Women s Imaging Original Research

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1 Women s Imaging Original Research Price et al. Screening Mammography in Women Years Old Women s Imaging Original Research Elissa R. Price 1 Alexander W. Keedy 2 Rita Gidwaney 3 Edward A. Sickles 1 Bonnie N. Joe 1 Price ER, Keedy AW, Gidwaney R, Sickles EA, Joe BN Keywords: breast cancer, breast density, family history, risk-based screening DOI: /AJR Received March 10, 2015; accepted after revision May 30, Based on a presentation at the Radiological Society of North America 2014 annual meeting, Chicago, IL. 1 Department of Radiology and Biomedical Imaging, University of California San Francisco, 1600 Divisadero St, Rm C-250, San Francisco, CA Address correspondence to E. R. Price (Elissa.Price@ucsf.edu). 2 Department of Radiology, Kaiser Permanente Medical Center, South San Francisco, CA. 3 City of Hope National Medical Center, Duarte, CA. AJR 2015; 205: X/15/ American Roentgen Ray Society The Potential Impact of Risk-Based Screening Mammography in Women Years Old OBJECTIVE. The purpose of this study was to determine the prevalence of very strong family history and extremely dense tissue in women years old with breast cancer detected on screening mammography. MATERIALS AND METHODS. All cancers detected by screening mammography at our institution between January 1997 and November 2012 in 40- to 49-year-old women were retrospectively identified. Those with a personal history of breast cancer were excluded. Family history, breast density, type of malignancy, hormone receptor status, and lymph node status were recorded. RESULTS. One hundred thirty-six cases of breast cancer were identified on screening mammography in 40- to 49-year-old women; 50% were invasive cancers, and 50%, ductal carcinoma in situ. Very strong family history was absent in 88%, and extremely dense breast tissue was absent in 86%. Seventy-six percent of patients had neither very strong family history nor extremely dense breasts, including 79% of the cases of invasive cancers, of which 25% had axillary nodal involvement and 89% were estrogen receptor positive. CONCLUSION. Very strong family history and extremely dense breast tissue were absent in most 40- to 49-year-old women with breast cancer detected at screening mammography. These cancers were frequently invasive (often with nodal metastases) and treatable (hormone receptor positive). Reducing the number of women to be screened in this age group by using this risk-based approach would reduce the number of screen-detected cancers by more than 75%, thereby precluding the benefit of mortality reduction. Even using a risk-based strategy with an expanded definition of high risk that included any first-degree family history, extremely dense tissue, or both, 66% of malignancies would still be missed. B reast cancer accounts for 29% of new cancer diagnoses and is the second leading cause of cancerrelated death among women in the United States [1]. In women younger than 50 years old, it was estimated that nearly 50,000 new cases of invasive breast cancer and nearly 5000 deaths from breast cancer would occur in 2013 [2]. In women years old, screening mammography has been shown to reduce breast cancer mortality by 15 44% in large randomized controlled trials, population-based service screening studies, and meta-analyses [3 17]. In addition, cancers identified at screening mammography in women of this age group require less aggressive, less intensive treatment regimens [18 21]. Therefore, multiple organizations, including the American College of Radiology and American Cancer Society, recommend annual screening mammography in women years old. In 2009, the United States Preventive Services Task Force (USPSTF) released a controversial statement that did not support routine screening mammography in women years old [22]. The USPSTF recommendation was qualified with the statement the decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take patient context into account [22]. Because of its emphasis on patient context, this qualification reignited interest in a risk-based approach to screening mammography in women younger than 50 years old [10, 23 28]. Specifically, it has been suggested that routine screening mammography be used for 40- to 49-year-old women only when there is a family history of breast cancer or dense breasts (or both) [23, 29], because these factors are known to increase the risk of breast cancer [30 32] AJR:205, December 2015

2 Screening Mammography in Women Years Old In this context, the objective of the current study was to answer the following question: What if a risk-based strategy had been employed at our institution? We sought to retrospectively assess the impact of such a riskbased strategy by determining the prevalence of positive family history and increased breast density in women years old with cancer detected at screening mammography. Materials and Methods Patients This retrospective study was approved by our institutional committee on human research with waiver of the requirement for written consent. The TABLE 1: Tumor Characteristics Characteristic n % Ductal carcinoma in situ 68 Grade Low 8 12 Intermediate High Invasive cancers 68 Grade Low Intermediate High 9 13 Lymph node status a 63 Negative Positive Receptor status Estrogen receptor b 65 Positive Negative 8 12 Progesterone receptor c 65 Positive Negative HER d 58 Positive 8 14 Negative Receptor grouping e 58 Hormone receptor+/her Hormone receptor+/her Hormone receptor /HER Hormone receptor /HER2 3 5 a Unknown in five patients. Unknown in three patients. Unknown in three patients. d HER2 (also known as ERBB2); unknown in 10 patients. e Complete receptor status unknown in 10 patients. study was compliant with HIPAA, and no industry support was provided. Study inclusion criteria were: age years at time of screening and histopathologic confirmation of primary breast cancer that was diagnosed during workup of findings identified at screening mammography. All women meeting these criteria at our tertiary referral center between January 1997 and November 2012 were considered for inclusion (n = 367). Symptomatic patients undergoing diagnostic mammography (n = 193) and patients with a prior personal history of breast cancer (n = 32) were excluded. Additionally, patients were excluded if the malignant lesion was incidentally discovered during diagnostic mammography for a symptom at a separate site (n = 4). If a biopsy yielding malignancy was prompted during surveillance for a BI-RADS category 3 assessment, then the patient was excluded if the initial study that identified the lesion was a diagnostic mammogram (n = 2) but included if the initial study was a screening mammogram (n = 1). The following variables were extracted from the medical record, which was available for all patients: patient age at screening mammogram (on which malignancy was identified), cancer type and grade, relationship and categoric age (< 50 or 50 years old) of family members with breast cancer, and breast density on screening mammogram (according to the BI-RADS density classified in the mammogram report). Because study dates spanned three editions of the BI-RADS Atlas (1995, 1998, and 2003), the density classification reported presumably reflected the BI-RADS classification system at the time of the study. Although the 2003 edition included quartile definitions of the four density categories, whereas the previous two editions did not, published data showed no significant difference in the distribution of density categories across the population of American women from 1996 to 2008 [33]. If the cancer grades at diagnostic biopsy and definitive surgery were discrepant, the highest grade documented was recorded. Additionally, if pathology showed both invasive and in situ disease, the patient was considered to have invasive disease. For patients with invasive cancer, the size of malignancy, tumor receptor status, and lymph node status were also recorded. For the purposes of receptor status grouping, borderline results for HER2 (also known as ERBB2) status were considered as negative. Risk Factors For the purposes of family history categorization, patients with one first-degree relative with breast cancer diagnosed at 50 years old or older were considered to have a strong family history. Patients with at least two first-degree relatives with breast cancer or one first-degree relative with breast cancer diagnosed when younger than 50 years old were considered to have a very strong family history. This stratification scheme has been described previously [28]. The remaining patients were not considered to have relevant family history. Results Patients During the study period, 39,715 screening mammogram examinations were completed at our institution in women years old, yielding 136 cancers (cancer detection rate, 3.4 per 1000). Mean age at the time of screening mammography was 46.4 years (interquartile range, years). Tumor Characteristics The characteristics of the malignancies identified in the study cohort are summarized in Table 1. Fifty percent (68/136) of the malignancies identified were ductal carcinoma in situ (DCIS), 88% (60/68) of which were intermediate or high grade. Fifty percent (68/136) of the malignancies identified were invasive, including 93% (63/68) with ductal features and 7% (5/68) with lobular features. The majority of patients (57% [39/68]) had intermediate- or high-grade disease. The median size of invasive tumors at excision was 1.2 cm (interquartile range, cm). Axillary lymph node status was unknown in five patients. Of the patients with invasive disease and known nodal status, 22% (14/63) had metastasis to the ipsilateral axilla. Hormone receptor (HR) status was unknown in three patients, and HER2 status was unknown in 10 patients. Of patients with complete receptor status available, 81% (47/58) were HR positive and HER2 negative, and 10% (6/58) were HR positive and HER2 positive. Risk Factors Family history Of all patients with screen-detected malignancies, a very strong family history was present in only 12.5% (17/136) and absent in 87.5% (119/136). Of patients with screen-detected invasive disease, very strong family history was present in only 13% (9/68) and absent in 87% (59/68). Of the patients with invasive disease and known lymph node status but lacking a very strong family history, 23% (13/56) were node positive. Allowing for a more liberal definition of risk related to family history, patients who AJR:205, December

3 Price et al. had either a strong or very strong family history (any first-degree relative with breast cancer) were also assessed. Of all patients with screen-detected malignancies, a strong or very strong family history was present in only 23% (31/131) and absent in 77% (105/136). Of patients with screen-detected invasive disease, a strong or very strong family history was present in only 25% (17/68) and absent in 75% (51/68). Of patients with invasive disease and known lymph node status, but lacking a strong or very strong family history, 20% (10/50) were node positive. Dense tissue Of all patients with screendetected malignancies, extremely dense tissue was present in only 14% (19/136) and absent in 86% (117/136). Of patients with screen-detected invasive disease, extremely dense tissue was present in only 12% (8/68) and absent in 88% (60/68). Of patients with invasive disease and known lymph node status, but lacking extremely dense breasts, 25% (14/56) were node positive. A more liberal definition of increased risk related to breast density could include patients with either heterogeneously dense or extremely dense tissue. As discussed later, the relevance of a risk-based strategy that includes women with heterogeneously dense breasts is likely limited, but these data are presented in Table 2 for completeness. Family history and extremely dense tissue Of all patients with screen-detected malignancies, 76% (104/136) had neither very strong family history nor extremely dense breasts. Of patients with screen-detected invasive disease, 79% (54/68) lacked both of these risk factors. Of patients with invasive disease and known nodal status but lacking both of these risk factors, 25% (13/51) had axillary nodal involvement. Of all patients with nodepositive disease, 93% (13/14) lacked both risk factors. When cases of invasive disease were considered that had complete receptor status available and lacked both very strong family history and extremely dense tissue, 89% (41/46) were estrogen receptor positive. Of all patients with screen-detected malignancies, 66% (90/136) had neither a first-degree relative with breast cancer (i.e., lacked strong or very strong family history) nor extremely dense tissue. Of patients with screendetected invasive disease, 68% (46/68) lacked both first-degree family history and extremely dense tissue. Among patients with invasive disease and known nodal status but lacking both a first-degree family history and extremely dense tissue, 22% (10/45) had axillary nodal involvement. TABLE 2: Risk Factors Risk Factor DCIS Invasive Cancers Both DCIS and Invasive Cancers Node Positive a Very strong family history Present 12 (8/68) 13 (9/68) 12.5 (17/136) 14 (1/7) Absent 88 (60/68) 87 (59/68) 87.5 (119/136) 23 (13/56) Strong or very strong family history Present 21 (14/68) 25 (17/68) 23 (31/136) 31 (4/13) Absent 79 (54/68) 75 (51/68) 77 (105/136) 20 (10/50) Extremely dense tissue Present 16 (11/68) 12 (8/68) 14 (19/136) 0 (0/7) Absent 84 (57/68) 88 (60/68) 86 (117/136) 25 (14/56) Heterogeneously or extremely dense tissue Present 82 (56/68) 62 (42/68) 72 (98/136) 21 (8/39) Absent 18 (12/68) 38 (26/68) 28 (38/136) 25 (6/24) Very strong family history or extremely dense tissue At least one present 26 (18/68) 21 (14/68) 24 (32/136) 8 (1/12) Both absent 74 (50/68) 79 (54/68) 76 (104/136) 25 (13/51) At least strong family history or extremely dense tissue At least one present 35 (24/68) 32 (22/68) 34 (46/136) 22 (4/18) Both absent 65 (44/68) 68 (46/68) 66 (90/136) 22 (10/45) At least strong family history or heterogeneously dense tissue At least one present 87 (59/68) 71 (48/68) 79 (107/136) 20 (9/44) Both absent 13 (9/68) 29 (20/68) 21 (29/136) 26 (5/19) Note Data represent percentages of patients, with proportion in parentheses. DCIS = ductal carcinoma in situ. a Lymph node status unavailable in five patients. Discussion In women younger than 50 years old, screening mammography decreases mortality [3 17], and it has been shown that screendetected cancers in this cohort are of smaller size, at a lower stage, and less likely to require chemotherapy compared with non screen-detected cancers [19, 21]. Reducing the number of women who undergo screening mammography will necessarily reduce the number of screen-detected cancers. Over a 15-year period, 104 of 136 women years old (76%) would have lost the potential benefit of early detection if a risk-based strategy limiting screening to women with either very strong family history or extremely dense breasts had been employed at our institution. Patients lacking these risk factors have substantial disease burden (including axillary nodal metastases) that would likely have responded well to therapy. In today s treatment paradigm, therapy is often determined by an individual tumor s molecular profile. It is well established that HR positive (especially estrogen receptor positive) cancer responds well to treatment and has an improved prognosis [34 36]. Of the cancers detected in our study, 81% were HR positive and HER2 negative. Data from the California Cancer Registry (CCR) demonstrate 5-year survival of greater than 96% for women with this receptor profile [37]. Of the cancers detected in our study, 10% were HR positive and HER2 positive, with CCR data showing a 5-year survival of greater than 91% for this cohort [37]. Given our location within California, the CCR data are generalizable to our population and imply that more than 90% of the screen-detected cancers in 40- to 49-yearold women at our institution would likely respond well to therapy. These are precisely the patients who are likely to realize the benefits of early detection at screening mammography. To perform screening mammography in only a subset of patients at high risk (riskbased screening) requires a determina AJR:205, December 2015

4 Screening Mammography in Women Years Old tion of which patients should be included in this subset. Family history of breast cancer and increased breast density are known to increase the risk of breast cancer [30 32], and some authors have suggested using these parameters to determine who should be screened [23, 29]. In particular, first-degree family history has been emphasized as a criterion for risk-based screening [27], and prior studies evaluating risk depending on degree of family history of breast cancer have used a stratification strategy similar to ours [28]. When compared with average-risk 50- to 74-year-old women, an age cohort in which routine screening is recommended for all, 40- to 49-year-old women with a twofold risk of breast cancer (i.e., relative risk of 2) have a similar benefit-risk ratio for screening mammography [24]. Therefore, a relative risk threshold of 2 has been suggested for risk-based screening [24]. In a recent meta-analysis of breast cancer risk factors specifically in women years old that assessed common risk factors (e.g., family history; density; history of atypia, surgery, or biopsy; body mass index), only first-degree family history and extremely dense breast tissue were found to consistently impart a relative risk above 2 [38]. Therefore, our analyses focused on these particular risk factors. Even with a risk-based strategy that had an expanded definition of high risk including any first-degree family history or extremely dense tissue, our data showed that 66% of malignancies would still be missed. Although data regarding heterogeneously dense breast tissue are provided, this risk factor would likely not be a criterion selected by risk-based screening proponents. The relative risk of heterogeneously dense breasts is substantially less than 2 [38 40], and defining high risk as women with either heterogeneously or extremely dense tissue would have resulted in 72% of 40- to 49-year-old women in our population being included. Inclusion of such a large majority of this cohort in risk-based screening recommendations approaches the recommendation for screening all women years old that is challenged by risk-based proponents and negates the riskbased screening goal of substantially reducing the number of screening examinations. Our results support findings of pertinent prior studies. Although the criteria that are used to classify family history vary among studies, the basic message is consistent. In 2014, Destounis et al. [41] found that 61% of 40- to 49-year-old women with screendetected cancer at their institution had no family history. Similar to our results, 65% of their patients had invasive disease, and 15% had axillary metastases [41]. In 2013, Arleo et al. [42] found that 92% of their 40- to 49-year-old screen-detected cancer patients lacked first-degree family history and that 74% lacked extremely dense breast tissue. In 1995, Curpen et al. [43] found that 81% of 40- to 49-year-old women with screendetected cancer lacked family history. The consistent message is that the majority of young women with screen-detected cancer do not have substantial risk factors. However, our study is the first along this line of inquiry to stratify by thresholds for risk (very strong vs strong family history, and extremely dense vs heterogeneously dense) and to assess various combinations of family history and breast density in young women with screen-detected breast cancer. In addition, the current study s emphasis on tumor receptor profiles adds important information to the literature. Our study has several limitations. First, this was a single-institution review from a large tertiary medical center, and our data may not be generalizable to the screening population as a whole. Second, though many breast cancer risk factors are known, our study involved only family history and breast density (emphasizing very strong family history and extremely dense tissue, for reasons already explained). It would not be possible to address all potential strategies and permutations for risk-based screening, and we were limited by the clinical information available in our database. Finally, we did not address other controversial issues related to screening of 40- to 49-year-old women, such as recall and false-positive rates. In conclusion, our study shows that very strong family history and extremely dense tissue, although meeting the suggested requirement of a relative risk of 2, are not sufficiently discriminatory to identify enough women with screen-detected breast cancer. 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