SAN ANTONIO (FRONTLINE MEDICAL NEWS)Though breast cancer survivors have a two- to sixfold higher risk of developing a second primary cancer compared with women in the general population, only a handful of studies have investigated potential ways for women to mitigate this risk, Dr. Christopher I. Li said at the San Antonio Breast Cancer Symposium.

The best established modifiable risk factors for a second primary contralateral breast cancer are obesity, smoking, and excessive alcohol consumption, while chemotherapy, adjuvant aromatase inhibitors, and tamoxifen are protective, he said

In addition, one study has found bisphosphonates have a protective effect against contralateral breast cancer (CBC), and another has identified diabetes mellitus as a significant risk factor. However, these two studies – both conducted by Dr. Li and coworkers – are the only ones to date that have looked at these potential risk modifiers. Confirmatory studies are warranted, emphasized Dr. Li, professor of epidemiology at the University of Washington and head of the translational research program at the Fred Hutchinson Cancer Research Center, Seattle.

An estimated 10% of breast cancer survivors will develop a second, distinct primary cancer. The most common site is the contralateral breast. Indeed, 35% of all second primary cancers in breast cancer survivors occur there. Lung cancer is next most common, accounting for 18%, followed by endometrial cancer at 10%, and colorectal cancer, which comprises 8% of all secondary primary cancers in breast cancer survivors.

Despite the high incidence of CBC, only three studies with 200 or more cases have looked at modifiable risk factors.

One was a population-based nested case-control study by Dr. Li and coworkers. It included 367 CBC cases and a control group of 734 matched breast cancer survivors without a second primary cancer. The investigators identified three modifiable risk factors for CBC: a body mass index of 30 kg/m2 or greater, associated with an adjusted 1.5-fold increased risk; consumption of at least seven alcoholic drinks per week after the first breast cancer diagnosis, with a 1.9-fold risk; and current smoking, which conferred a 2.2-fold increased risk.

Upon further analysis, however, an important interaction was noted between alcohol consumption and current smoking such that neither behavior alone was associated with significantly increased risk of CBC. But current smokers who also drank at least seven alcoholic beverages per week were at a highly significant 7.2-fold increased risk (J. Clin. Oncol. 2009;27:5312-8 ).

Today, bisphosphonates are widely prescribed to prevent and treat bone metastases in breast cancer patients. Dr. Li and coinvestigators conducted a nested case-control study looking at the use of bisphosphonates for another indication: the prevention of osteoporosis-related events. The study comparison involved 351 patients with CBC and 662 controls who were breast cancer survivors without CBC. They found that patients who had ever used a bisphosphonate for 6 months or longer were 47% less likely to develop a CBC.

Moreover, the protective effect increased with duration of therapy. Among current bisphosphonate users who had been taking the medication for at least 6 months, there was an adjusted 59% reduction in the risk of CBC. For current users of at least 12 months, there was a 69% reduction in relative risk compared to nonusers. And among current users of a bisphosphonate for 24 months or longer, the relative risk reduction climbed to 79%, ( J. Natl. Cancer Inst. 2011;103:1752-60 ).

The diabetes study included 332 patients who developed a second primary CBC and 616 matched controls with only a first breast cancer. Women diagnosed with diabetes prior to age 54 had a 6.2-fold increased risk of CBC after Dr. Li and coworkers controlled for obesity and other potential confounders in a conditional logistic regression analysis, while those diagnosed with diabetes at age 55 or older had a twofold increased risk ( Breast Cancer Res. Treat. 2011;125:545-51 ). If these findings are confirmed in another study, more frequent surveillance for CBC will be warranted in diabetic breast cancer survivors, Dr. Li said.

One risk factor for CBC that patients can’t modify involves their breast cancer subtype. In another population-based nested case-control study, this one involving 482 women with a first breast cancer followed by a CBC and 1,506 controls with only a first breast cancer, Dr. Li and colleagues showed that women with HER2-overexpressing primary disease – estrogen receptor-negative/HER2-positive tumors – had a twofold greater likelihood of CBC compared with women who were ER-positive/HER2 positive.

Women with triple-negative breast cancer had an increased risk of CBC that did not become significant until at least 4 years had gone by since diagnosis of the first breast cancer. At that point they had a 2.2-fold greater risk of CBC and patients with HER2-overexpressing disease had a 2.7-fold greater risk compared with ER-positive/HER2-positive patients.

Patients with these more aggressive breast cancer subtypes – the HER2-overexpressing and triple-negative forms of the disease – were also at particularly high risk for more advanced stage CBC. Their CBCs were greater than three times more likely to be at a regional or distant stage at diagnosis than those occurring in patients with ER-positive/HER2-positive primary breast cancer ( Breast Cancer Res. Treat. 2012;135:849-55 ).

Dr. Li closed by noting that the growing problem of CBC is finally receiving extra attention from funding agencies. A new Consortium of CBC has been created, enabling investigators from 28 different CBC studies to interact more closely. The consortium is led by physicians at Memorial Sloan Kettering Cancer Center in New York, and at Fred Hutchinson.

The National Cancer Institute recently approved funding for a new population-based case-control study focusing on second primary cancers. It will include 700 controls with only a single breast cancer diagnosis along with 600 women with a second primary cancer of the lung, 600 with CBC, 350 with a second primary colorectal cancer, and another 350 with a second primary in the endometrium. The study will look in-depth at risk factors, treatments, and clinical and molecular characteristics and their impact on second primary cancers in breast cancer patients.

“We really hope through this study to move the field forward,” Dr. Li said.

His studies have been funded by the National Institutes of Health. He reported having no financial conflicts.


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