Low-Dose Tamoxifen May Be an Option to Reduce Risk of Recurrence, Invasive Disease After Non-Invasive Breast Cancer

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A study found that a daily, low dose of tamoxifen after surgery reduced the risk of recurrence (the disease coming back), as well as the risk of new invasive breast cancer, in women diagnosed with hormone-receptor-positive breast intraepithelial neoplasia, which is non-invasive breast disease.

The research was presented on Dec. 6, 2018, at the San Antonio Breast Cancer Symposium. Read the abstract of “A randomized placebo controlled phase III trial of low dose tamoxifen for the prevention of recurrence in women with operated hormone sensitive breast ductal or lobular carcinoma in situ.”

Watch Marisa Weiss, M.D., chief medical officer of Breastcancer.org, discuss the TAM-01 study and what the findings mean for you.

What is breast intraepithelial neoplasia?

Breast intraepithelial neoplasia refers to a group of non-invasive conditions where abnormal cells are found in specific areas of the breast. A neoplasia is a collection of abnormal cells. Intraepithelial cells are cells that form the surface or lining of an organ, such as the breast ducts or lobules (the milk-producing gland at the end of the ducts). Non-invasive means the abnormal cells haven’t spread from the milk ducts or lobules into any healthy surrounding breast tissue.

Ductal carcinoma in situ (DCIS)
When the abnormal cells are in the milk ducts, the growth is called ductal carcinoma in situ (DCIS). DCIS isn’t life-threatening, but having DCIS can increase the risk of developing an invasive breast cancer later on. When you have had DCIS, you are at higher risk for the DCIS coming back or for developing a new, invasive breast cancer compared to a person who has never had DCIS.

Atypical ductal hyperplasia (ADH)
With atypical ductal hyperplasia (ADH), there are more cells than usual in the lining of the breast duct. The cells are abnormal, but not as abnormal as they would be in a diagnosis of DCIS. ADH is considered a benign breast condition that is linked to a moderate increase in the risk of invasive breast cancer.

Lobular carcinoma in situ (LCIS)
When the abnormal cells are in the lobules, the growth is called lobular carcinoma in situ (LCIS). LCIS is much less common than DCIS. Despite the fact that its name includes the term “carcinoma,” LCIS is not a true breast cancer. Rather, LCIS is an indication that a person is at higher-than-average risk for developing invasive breast cancer at some point in the future.

Hormonal therapy to reduce the risk of invasive breast cancer

Most DCIS, ADH, and LCIS are hormone-receptor-positive. So most people diagnosed with DCIS, ADH, and LCIS take hormonal therapy to reduce the risk of developing invasive disease, as well as the risk of the non-invasive disease recurring.

Hormonal therapy medicines work in two ways:

  • by lowering the amount of estrogen in the body
  • by blocking the action of estrogen on breast cancer cells

There are several types of hormonal therapy medicines. Tamoxifen, a selective estrogen receptor modulator (SERM), is one of the most well-known. Tamoxifen can be used to treat both premenopausal and postmenopausal women. In the early 2000s, the aromatase inhibitors:

  • Arimidex (chemical name: anastrozole)
  • Aromasin (chemical name: exemestane)
  • Femara (chemical name: letrozole)

were shown to be more effective at reducing recurrence risk in postmenopausal women and are now used more often than tamoxifen to treat women who’ve gone through menopause. Aromatase inhibitors aren’t commonly used to reduce recurrence risk in premenopausal women.

Most women take hormonal therapy for 5 to 10 years after breast cancer surgery.

For people diagnosed with DCIS, ADH, or LCIS, the treatment is most commonly 5 years of tamoxifen, at a dose of 20 mg per day, after surgery to remove the abnormal cells.

Still, like most cancer medicines, both tamoxifen and aromatase inhibitors can cause side effects. Tamoxifen may cause hot flashes and increase the risk of blood clots and stroke. Aromatase inhibitors may cause muscle and joint aches and pains. Less common but more severe side effects of aromatase inhibitors are heart problems, osteoporosis, and broken bones. Endometrial cancer is a less common but more severe side effect of tamoxifen.

Other research has shown that about 25% of women who are prescribed hormonal therapy to reduce the risk of recurrence after breast cancer surgery either don’t start taking the medicine or stop taking it early, in many cases because of side effects.

Could a lower dose of tamoxifen effectively reduce invasive disease risk?

Because so many women stop taking tamoxifen early, researchers wondered if a lower dose of tamoxifen could still reduce the risk of invasive breast cancer and cause fewer or less severe side effects.

In this Italian study, called the TAM-01 trial, the researchers randomly assigned 500 women diagnosed with DCIS, ADH, or LCIS to one of two treatments after surgery (and radiation, if needed):

  • 253 women took 5 mg of tamoxifen once per day for 3 years.
  • 247 women took a placebo pill once per day for 3 years; the placebo pill looked just like the tamoxifen pill but contained no medicine.

Half the women were followed for longer than 5 years, and half the women were followed for shorter periods of time.

The results showed that the low dose of tamoxifen helped reduce the risk of invasive breast cancer. During follow-up:

  • 14 women taking tamoxifen were diagnosed with invasive breast cancer.
  • 28 women taking placebo were diagnosed with invasive breast cancer.

"Our phase III TAM-01 study shows that a lower dose of tamoxifen — 5 mg per day given for 3 years — decreases by 52% the risk of a recurrence in women with breast intraepithelial neoplasia, that is, ductal carcinoma in situ, lobular carcinoma in situ, and atypical ductal hyperplasia," said Andrea De Censi, M.D., director of the medical oncology unit at the National Hospital E.O. Ospediali Galliera — S.C. Oncologia Medica in Genoa, Italy.

"I think our study is practice-changing because we show a great effect that is similar to what was seen with the standard dose in previous trials, but with much lower adverse side effects," he continued. "So the women with this disease can benefit from low-dose tamoxifen — either 10 mg every other day or by cutting the tablets in half, for a dose of 5 mg a day. The most important implication is among the women who are healthy but who may be at risk for breast cancer, [that they] may benefit from a lower dose of tamoxifen."

It’s important to know that only 64.8% of women taking placebo and 60.7% of women taking tamoxifen completed the 3-year course of treatment. De Censi said that if compliance to treatment had been higher, he would have expected to see a greater benefit of tamoxifen.

He also mentioned that tamoxifen currently is only available in 10-mg tablets, but prior studies have shown that 10 mg every other day is as effective as 5 mg per day at reducing the risk of invasive disease.

Side effects of low-dose tamoxifen

Overall, women taking the low dose of tamoxifen had only slightly more side effects than the women taking placebo:

  • Women taking tamoxifen had more hot flashes than the women taking placebo, but this difference was barely statistically significant, meaning that it could have been due to chance rather than because of the difference in treatment.
  • There were no differences in vaginal dryness, pain during sex, or joint pain between the treatment groups.
  • There was one case of endometrial cancer in the tamoxifen group and no cases in the placebo group, though the researchers pointed out that in studies using a 20-mg dose of tamoxifen, 2.7 cases of endometrial cancer would have been expected.

What does this mean for you?

"This study did not compare 5 mg with 20 mg [of tamoxifen], but the data seen here were pretty similar to data with the 20-mg dose as far as protecting against cancer,” said Virginia Kaklamani, M.D., professor of medicine and leader of the Breast Cancer Program at the UT Health San Antonio MD Anderson Cancer Center, who moderated the media briefing on the study. “This is pretty compelling and something I would try in my clinic," she said. "Whether to go lower than 5 mg is an interesting question, but the reason to stick with 5 mg is mainly pragmatic. The smallest tablets we have are 10 mg, so to split them more than in half would be difficult. I think that for the time being, 5 mg would seem to be a good dose."

If you’ve been diagnosed with DCIS, ADH, or LCIS and are deciding on treatments after surgery, you may want to ask your doctor about this study and whether a low dose of tamoxifen would be a good fit for you and your unique situation.

If you are prescribed any dose of hormonal therapy, it’s important that you take the medicine for as long as it’s prescribed and at the dose at which it is prescribed. Hormone-receptor-positive breast cancer can come back, and hormonal therapy after surgery reduces that risk.

Side effects caused by hormonal therapy can be very troublesome for many women. It’s extremely important to talk to your doctor as soon as you start having any side effects, including hot flashes, joint pain, blood clots, trouble sleeping, fatigue, or difficulty concentrating. Don’t wait until the symptoms are intolerable and you have to stop taking the medicine. There are steps you can take to ease these side effects, including switching to a different type of hormonal therapy.

For more information, visit the Breastcancer.org pages on Staying on Track With Treatment. You can read about why it’s so important to stick to your treatment plan, as well as ways to manage side effects after radiation, chemotherapy, and hormonal therapy. If you’re taking hormonal therapy after surgery now, stick with it as prescribed. If you’re thinking of stopping early, talk to your doctor first. Together, you can find a solution that is best for you.

To talk with others about sticking to your hormonal treatment plan, join the Breastcancer.org Discussion Board forum Hormonal Therapy - Before, During, and After.

Written by: Jamie DePolo, senior editor


Lilly Oncology

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