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2 November 2020

Endocrine therapy is a key component of breast cancer treatment for those with both early stage and metastatic hormone receptor-positive disease. However, side effects can be significant, and many patients do not complete recommended therapy. Our recent study* showed that over 90% of women and men prescribed endocrine therapy experience treatment-related side effects, and approximately 30% discontinue treatment early. 

Musculoskeletal issues such as bone pain, joint pain and stiffness, and bone loss (osteopenia and osteoporosis) are among the most common side effects related to aromatase inhibitors (AIs). A recent review by Gupta et al* discussed several side effect mitigation strategies and the evidence behind them. The most effective included exercise including yoga, acupuncture, duloxetine (brand name Cymbalta), treatment breaks, changing to a different AI, or changing from an AI to tamoxifen.

In my accompanying editorial*, I noted that there are barriers to successfully managing side effects, including cost, access and adherence to structured exercise programs and acupuncture, reluctance to add a new medication which comes with its own side effects, and anxiety regarding treatment breaks both on the part of the patient and their oncologist. In addition, none of the side effect treatments have been found to be universally effective. In fact, in our survey, only 41% of respondents noted that any side effect management was effective.

Clearly a new approach is needed, focusing on open and active communication between the patient and his or her oncologist. Endocrine therapy is often the “last” phase of breast cancer treatment, and patients may not remember conversations held at the time of diagnosis regarding benefits and side effects of endocrine therapy. Re-visiting the role of endocrine therapy, along with associated side effects and management techniques should occur before treatment. The absolute benefits of treatment should be clearly discussed – statements such as “this will reduce your risk of recurrence by 50%” are not meaningful unless a patient understands what her absolute risk of recurrence is – are we trying to reduce a 50% recurrence risk down to 25% or a 5% recurrence risk down to 2.5%? 

Common and expected side effects, such as bone and joint pains, hot flashes, cognitive dysfunction (commonly termed “chemo-brain”) and impact on sexual function should be discussed, along with the evidence-based strategies to help manage these symptoms. In our study, patients noted that peer support (such as an in-person or virtual support group) as well as a website that provided clear information about side effects and management would be helpful, but these were not often provided. Patients also noted that an in-person or virtual visit with their physicians to discuss side effects would be helpful – this should ideally occur within 4-6 weeks of treatment initiation so that issues and concerns can be promptly addressed. 5-10 years is a long time to take a medication that is having a significant impact on quality of life – it is important that patient concerns are heard and addressed at every visit. 

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

17 August 2020

Last year, we asked the online breast cancer community to participate in a survey to assess experiences with endocrine therapy (ET). We are proud to announce that the study has now been published, in the Journal of Cancer Survivorship*.

First of all, I would like to thank all of the participants – we surpassed our accrual goals and this is the largest survey of ET use by patients who participate in online breast cancer communities! 

About the respondents:

  • 111 respondents did not start the recommended ET, and concern about side effects was the primary reason
  • Of those who took ET (2407), 2353 were women and 54 were men
  • Most of the women (74%) were post-menopausal
  • Mean age at diagnosis was 50 for women (range: 23-82) and 54 for men (range: 24-73)
  • Most (87%) were diagnosed at Stage 1-3
  • 100 (4.2%) were diagnosed with de novo Stage 4 / metastatic breast cancer
  • 12% of those diagnosed at an early stage eventually developed Stage 4 / metastatic breast cancer

Treatment:

  • Aromatase inhibitors (AIs) were the most commonly used medication
  • 91% of respondents reported at least one class of side effect that they felt was related to treatment (92% of women and 74% of men)
  • Musculoskeletal and general physical changes (such as weight gain and unhappiness with body image) were the side effects most commonly reported by women
  • Men most commonly reported sexual and cognitive / mood side effects
  • 33% (33% of women and 50% of men) discontinued therapy early
  • 9% reported that they took treatment breaks or discontinued therapy early either without informing their medical team or against their medical team’s advice

Side effect management:

  • 3 classes of side effect management strategies were felt to be most helpful:
    • Healthy diet, exercise, physical therapy
    • Complementary therapy such as yoga, acupuncture and meditation
    • Vitamins, supplements and herbs including medical marijuana 
  • Only 41% of respondents noted any relief from side effect management strategies

Medical team communication: (multiple responses permitted so this category did not add up to 100%)

  • 70% felt supported by their medical team in attempting to discuss side effects
  • 32% were made to feel that they should be better able to handle side effects or that the side effects were not related to treatment
  • 7% did not discuss side effects with their treatment team, feeling that there were more important issues to discuss, that there was not enough time, or they did not feel comfortable

Some other findings:

  • Respondents with early-stage and metastatic breast cancer reported similar side effects and management experiences, even though these two groups of patients have very different supportive needs
  • Men who responded to our survey were less likely to report side effects but more likely to discontinue therapy early compared to women – more information is needed about the experience of men with breast cancer and those taking endocrine therapy

Clearly, there is room for improvement in terms of medical team support and understanding. In addition, as only 41% of respondents noted any relief from side effect management strategies, we need more effective treatments for ET-related side effects. Thank you to all who participated in this survey! We are hopeful that your responses and comments will inspire researchers devote more time to addressing these important issues.

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

8 July 2019

Patients who have been diagnosed with atypical ductal hyperplasia (ADH) and lobular carcinoma in-situ (LCIS) have a much higher risk of developing breast cancer compared with the average population, usually well over the “high risk” threshold of 20%. Tamoxifen is recommended for these patients to reduce help reduce subsequent breast cancer risk, but a relatively low percentage of patients actually take it, often due to concerns about side effects. 

In December 2018, the TAM-01 study was presented at the San Antonio Breast Cancer Symposium. This study used a reduced dose (5 mg instead of the usual 20 mg daily) of tamoxifen in women who had ADH, LCIS or ductal carcinoma in situ (DCIS) to see if a lower than standard dose could effectively reduce breast cancer risk.

The full manuscript* has recently been published. 500 women with a history of ADH, LCIS or DCIS were randomized to receive 3 years of either low dose tamoxifen or placebo. The study was performed in Italy. Mean patient age was 54, and 55% of the patients were post-menopausal. 20% had ADH, 11% had LCIS, and 69% had DCIS. 

With a median follow up of 5.1 years, there were 14 cancers (invasive or DCIS) in the tamoxifen group and 28 in the placebo group (11.6 versus 23.9 per 1000 person-years). Tamoxifen decreased the number of contralateral (opposite side) events by 75% but numbers were low (3 versus 12). Daily hot flashes in patients receiving tamoxifen were more frequent (2 versus 1.5 per day) than in patients receiving placebo. There were no differences in patient-reported hot flash score (combination of hot flash frequency and intensity), vaginal dryness, pain during sexual intercourse, or joint / muscle pains between the 2 groups. There were fewer serious adverse events (blood clot, pulmonary embolus, uterine cancer) in the patients receiving tamoxifen versus placebo (12 versus 16). 65% of patients in the tamoxifen arm and 61% in the placebo arm took ≥85% of pills for the first 2 ½ years of the study. The authors concluded that low dose tamoxifen for 3 years can reduce the risk of invasive or non-invasive breast cancer, with similar side effects to placebo. 

It is important to stress that this is one study, with a relatively small number of patients – 195 of the 253 in the tamoxifen arm completed the study. An important finding is that the authors found risk-reducing effects after only 3 years of therapy. However, current guidelines do still recommend standard (20mg) tamoxifen for 5 years for high risk patients as well as those with a history of estrogen-receptor positive (ER+) DCIS. There is no data on the use of low dose tamoxifen for invasive breast cancer treatment. However, for patients who are reluctant to take the full dose of tamoxifen, or who have significant side effects, it may be reasonable to consider a reduced dose – taking into account the patient’s individual risk, side effects of the standard 20mg dose, and the limitations of this study.

*Journal of Clinical Oncology Editorial: Will a low-dose option improve uptake of tamoxifen for breast cancer risk reduction?

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

13 May 2019

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: [email protected]; 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 protected]; or by mail: Box 951406, Los Angeles, CA  90095-1406

Research Survey Link

15 January 2019

The US Preventative Services Task Force (USPSTF) has released draft recommendations for the use of medications to reduce the risk of breast cancer development in women who are at increased risk. The draft document, which is open for public comment until February 11, 2019, is an update of their 2013 recommendation – the conclusions are similar, and the current document now includes aromatase inhibitors. The recommendations apply to women at high risk (see next 2 paragraphs) and do not apply to women with a current or previous diagnosis of invasive breast cancer or ductal carcinoma in situ (DCIS). 

Various factors are taken into account when assessing breast cancer risk. Family history is certainly important, but other factors such as age at first menstrual cycle, age at first pregnancy, and prior biopsies showing abnormal cellular changes (such as atypical hyperplasia and lobular carcinoma in situ) and impact risk. Weight gain after menopause, breast density, and sedentary lifestyle also contribute to increased risk. Various risk assessment calculators can be used to estimate a woman’s risk of developing breast cancer. Unfortunately, risk assessment is not an exact science – we have a long way to go in terms of predicting whether an individual woman will or will not develop breast cancer.

An “average” woman’s risk of developing breast cancer over 5 years is approximately 1.0 – 1.5%, and 8-12% over her lifetime. Women are considered to be “high risk” if their 5-year risk is greater than 1.7-(although the USPSTF uses 3%) and if the lifetime risk is 20% or greater. In these patients, we often utilize supplemental imaging such as MRI and/or ultrasound in addition to mammography, and these patients are candidates for taking risk-reducing medications. The medications used to reduce risk are also used for breast cancer treatment: tamoxifen, raloxifene, and the aromatase inhibitors (anastrozole, exemestane, and letrozole).

The USPSTF reviewed available data and concluded with “moderate certainty” that there is a “moderate net benefit” from taking risk reducing medications in women who are at increased risk. In addition, they noted that the potential harms of the medications outweigh any potential benefit in women who are notat increased risk. As these medications either block the estrogen receptor in the breast (tamoxifen and raloxifene) or diminish estrogen production (aromatase inhibitors) they will only reduce the risk of estrogen receptor positive breast cancer. 

Compared to placebo, tamoxifen reduces the likelihood of invasive breast cancer development by 7 events per 1000 women over 5 years. Raloxifene results in 9 per 1000 fewer invasive breast cancers, and aromatase inhibitors result in 16 per 1000 fewer invasive cancers. The benefit increases as a woman’s level of risk increases. Tamoxifen can be used in premenopausal women, but raloxifene and the aromatase inhibitors are only used in postmenopausal women. The report noted that aromatase inhibitors are primarily used to treat breast cancer, and are not currently FDA approved for risk reduction.

All of the medications have the potential for side effects, which the USPSTF considered to be “small to moderate”. Both tamoxifen and to a lesser extent, raloxifene, can increase the risk of blood clots – this risk is greater in older women. Tamoxifen can increase the risk of endometrial cancer and cataract development, and both medications can increase the likelihood of hot flashes. Both medications can reduce the risk of some types of fractures. Aromatase inhibitors can be associated with hot flashes, gastrointestinal symptoms, musculoskeletal pains, possible cardiovascular events (primarily stroke) and may increase fracture risk.

Most trials utilized the medications for 3-5 years for risk reduction.  The report notes that the benefits of tamoxifen continue at least 8 years after discontinuation of therapy, and the risk of tamoxifen-associated blood clots and endometrial cancer return to baseline after treatment has ended. They noted insufficient data on length of protection for raloxifene or the aromatase inhibitors. 

The USPSTF did identify research needs and gaps, including how to better identify individuals at increased risk, racial disparities, and that longer follow up of patients using raloxifene and aromatase inhibitors for risk reduction is needed. In addition, as there are multiple risk assessment models, more work needs to be done to determine which is “best” – different models may be more appropriate depending on specific clinical factors. 

Not addressed in the USPSTF document is that fact that many patients who are at high risk, as well as those who have been diagnosed with breast cancer, discontinue medication early (or do not start at all) due to side effects. An abstract presented at the December SABCS conference compared 5mg of tamoxifen (usual dose is 20mg) to placebo in high risk woman and found similar reduction in breast cancer development with fewer side effects. Lower dosing could be one answer, but more effective mediations with fewer side effects would certainly be welcome by all.

15 July 2014

A study published today in Clinical Cancer Research demonstrates that tamoxifen applied to the skin in a gel form was as effective as oral tamoxifen in decreasing breast cancer cell growth and was associated with fewer side effects in patients with ductal carcinoma in-situ (DCIS).

Dr. Seema Kahn and colleagues randomized 27 women diagnosed with DCIS to receive either tamoxifen gel or oral tamoxifen for 6-10 weeks prior to surgery. They measured blood and breast tissue concentration of tamoxifen as well as the proliferative activity (growth rate – also known as Ki67) of breast cancer cells before and after treatment. They found that both forms of tamoxifen resulted in a decrease in the growth rate of cancer cells. Both groups showed similar concentrations of tamoxifen in the breast tissue, but the women who used the gel had lower tamoxifen concentrations in the blood.

Tamoxifen is used to treat breast cancer and is also used to reduce the risk of developing breast cancer in those at high risk. In women who have been diagnosed with breast cancer, tamoxifen can reduce the risk of cancer returning and can improve overall survival rates. However, many studies have shown that women often stop tamoxifen due to side effects. Those side effects can include vaginal discharge and exacerbation of menopausal symptoms such as hot flashes, sleep and mood disturbance, depression, and weight gain. The two most significant potential complications related to tamoxifen use are uterine cancer and blood clots. The study was too small to note any difference in side effects, but as the concentrations of tamoxifen in the blood are lower in patients using the gel, it is thought that this might result in fewer side effects.

This was a small study and many questions remain, but it is promising that an effective form of tamoxifen associated with fewer side effects may be eventually be available for widespread use.

11 May 2013

In May 2013, I was invited to give a talk with my colleague Dr. Carol Connor at the annual meeting of the American Society of Breast Surgeons.  Our topic was “Endocrine Therapy for Breast Cancer”, and we discussed the literature supporting the use of tamoxifen and aromatase inhibitors for breast cancer, as well as adverse effects and treatment of adverse effects. We were then invited to submit a manuscript which was published in the Annals of Surgical Oncology. The following is a summary of our talk and manuscript. I would like to express my appreciation to the #BCSM Community, who responded to my request for information about adverse effects  – it allowed me to discuss not only the literature, but also real patient experiences.

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