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Risk Reducing Medications

6 September 2019


The US Preventative Services Task Force (USPSTF) and the American Society of Clinical Oncology (ASCO) have both released updated recommendations on the use of medications (tamoxifen, raloxifene, anastrozole and exemestane) to reduce the risk of estrogen-receptor positive breast cancer in women who are considered to be at high risk for the disease. The use of these medications to reduce breast cancer risk is commonly known as “chemoprevention.” Tamoxifen, anastrozole and exemestane are also used in the treatment of estrogen receptor positive breast cancer. Summaries of the statements and links to the manuscripts and associated publications are provided at the end of this post.

Risk assessment may be performed using a variety of online calculators that take into account age, menstrual and pregnancy history, family history and prior breast biopsies – especially biopsies that show atypical hyperplasia or lobular carcinoma in situ (LCIS). Some models also take into account body mass index and breast density. These models tend to perform well in populations of women, but are not as accurate as predicting the likelihood of breast cancer development in an individual woman. The models calculate 5-year and lifetime breast cancer risks. The “average” woman has a 5-year risk of approximately 1% and lifetime risk of approximately 10-12%. The early studies evaluating risk-reducing medications considered a 5-year risk of 1.66% or greater as “high risk” (lifetime risk over 20% is also considered “high risk”). Both the USPSTF and ASCO statements focus on women age 35 and older with a 5-year risk of 3% or higher. 

The USPSTF and ASCO recommendations are similar. For women at high risk of developing breast cancer (3% or greater 5-year calculated risk OR high risk due to combination of factors – see below), it is recommended that patients consider the use of a risk-reducing medication, taking into account side effects of the medications and an individual patient’s medical condition and preferences. Both guidelines specifically do NOT recommend the use of risk-reducing medications in women who are not at elevated risk for the development of breast cancer. 

The risk factor combinations that convey increased risk and should prompt consideration of risk-reducing medications include:

From the USPSTF Statement:

  • Age 65 or older with one 1st degree relative with breast cancer
  • Age 45 or older with more than one 1st degree relative with breast cancer or one 1st degree relative who developed breast cancer before age 50
  • Age 40 or older with atypical hyperplasia or lobular carcinoma in-situ, or with a 1st degree relative with bilateral breast cancer 

From the ASCO Statement:

  • 1st degree relative with breast cancer diagnosed before age 45
  • Two 1st degree relatives with breast cancer diagnosed at any age
  • A 1st and 2nd degree relative with breast cancer

The USPSTF statement acknowledges that women with BRCA mutations and those who have received chest wall radiation at a young age are at increased risk, but it was felt that there was insufficient evidence to recommend chemoprevention in these patients. These women are included in the ASCO statement in the Clinical Considerations section of the manuscript.

Risk assessment and the decision to use risk-reducing medications is a challenging and at times confusing topic. Many studies report that the use of risk-reducing medications in high risk women can result in a 50% or greater reduction in the likelihood of developing invasive breast cancer compared with placebo. However, as the JAMA editorial by Drs. Pace and Keating notes, the absolute reduction in risk for an individual woman could be very low – less than 1 percentage point. They noted that over 100 high-risk women would need to be treated to prevent one breast cancer. Obviously when multiplied by the large number of women that might be impacted by these guidelines (noted to be approximately 10 million women in the US in the JAMA editorial by Drs. Daly and Ross) there is the potential to make a significant impact on the incidence of breast cancer. None of these medications have been shown to improve breast cancer-related survival rates in high-risk women. 

Many of the early studies that determined the effectiveness of these medications in reducing risk defined “high risk” as a 1.66% or greater 5-year risk. However, both USPSTF and ASCO recommend using the 3% or greater level of 5-year risk as it was felt that these women at the highest level of risk are most likely to benefit from the medications, and that this benefit will be more likely to outweigh potential harms. But even these women may be more likely to NOT develop breast cancer.

In deciding on a medication, tamoxifen may be used in pre- or post-menopausal women. Raloxifene, anastrozole and exemestane are only for use in post-menopausal women.

Both statements acknowledge the potential side effects that may occur with use of these medications. Some of the more common potential side effects include uterine cancer (tamoxifen), blood clots (tamoxifen and raloxifene), bone / joint / muscle pains and bone loss (anastrozole and exemestane) and hot flashes (all medications). Generally, risk-reducing medications are used for 5 years although raloxifene may be used for longer periods of time as it is often used as a treatment for osteoporosis. The risk reduction appears to last approximately 8-10 years after the medication is stopped, and many studies report that side effects tend to improve shortly after medications are discontinued. The ASCO statement notes that 3 years of risk-reducing therapy may be effective. The paper also discusses a recent study that evaluated the use of low dose (5 mg as opposed to the usual 20mg)  tamoxifen versus placebo in high risk women. There was an approximately 50% reduction in the risk of invasive breast cancer among patients who took the low dose of tamoxifen – similar risk reduction to what is seen with the full 20mg dose.

Both statements mentioned other ways that risk can be reduced, including adoption of a healthy lifestyle (exercise, alcohol limitation, and weight management). Challenges in the use of risk assessment models and in discussing risk reducing medications include limited time and lack of patient decision aids. More data is needed on the risks and benefits of the medications in some patient populations. 

It is hoped that ongoing research evaluating the use of polygenic risk scores (a form of genetic testing) will add more insight to an individual’s level of risk in the (hopefully) near future. Drs. Daly and Ross noted in their editorial that “In the new era of precision medicine, there is a realization that one size fits all is no longer acceptable for most treatments.” and that “More efficient and sophisticated tools to more precisely quantify each individual’s benefit / risk for a variety of chemoprevention drugs may ultimately translate into precision medicine for breast cancer prevention.” Physicians and patients will certainly welcome more precise, tailored information to help guide the decision-making process for women who are at high risk for breast cancer.

USPSTF Recommendation: Medications to Reduce the Risk of Breast Cancer
ASCO Guideline Update: Use of Endocrine Therapy for Breast Cancer Risk Reduction

If access to any of the references articles is desired, please email me:  contact at drattai dot com and I will be happy to provide a copy.

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A New Option to Treat Metastatic Breast Cancer

4 June 2019

Encouraging news for patients with metastatic estrogen receptor-positive (ER+), Her2/neu negative breast cancer was presented at the 2019 American Society of Clinical Oncology annual meeting, and published in the New England Journal of Medicine.

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.

Additional Information:
ASCO Post – 2019 ASCO: MONALEESA 7
NBC News – Breast Cancer Treatment Shows Hope for Younger Women

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SSO – ASTRO – ASCO DCIS Margin Guidelines

15 August 2016

A consensus statement was released today by the Society of Surgical Oncology, the American Society for Radiation Oncology, and the American Society of Clinical Oncology. It addresses the issue of surgical margins for patients undergoing breast conserving surgery (lumpectomy) for ductal carcinoma in-situ (DCIS). The summary notes “Use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irradiation is associated with lower rates of IBTR [in-breast tumor recurrence, also known as local recurrence] and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.”

We know from many years of research that women who undergo lumpectomy have the same survival rates as those who undergo complete breast removal. When a lumpectomy is performed, the goal is to remove the tumor with a rim of normal breast tissue (margin). It has long been debated how much margin is needed. If clear margins are not obtained, repeat surgery is usually recommended, and due to lack of standardized guidelines, re-excision has been recommended for many patients with close margins. Nationally re-excision rates have been reported as high as 50%. Additional surgery increases the likelihood of complications, increases overall breast cancer treatment time, and may have a negative impact on cosmetic results.

In 2014, margin guidelines were published for invasive breast cancer, and they noted that for patients with early stage breast cancer undergoing lumpectomy and radiation therapy, “no ink on tumor” is an acceptable margin. Today’s DCIS statement notes that a 2mm margin is acceptable in most cases of non-invasive cancer. Why the discrepancy? Shouldn’t invasive cancer be treated with a wider margin than DCIS? An important distinction between invasive cancer and DCIS is that DCIS lesions are more likely to have “skip areas”, so a clear margin may not be as predictive of a low likelihood of residual disease. However, just as with the invasive cancer guidelines, the current consensus guideline notes that wider margins do not improve outcomes.

Both the invasive and DCIS statements apply to patients with stage I and II breast cancer, undergoing lumpectomy with postoperative radiation therapy. Without radiation therapy, the risk of local recurrence (the same cancer returning in the breast) can be as high as 30-40%. However, there are certain situations when radiation therapy may not be recommended, depending on tumor type, patient age, and other factors.

As with other clinical practice guidelines, the current statement is not a substitute for good clinical judgement and multidisciplinary case discussion. There are situations when a smaller margin may be acceptable, and settings where a larger margin may be desired for various reasons. However, patients and physicians need to be aware that more surgery is not better when it comes to breast cancer treatment. Dr. Monica Morrow, lead author on the statement, advised that “if a woman with a negative margin is told to have a re-excision, she needs to ask what factors are prompting the surgeon to recommend that re-excision.”

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Extended Hormone Therapy for Postmenopausal Breast Cancer

09 June 2016

A study presented at the recent American Society of Clinical Oncology meeting evaluated the use of extended endocrine therapy in post-menopausal women. I’ve covered some of the basics of endocrine therapy for breast cancer in a previous post. In 2012, results of the ATLAS Trial were published, and found that when tamoxifen was given for 10 years instead of the standard 5, improvements were noted in overall and disease free survival.

Up until this point, no study has demonstrated similar findings for post-menopausal women taking aromatase inhibitors. Results of the MA.17R study were reported at the 2016 ASCO meeting, Patients in the study had already completed at least 5 years of endocrine therapy with the aromatase inhibitor letrozole. They were then randomized to receive either an additional 5 years of letrozole or a placebo. Median follow up was 6.3 years.

The key study findings were as follows:
–   Disease free survival was 95% in the treatment group and 91% in the placebo group, a 34% reduction. This was statistically significant.
–  Contralateral breast cancer (a new cancer developing in the opposite breast) occurred in 1.4% of the treatment group, and 3.2% of the placebo group a 58% reduction. This was also statistically significant.
–  Overall survival was the same in both groups.
–  More bone fractures (14% vs. 9%) and new-onset osteoporosis (11% vs. 6%) were seen in the patients undergoing extended endocrine therapy – it is well known that these medications accelerate bone loss. These findings were statistically significant.
– Rate of discontinuing therapy was 5.4% in the letrozole group, and 3.7% in the placebo group.

Several points were brought up in the discussion immediately following the presentation as well as in post-plenary “town hall” style session held later in the day, including:

–  It is not clear what the long-term effects of medications used to treat bone loss will be – if patients are on endocrine therapy for longer periods of time, they likely will need to be on the bone protective medications for longer as well.
–  Reported quality of life was similar in both groups, as reported by Dr. Julie Lemieux. However, as Dr. Don Dizon noted: “without compromising quality of life” isn’t the same as “everything’s peachy.”

– It was noted that the patients enrolled in the study were self-selected which may bias the results. As they had already completed at least 5 years of letrozole therapy, these patients likely had few existing side effects from treatment. Concern was raised in the post-plenary discussion that we may see more of an impact on quality of life if a broader population of women is treated with extended endocrine therapy.
– Dr. Lisa Carey noted that adherence to endocrine therapy remains a significant issue in part due to medication side effects. While the rate of discontinuation of therapy in this study was low, this does not reflect real-world experience.

The disease free survival improvement and contralateral breast cancer reduction were widely reported in the press as percentages (34% disease free survival benefit, 58% reduction in contralateral breast cancer). It is important to realize that the absolute benefits are very small – only a few percentage points. While the results achieved statistical significance, they may or may not be significant to an individual patient. It is important that patients understand the concept of absolute risk vs. relative risk.

Professor Ian Smith, who discussed the abstract during the plenary session, concluded by saying that the MA.17R findings do not justify extended endocrine therapy in all patients. Rather, patients with more aggressive features such as larger tumors, positive lymph nodes, and higher cell grade may benefit. He called for physicians to carefully discuss the study results with their patients, and allow them to participate in the decision for or against extended endocrine therapy.

This conclusion prompted the following Twitter exchange with an oncology colleague:

While it should go without saying that we need to discuss study results as well as advantages and disadvantages of treatment with our patients, this point is not emphasized enough during national presentations. The lead author, Dr. Goss, commented during the post-plenary discussion that he is not specifically recommending extended hormonal therapy. Rather, he acknowledged that this is a decision that needs to be made by an individual patient, in consultation with her physician, after carefully reviewing all of the information. The study received a significant amount of media attention, and the discussion at the conference session was very spirited. At the end of the day, it’s important that patients to realize that we don’t have a definitive answer for the individual.

It is also important not to forget the impact of lifestyle factors in terms of reducing risk of recurrence. Regular exercise, weight maintenance, healthy food choices, and moderation in alcohol intake all will help reduce the risk not only of breast cancer recurrence, but also of cardiovascular disease, which remains the number one killer of women in the United States.

Additional Reading:
ASCO Post Overview of MA.17R
Changing Adjuvant Breast Cancer
Dr. Elaine Schattner in Forbes

 

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ACS / ASCO Breast Cancer Survivorship Guidelines

7 December 2015

The American Cancer Society and the American Society of Clinical Oncology have just released updated guidelines for breast cancer survivors. The purpose “is to provide recommendations to assist primary care and other clinicians in the care of female adult survivors of breast cancer”.

Patients and physicians are well aware that health concerns do not end when cancer treatment is over. The guidelines outline potential signs of recurrence, note appropriate tests to help detect recurrence, review general health recommendations, and discuss management of long-term side effects. It is important that patients who have been treated for any type of cancer remain vigilant regarding their health. Changes or new findings should be reported to your physician, and efforts should be made to maintain a healthy diet, weight and lifestyle.

I encourage every patient to review the guidelines. If you have questions or concerns, do not hesitate to inform your oncology or primary care physicians. Education and open communication are important in order to maximize quality of life after cancer treatment.

ACS / ASCO Breast Cancer Survivorship Care Guideline

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