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Data Points #15: Prognostic factor testing among older women with ductal carcinoma in situ and early invasive breast cancer

Research Report

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This report is from AHRQ's Data Points Publication Series.

Overview

Estrogen receptor (ER) testing rates have increased over time for both ductal carcinoma in situ (DCIS) and early invasive cancers. However, rates of positive ER tests have not increased.

Rates of BRCA genetic testing are very low (<2%) for both DCIS and early invasive breast cancers.

Current guidelines do not recommend routine testing for human epidermal growth factor receptor 2 (HER2) for women with DCIS. Yet, rates of this testing increased between 2004 and 2007 in both DCIS and early invasive breast cancer groups.

Rates of testing varied significantly across race groups for all tests. However, the pattern of change differed between tests.

The American Cancer Society estimates that in the United States in 2012, 229,060 new cases of invasive breast cancer were diagnosed, and 39,920 people died of the disease. In the same year, approximately 63,300 women were diagnosed with ductal carcinoma in situ (DCIS) of the breast. DCIS is noninvasive breast cancer representing a wide a variety of cell abnormalities confined to the ducts of the breast. While we do not know the percentage of DCIS cases that will progress to invasive breast cancer, many studies suggest that women diagnosed with DCIS are at high risk for invasive breast cancer (see Virnig, Shamliyan, et al., for a review).

Typical treatment for DCIS includes surgical removal of the tumor by mastectomy or breast-conserving surgery (BCS). After tumor removal, some DCIS will recur or progress to invasive cancer. However, lack of knowledge about prognostic and predictive markers makes it difficult to assess a patient's prognosis. Known risk factors for DCIS progression and recurrence include comedo histology, younger age, larger tumor size, high pathologic or nuclear grade, and positive surgical margins.

For invasive breast cancer, specific markers of tumor aggressiveness are used to guide assessment of patient prognosis. Well-recognized treatment pathways exist; however, scant evidence supports the applicability of this knowledge to DCIS. In invasive breast cancer, removed tissue is tested for estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). These tests provide information about the tumor's aggressiveness, based on how it responds to external stimuli. ER and HER2 testing helps identify women who might benefit from treatments intended to reduce the risk of ipsilateral breast tumor recurrence (IBTR) and of contralateral breast cancer. ER and HER2 testing could be used to identify the subgroup of DCIS patients most likely to benefit from endocrine treatment or trastuzumab.

For women with ER+ DCIS and invasive breast cancer, treatment with antiestrogens such as tamoxifen and aromatase inhibitors might prevent recurrence or progression.

Randomized trials have evaluated the benefit of tamoxifen after BCS for DCIS. In the National Surgical Adjuvant Breast and Bowel Project (NSAPB) B-24 trial, use of tamoxifen was associated with a modest decrease in ipsilateral and contralateral breast cancer events after BCS. However, in a study conducted by the United Kingdom Coordinating Committee on Cancer Research, tamoxifen did not significantly reduce overall breast cancer events. Neither study included ER testing.

A recent meta-analysis found ER+ DCIS to be associated with significantly lower IBTR rates, while HER2+ DCIS was significantly associated with higher IBTR rates. However, none of the included studies had more than 140 subjects. Current National Comprehensive Cancer Network (NCCN) guidelines recommend ER testing for patients newly diagnosed with DCIS. Further, these guidelines suggest that physicians "consider" tamoxifen for ER+ DCIS but note that use of tamoxifen is of unknown benefit for ER-DCIS. ER testing is considered standard of care for women with early invasive cancer. HER2 positivity may be linked to an increased risk of recurrence, as well as to tumor sensitivity to trastuzumab (Herceptin).

At present, groups such as NCCN consider HER2 testing a standard of care for women with early invasive cancer but do not recommend it for women with DCIS. Studies of PR testing are inconclusive in the context of DCIS. Therefore, treatment guidelines do not include PR tests, despite their being considered standard care for early invasive breast cancer.

Testing for BRCA (the "breast cancer gene") helps to identify women with a hereditary risk of breast cancer. Family history of breast cancer is thought to be associated with increased risk of both DCIS and invasive breast cancer recurrence. BRCA testing for patients with DCIS offers the main benefit of identifying patients who have high rates of IBTR after BCS, contralateral breast cancer, and ovarian cancer. For patients with BRCA-associated DCIS or invasive cancer, treatment recommendations frequently include bilateral mastectomy with or without bilateral oophorectomy.

Lymph node testing is used to detect whether the cancer has progressed beyond the breast tissue. In the past decade, sentinel lymph node biopsy (SLNB) has replaced routine axillary lymph node dissection (ALND) for most patients with invasive breast cancer. ALND has not been recommended for patients with confirmed DCIS, because the preinvasive cells do not metastasize and thus are not associated with risk of lymph node involvement. In 1991, Silverstein, et al., reported that less than 1 percent of patients with DCIS had lymph node metastases detected by ALND. Today, most DCIS diagnoses are made by image-guided core needle biopsy. About 15 percent of patients with DCIS originally diagnosed by core needle biopsy will have a final diagnosis of invasive breast cancer after excision or mastectomy. If invasive breast cancer is identified in the excision or mastectomy specimen, axillary staging is recommended to determine stage and guide treatment decisions. Therefore, some scientists recommend SLNB for all or selected patients with DCIS detected by core needle biopsy. A systematic review of studies evaluating SLNB for pure DCIS found the incidence of lymph node positivity and lymph node micrometastases to be 0.9 percent and 1.5 percent, respectively. In women with invasive disease, lymph nodes are sampled to ascertain the extent to which the cancer has spread. This is an essential component to determining cancer stage.

This report examines variation in testing of ER, PR, HER2, BRCA, and lymph nodes in women ages 65 and older who were enrolled in the Medicare program and diagnosed with DCIS between 2004 and 2007. We analyzed how testing varied by patient age, tumor size, and tumor grade--all factors known to increase women's risk of developing invasive disease. We also examine how testing varies by race and geographic location, as well as over time. We compare the rates of testing for patients with DCIS and those with invasive disease to provide context and to better understand how testing rates differ between both groups.

Conclusion

As the incidence of DCIS has increased, so has the interest in factors predicting recurrence or subsequent invasive disease. For all examined tests, we found lower rates of testing for women with DCIS than for women with early invasive disease. In addition to significant geographic and racial variation in testing, we found large increases in the use of diagnostic tests over a relatively short period of time.