Gold-standard treatment tamoxifen (AstraZeneca’s Nolvadex, various generics) is more effective than fellow selective oestrogen receptor modulator raloxifene (Eli Lilly’s Evista) at preventing both invasive and non-invasive breast cancer, long-term results from the STAR trial have shown.

However, the updated analysis presented at the American Association for Cancer Research annual meeting in Washington, DC, and published simultaneously online in the journal Cancer Prevention Research, also confirmed that raloxifene was significantly less likely to cause serious side-effects than tamoxifen, in particular endometrial cancer.

Researchers from the US National Surgical Adjuvant Breast and Bowel Project concluded that both tamoxifen and raloxifene were good preventive options for post-menopausal women at elevated risk of breast cancer, while the US National Cancer Institute (NCI) – which sponsored the STAR (Study of Tamoxifen and Raloxifene) trial –said women should make up their own minds based on their personal health history and the balance of risks and benefits.

The initial results of the STAR trial, which enrolled a total of 19,747 post-menopausal women at more than 500 centers across the United States, Canada and Puerto Rico, were released in April 2006. They showed that raloxifene and tamoxifen were equally effective at reducing invasive breast cancer risk in post-menopausal women at increased risk of the disease after an average of 47 months.

Both drugs cut the risk of disease by around 50% but Evista scored better on safety, with 36% fewer cases of endometrial cancer than tamoxifen and 29% fewer blood clots. These initial findings were the source of some controversy, with the STAR researchers presenting further details on the prevention trial at the American Society of Clinical Oncology annual meeting in June 2006, and revealing that the difference in uterine cancer rates was not statistically significant.

The US Food and Drug Administration subsequently approved raloxifene for reducing the risk of invasive breast cancer in post-menopausal women with osteoporosis and in post-menopausal women at high risk for invasive breast cancer in September 2007. Evista was already marketed for the prevention and treatment of osteoporosis.

The FDA approved tamoxifen for breast cancer prevention in October 1998, although uptake has been slow in this indication, largely due to concerns about side-effects.

STAR update

In the STAR update, after an average of 81 months (five years of medication and 21 months of follow-up) there were 247 cases of invasive breast cancer among the 9,736 women taking tamoxifen and 310 cases of invasive breast cancer out of 9,754 women in the raloxifene group, the NCI reported.

That meant tamoxifen and raloxifene reduced the risk of invasive breast cancer over nearly seven years by about 50% and 38% respectively. Raloxifene was around 76% as effective as tamoxifen at preventing invasive breast cancer over that period, widening the risk ratio between the two drugs compared with the initial STAR results.

The risk ratio narrowed for non-invasive breast cancer. The STAR update showed that raloxifene was about 78% as effective as tamoxifen at reducing the risk of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) – otherwise known as non-invasive or stage 0 breast cancers.

At 81 months, 111 of 9,736 women in the tamoxifen group had developed LCIS or DCIS, compared with 137 of 9,754 women in the raloxifene group. In other words, tamoxifen reduced the risk of non-invasive breast cancer by around 50% and raloxifene by around 38%.

In terms of side-effects, more than half of the women who entered the STAR trial had already had a hysterectomy, eliminating the risk of endometrial cancer. But among those participants with a uterus, the raloxifene group developed 45% fewer endometrial cancers than women taking tamoxifen – a statistically significant reduction this time.

Specifically, 65 of 4,739 women in the tamoxifen group developed uterine cancers compared with 37 of 4,717 women in the raloxifene group. As the NCI pointed out, tamoxifen is known to increase the risk of uterine cancer by two to three times compared with women not taking the drug.

Evista also came out better on blood clots. In the STAR update, women in the raloxifene group had 28% fewer deep-vein thromboses and 20% fewer pulmonary embolisms than women on tamoxifen. A total of 118 women taking tamoxifen developed deep-vein thrombosis, against 86 women in the raloxifene group, while 84 and 68 women on tamoxifen and raloxifene respectively had a pulmonary embolism.