nodes or through the blood stream and then deposit in other organs. This is termed systemic recurrence, metastatic breast cancer, or stage 4 breast cancer. The lungs, liver, bones and brain are the most common sites for metastatic breast cancer. Metastatic breast cancer is not curable, and patients who develop metastatic disease will require lifelong treatment.
Anyone who has been treated for breast cancer can develop metastatic disease. It is estimated that as many as 30% of patients will eventually develop metastatic disease but it difficult to get exact numbers because recurrences are not tracked like initial diagnoses are. The likelihood of developing metastatic disease is higher in patients who are diagnosed at more advanced stages and in those with more aggressive tumor biology / behavior, but even the less aggressive or slower growing tumors have the potential to spread.
Since the most common sites of spread are the lungs, liver, bones and brain, attention should be paid to changes such as persistent cough or shortness of breath, abdominal pain, increased abdomen size, jaundice (yellowing of the eyes), persistent bone pain, fractures with no history of trauma, severe headaches, and new onset seizure. However, patients may have metastatic disease without any symptoms. While there is no true prevention, endocrine therapy (for those with estrogen receptor positive breast cancer) can reduce risk. A healthy diet, regular exercise, and weight control can also reduce risk. It is of course possible to do “everything right” and still develop metastatic cancer.
As mentioned, treatment for stage 4 breast cancer is lifelong. There have been many advances in the treatment of metastatic breast cancer – chemotherapy is not always required and newer targeted therapies have been developed. This is an area of active research. However, approximately 40,000 women and 500 men will die each year in the US due to metastatic breast cancer. More work is needed to better understand why some patients develop metastatic breast cancer, how to prevent breast cancer from spreading, and how best to treat it once it does spread.
https://drattai.com/wp-content/uploads/2020/02/101534502_s.jpg576831drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2020-02-05 03:07:442020-02-05 03:07:46Stage 4 Breast Cancer
Two studies recently presented at the recent San Antonio Breast Cancer Symposium focused on a subtype of breast cancer known as Her2/neu over-expressed, which include up to 20% of breast cancers. In these tumors, the gene that codes for the Her2 protein receptor has more than the usual number of copies. These tumors tend to have more aggressive growth patterns and up until the development of targeted antibody therapy, prognosis was very poor.
Targeted antibody therapy including trastuzumab (Herceptin) and pertuzumab (Perjeta) is now standard of care for Her2 breast cancers, even in the setting of early-stage disease. Trastuzumab emtansine (Kadcyla, T-DM1) is an antibody-drug conjugate (ADC, a combination of the antibody and a chemotherapy agent) and is most commonly used in patients with metastatic disease. Unfortunately, not all Her2 tumors respond to therapy, and some tumors that initially respond can mutate and become resistant to therapy. Brain metastases can occur in up to 50% of patients with metastatic Her2 breast cancer, and can be challenging to treat as medications may not be able to pass through the blood-brain barrier to get to the cancer cells.
Trastuzumab deruxtecan (DS-8201, Enhertu) is an ADC and results of a phase 2 study (DESTINY-Breast01*) were presented. This study included 184 patients with metastatic Her2 breast cancer, who were experiencing disease progression after receiving 2 or more different anti-Her2 treatment protocols (including trastuzumab emtansine, median 6 prior therapies, range 2-27). This was an “open label” study and patients were not randomized. Median follow up was 11 months and findings included:
Median treatment duration was 10 months
Overall response rate was 60.3% (at least 2 follow up scans, 6 weeks apart)
11 patients (6%) experienced a complete response (apparent resolution of disease)
101 patients (55%) experienced a partial response
Median duration of response to treatment was 14.8 months
In patients with brain metastases (24 patients), median progression-free survival (PFS, time to disease advancement) was 18 months
Adverse events (AE) occurred in all but one patient. The most common AE were nausea, hair loss, vomiting, constipation and neutropenia (low white blood cell count)
57% of patients experienced more serious (≥ grade 3) AE
28.8% of patients stopped treatment due to disease progression
15.2% of patients stopped treatment due to AE
One of the more serious complications, interstitial lung disease (ILD), was reported in 25 patients and 4 patients died due to ILD-related causes
Shortly after the study was presented, the drug received accelerated FDA approval for patients with unresectable (not able to be removed with surgery) or metastatic Her2 breast cancer who have experienced disease progression after treatment with 2 or more targeted agents. The approval is accompanied by a warning due to risks of ILD as well as embryo-fetal toxicity.
The other study involved Tucatinib, which is a tyrosine kinase inhibitor, administered in pill form. The Her2CLIMB trial* was a Phase 3 study that included patients with Her2 metastatic breast cancer who previously received treatment with trastuzumab, pertuzumab, and trastuzumab emtansine. Patients with and without brain metastases, including untreated brain metastases, were included. Patients in this trial received either tucatinib or placebo, in combination with trastuzumab and capecitabine (Xeloda – an oral form of chemotherapy).
The study included 612 patients. 410 received tucatinib-trastuzumab-capecitabine (T-C) and 202 received placebo-trastuzumab-capecitabine (P-C). 48% of patients in the T-C group and 46% of patients in the P-C group had brain metastases at enrollment. Median follow up was 14 months and findings included:
At one year, PFS was 33% in the T-C group and 12% in the P-C group
At one year, median duration of PFS was 7.8 months in the patients who received T-C and 5.6 months in the patients who received P-C
Overall survival (OS) at 2 years was 45% in the patients receiving T-C and 27% in those who received P-C
Median OS was 21.9 months in the patients receiving T-C and 17.4 moths in the patients who received P-C
Among patients with brain metastases, estimated PFS at one year was 24.9% in the T-C group and 0% in the P-C group
Among patients with brain metastases, median duration of PFS was 7.6 months in the T-C group and 5.4 months in the P-C group
The most common adverse effects in the patients in the T-C group were diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting
23 (5.7%) patients in the T-C arm and 6 (3.0%) patients in the P-C arm discontinued therapy due to side effects
Of the 215 deaths that occurred during the study, the most common reason was disease progression. Adverse events were the cause of death in 6 (1.5%) of patients in the T-C group and 5 (2.5%) in the P-C group
While these 2 studies demonstrate the progress that has been made in treating an aggressive form of breast cancer, they also serve as a sobering reminder of the work that remains. The hope with targeted therapy is that cancer cells will be killed with minimal toxicity to other cells or the person – we are not quite there yet. In addition, while the improvements in progression free and overall survival is encouraging, we are not yet able to ensure long-term survival for patients with metastatic Her2 breast cancer. If you donate to breast cancer research organizations, please consider this when deciding which groups to support.
*If you are not able to access the full studies and would like a copy, please email me: contact at drattai dot com
https://drattai.com/wp-content/uploads/2019/12/56484315_s.jpg692692drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2019-12-25 21:13:002019-12-26 04:17:24New Treatments for Her2 Breast Cancer
The UCLA Center for Health Policy Research (UCLA CHPR) is developing a report on metastatic breast cancer, with the goal to drive actionable change in policy and practice. On Monday November 18th, the community will be asked to provide their thoughts for the UCLA CHPR team as part of their research study. The goal is to hear from patients, healthcare providers, researchers, caregivers, and advocates about the different types of barriers and challenges that patients with metastatic breast cancer may encounter when seeking and undergoing treatment.
No idea too small or idealistic – we want creative, actionable solutions! The information gathered in this research study will be shared more broadly with other stakeholders, advocates, and policy makers. Please add your voice to this important conversation! This study has been funded by the California Breast Cancer Research Program.
https://drattai.com/wp-content/uploads/2019/11/centerLogo.jpg6191326drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2019-11-14 02:37:582019-11-15 17:04:02Public Policy and Metastatic Breast Cancer
The US Food and Drug Administration (FDA) has issued a safety announcement about a “rare but severe” lung inflammation that can result from the use of any of 3 breast cancer medications – palbocilcilb (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). These 3 medications are in a class of drugs called cyclin-dependent kinase (CDK) 4/6 inhibitors. They are used in estrogen receptor positive (ER+), Her2/neu negative metastatic (Stage 4) breast cancer, and work by interfering with cell division.
The FDA announcement states that “the overall benefit of CDK 4/6 inhibitors is still greater than the risks when used as prescribed.” Palbociclib has been FDA-approved since 2015, and ribociclib and abemaciclib hae been approved since 2017. In evaluating studies of all 3 of the CDK 4/6 inhibitors, the FDA alert noted that 1-3% of patients taking these medications developed severe lung inflammation, and less than 1% died due to the condition.
The FDA recommended that patients notify their physicians immediately if they develop difficulty or discomfort with breathing or shortness of breath while at rest or at low activity when taking any of these medications. The FDA alert notes that there no specific risk factors that have been identified to determine how likely an individual patient is to develop severe lung inflammation while taking one of the CDK 4/6 inhibitors. They recommended that physicians routinely monitor their patients for lung symptoms that could indicate the development of severe inflammation. They also recommended that any side effects be reported to the FDA MedWatch Program. The alert noted that common side effects include “nausea, vomiting, diarrhea, constipation, decreased appetite, abdominal pain, infections, low red blood cell counts, low white blood cell counts, low platelet count, headache, dizziness, hair thinning or loss, rash, tiredness, and weakness”. I will post an update as more information becomes available.
https://drattai.com/wp-content/uploads/2019/09/Screen-Shot-2019-09-15-at-7.39.59-PM.png144447drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2019-09-15 23:54:362019-09-16 00:24:36FDA Alert for Breast Cancer Medication
The MONALEESA-7 Phase III trial evaluated the use of ribociclib in combination with endocrine therapy. Patients who received ribociclib and endocrine therapy were found to have improved overall survival rates compared to those who received endocrine therapy alone. Prior studies demonstrated improved progression free survival, but this was the first demonstration of an improvement in overall survival. Patients enrolled in this study were pre- or peri-menopausal.
Ribociclib is an oral medication belonging to the CDK 4/6 inhibitor class of targeted agents. The CDK 4/6 pathway is important for cell division. CDK 4/6 inhibitors block progression through the normal cell cycle, so cancer cells are “arrested” in a resting phase and cannot divide. This study found that at 42 months, patients treated with ribociclib had a 70% overall survival rate, compared to 46% for the patients who received endocrine therapy alone. In absolute numbers, there were 26 fewer deaths (83 or 337 versus 109 of 335) in the treatment group. Because patients who develop metastatic breast cancer after a diagnosis of early-stage disease are not re-staged, it is not possible to determine with certainty how many patients this medication may be appropriate for. Approximately 40,000 women and 500 men die from metastatic breast cancer every year. ER+ is the most common breast cancer subtype.
Prior studies have evaluated a similar drug, palbociclib, which has been approved for use in women and men with metastatic breast cancer. There are ongoing studies evaluating all 3 of the “ciclib” agents to get a better sense of whether the results will be similar across all patient populations or if a particular drug will be better for a particular subset of patients. All 3 agents are oral (pills). While side effects may be an issue for some patients, these medications are much better tolerated compared to traditional chemotherapy. Unfortunately, cost and insurance coverage may be an issue in some situations.
In addition, I do think that it is important to point out that in the current study, the majority of patients (67% in the ribociclib arm and 73% in the endocrine therapy alone arm) went on to receive other therapy – meaning that the disease progressed. We are still a long way from a “cure” despite improvements in overall survival, and we’re a long way from single-agent therapy in patients with metastatic breast cancer. Patients with metastatic breast cancer are still expected to need more than one, and in some cases multiple, agents over time as the cancer finds ways to mutate and continue to grow. The findings of this study are a step in the right direction, but much more research is needed.
https://drattai.com/wp-content/uploads/2019/06/2.jpg534920drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2019-06-04 22:36:512019-06-18 18:49:17A New Option to Treat Metastatic Breast Cancer
Note – the survey closed on July 7th 2019. Thank you to all who participated and shared, and we will be sure to post the results when they are available!
Approximately 25-30% of patients with breast cancer who are prescribed endocrine therapy do not complete the full course of treatment, and some patients never start. Side effects of endocrine therapy are well documented but there is very little literature on the role of the medical team in helping patients manage treatment-related side effects.
This survey is being conducted for research purposes. It is a UCLA research survey, open to women and men with a history of breast cancer who have been treated with or who have received a recommendation for endocrine therapy.
This survey is voluntary and is completely anonymous – no identifying information, including internet protocol (IP) addresses, will be collected. The survey should take approximately 15 minutes to complete. We value your time and your opinions.
For questions regarding this study, you may contact principal investigator Dr. Deanna Attai By phone: (818) 333-2555; by email: firstname.lastname@example.org; or by mail: 191 S. Buena Vista #415, Burbank, CA 91505
UCLA Office of the Human Research Protection Program (OHRPP): If you have questions about your rights as a research subject, or if you have concerns or suggestions and you want to talk to someone other than the researchers, you may contact the UCLA OHRPP By phone: (310) 206-2040; by email: email@example.com; or by mail: Box 951406, Los Angeles, CA 90095-1406
https://drattai.com/wp-content/uploads/2019/05/38248826_s-1-1.jpg534660drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2019-05-13 23:16:242019-07-08 01:33:23Endocrine Therapy for Breast Cancer - Research Survey
Not mentioned in the headline: the study was performed in mice. Mice were injected with breast cancer cells, developed tumors, and then underwent a surgical procedure to implant a small sponge, I presume similar to the surgical gauze that is used in the operating room. Note – the mice did not have traditional breast cancer surgery. The study found that the mice that underwent the surgical procedure had a higher rate of developing metastatic breast cancer – spread to other organs of the body. They also found that when mice received anti-inflammatory agents (meloxicam – brand name Mobic – was used in the study), they had a lower rate of developing metastatic disease.
It is well known that surgery can cause an inflammatory response and alteration in immune system function.. It is not entirely clear what that means for the average patient undergoing breast cancer surgery, and we certainly do not see metastatic disease develop in the majority of patients treated with surgery. If inadvertently left behind in a surgical wound (a very rare event), surgical gauze causes significant swelling, pain, inflammation and often infection – not at all similar to the healing process from lumpectomy or mastectomy. We cannot make assumptions from this mouse study if the use of anti-inflammatory agents after surgery would be helpful in human patients.
The take-home point for me is from my quote in the Stat News coverage: “I do not know if this mimics the potential effect of a lumpectomy or mastectomy, but the inflammatory response to an implanted foreign body would be expected to be quite robust,” said UCLA’s Dr. Deanna Attai, a past president of the American Society of Breast Surgeons. That inflammation, not surgery, might be awakening dormant cancer cells. Nevertheless, she said, “this study and the handful of others like it certainly are interesting and warrant further study.”
Until we have more information, and studies in humans with breast cancer, breast cancer surgery remains an important component of treatment.
https://drattai.com/wp-content/uploads/2018/04/44233734_s.jpg565848drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2018-04-16 01:24:182019-06-22 02:11:39Does Breast Cancer Surgery Cause Metastatic Disease?
In patients with a common form of breast cancer, known as estrogen receptor (ER) “positive”, endocrine therapy is often recommended after other treatments such as surgery, chemotherapy, and radiation are complete. Tamoxifen, most commonly used in pre-menopausal women, blocks the estrogen receptor on the breast cell, so estrogen cannot impact cell growth. In post-menopausal women, aromatase inhibitors (AI) are commonly used – these medications block the production of estrogen in the fat cells – a primary source of estrogen after menopause. Historically, these medications have been used for 5 years after completion of other treatment, although there are some studies suggesting longer courses may benefit certain patients. However, longer courses of therapy are associated with a higher incidence of side effects.
A study just published in the New England Journal of Medicine demonstrated that after 5 years of endocrine therapy, patients have an increasing risk of breast cancer recurrence with long term follow up. The authors evaluated individual patient data from a large database of randomized trials. They found that in patients with stage I tumors (tumor less than 2 centimeters and no lymph node involvement) the 20 year risk of recurrence was approximately 13%. In patients with 4-9 involved nodes, the risk ranged from 34-41% depending on the size of the main tumor.
This study is important as it confirms what many of us see in our practices – that breast cancer can and does recur, even many years after therapy. However, it also raises an important discussion point about our treatments. Studies have estimated that as many as 30% of women prescribed endocrine therapy stop treatment due to side effects which significantly interfere with quality of life such as menopausal symptoms, bone and joint pains, bone loss (osteoporosis) and fracture, and mental status changes (“chemobrain”). Patients should discuss any of these symptoms, especially if they are considering stopping their medication, with their physicians. Lifestyle changes, exercise programs, and medications may be of benefit. It is also important to understand that despite all appropriate treatment, cancer can and does come back – so health maintenance and surveillance are important even long after cancer therapy has ended.
https://drattai.com/wp-content/uploads/2019/06/2.jpg534920drdeannaattaihttps://drattai.com/wp-content/uploads/2019/06/logo.pngdrdeannaattai2017-11-09 22:11:182019-06-22 22:47:36Risk of Breast Cancer Recurrence after Endocrine Therapy
This website does not provide medical advice and should not be used to diagnose or treat any medical condition. The opinions expressed on this website are those of Dr. Attai and do not reflect the views of the University of California Los Angeles or the David Geffen School of Medicine. Dr. Attai does not consult for or have financial relationships with any websites, companies or products, including those that are referenced on this website.
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