The Comparative Value of Mammographic Screening for Women Years Old Versus Women Years Old

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1 X/95/ American Roentgen Ray Society Belinda N. Curpen1 2 Edward A. Sickles1 Richard A. Sollitto1 Steven H. Ominsky1 Helen B. Galvin1 Steven D. Frankel1 Received June 29, 1994; accepted after revision December 12, Presented in part at the annual meeting of the American Roentgen Ray Society, New Orleans, LA, April B. N. Curpen is supported in part by the McEachren Award of the Canadian Society. of Radiology, Box 0628, University of California School of Medicine, San Francisco, CA Present address: Department of Radiology, Notre-Dame Hospital, 1560 Sherbrooke St. E., Montreal, Quebec, Canada H2L 4M1. Address correspondence to B. N. Curpen. The Comparative Value of Mammographic for Women Years Old Versus Women Years Old OBJECTIVE. The purpose of our study was to compare the major prognostic factors (tumor size, axillary lymph node status, and tumor stage) of breast cancers detected at mammographic screening in women ages years old with those in women ages years old. MATERIALS AND METHODS. Study subjects were women ages years old who participated in our mobile van mammographic screening program from April 1985 to June We retrospectively reviewed the clinical and pathology records of women in whom breast cancer was detected at mammographic screening. All examinations were performed with dedicated equipment using screen-film technique. RESULTS. A total of 44,301 screening examinations were done during the study period. Seventy-five cancers were detected in women ages years old, and 128 cancers were detected in women ages years old. The cancer detection rate was 3.0 per 1000 examinations in the younger age group compared with 5.5 per 1000 examinations in the older age group. The median size of breast cancers was 1 0 mm for women ages versus 11 mm for women ages Eighty-eight percent of the patients in both age groups had no evidence of metastasis to axillary lymph nodes. Nineteen percent of women in the younger age group had advanced breast cancer (stage II or higher) compared with 26% of women ages (p =.25). No statistically significant difterences were noted between the two age groups in the size, lymph node status, or stage of breast cancers detected at mammographic screening. However, the cancers found in younger women had slightly more favorable prognoses. CONCLUSION. The major prognostic factors of cancers detected with modern mammographic equipment appear to be at least as favorable for women ages years old as for women ages years old. As mammographic screening has already been shown to be beneficial for women ages years old, screening should also be beneficial for women ages years old. AJR 1995;164: The efficacy of breast cancer screening for women ages years old is widely accepted, but there is much controversy concerning the screening of women ages years old. The recent review of Fletcher et al. [1] states that eight randomized controlled screening trials [2-7] showed no reduction in breast cancer mortality for women ages years old. However, an editorial accompanying that review indicates that all the randomized controlled trials are flawed by low statistical power, some trials suffer from poor experimental design, and some are flawed in execution [8]. Furthermore, there is emerging evidence of the benefit of screening women ages years old from those trials in which there was at least years of follow-up: the average mortality reduction for these women ranged from 1 7% to 21 % [9, 10]. As data from the randomized controlled trials are limited in statistical power for women ages years old, and as the quality of mammography has improved substantially since completion of the trials [11], there is considerable value in examining other evidence regarding the efficacy of screening using modern mammographic techniques.

2 1100 CURPEN ET AL. AJR:164, May 1995 In the current study, we compared the major prognostic factors (tumor size, axillary lymph node status, and tumor stage) of breast cancers detected at mammographic screening in women ages years old with those in women ages years old, using the findings of a large-scale modern mammographic screening program. Materials and Methods We retrospectively reviewed the clinical and pathology records of all breast cancers detected on first and subsequent mammographic screening examinations performed from April 1985 to June 1994 in our mobile van screening program. Mammography was done with dedicated equipment (Mamex DC and Instrumentarium Alpha Ill, Milwaukee, WI) using screen-film technique. The standard screening examination consisted of mediolateral oblique and craniocaudal views of each breast. Most (60%) of the screening examinations were interpreted by one radiologist subspecializing in breast imaging. The remaining examinations were interpreted in approximately equal numbers by five other general radiologists. Most examinations also were previewed by another radiologist engaged in subspecialty training as a breast imaging fellow, with results of this double reading available to the interpreting radiologist. records were stored in a computerized data management program that allows for ready and reliable retrieval of statistical information [12, 13]. Further details of our practice have been reported previously [14, 15]. During the study period, we performed 44,301 screening examinations: 22,478 examinations among women ages years old and examinations among women ages years old. Most women who had more than one screening examination were screened at approximately yearly intervals, for both age groups, despite the recommendations of most national medical organizations that women ages years old be screened at either 1 - or 2-year intervals. Women with a diagnosis of screening-detected ductal carcinoma in situ (DCIS), invasive ductal carcinoma, or invasive lobular carcinoma were included in the study. The variables studied were tumor size, lymph node status, and tumor stage. These are among the most powerful prognostic indicators described for breast cancer. Tumor grade was not evaluated because it was unavailable in approximately 40% of the cases and was assessed by many different pathologists in the remaining cases, potentially introducing substantial subjective variation [16]. Pathology reports were used to provide the tumor size and the axillary lymph node status for all cancers. When tumor size was not stated in the pathology report, it was estimated to be the greatest tumor dimension measured on preoperative mammograms. All breast cancers were classified according to the staging system of the American Joint Committee on [17]. The following additional data were obtained from clinical records: patient age, family history of breast cancer, and tumor palpability. Statistical analysis was conducted by use of the x2 test for differences between the age groups and 50-64; p values equal to or greater than.05 were considered significant. Results Concerning the major breast cancer risk factors, 72 examinations (0.3%) in the age group involved women with a prior diagnosis of breast cancer, compared with 122 cases (0.5%) in the age group. In the younger age group, 2598 examinations (1 2%) were performed in women with a strong or very strong family history of breast cancer, compared with 2249 examinations (10%) in the older age group. Table 1 lists the breast cancers detected at screening as a function of age and family history of breast cancer. Although cancer detection rates are higher in women with a positive family history, for age group this high-risk cohort comprises only 19% of women with breast cancer, and for age group it comprises only 15% of women with breast cancer. As shown in Table 2, there were proportionately more cases of DCIS and fewer cases of invasive carcinoma detected in women ages than in older women. This difference is statistically significant (p =.02). Fifty-seven breast cancers (76%) were impalpable before mammographic screening in women ages 40-49, compared with 113 (88%) in women ages Some cancers were detected at physical examination only after a lesion was seen mammographically and its precise location was described. Results of physical examination directed at sites of mammographic abnormality decreased the number of impalpable cancers to 4(72%) in the younger age group and to 89 (70%) in the older age group, a difference that is not statistically significant (p =.50). The median size of all breast cancers, including DCIS and invasive cancers, was 10 mm for women ages and 11 mm for women ages Forty percent of the invasive cancers were 10 mm or smaller in the younger age group, compared with 37% in the older age group (Table 3). This difference is not statistically significant (p =.70). Table 4 shows the axillary lymph node status and the stage of breast cancers detected at screening. Axillary lymph TABLE 1 : Detection Rates by Age and Family History of Breast None or minorb. Mammographic Examinations s Detected Mammographic at Detection Ratea Ages , Ages , Strong or very strongc Ages , Ages5O-64 2, Total Ages , Ages anumber of women with cancer per 1000 examinations. bonly distant relative(s) with breast cancer. cfirstdegree relative(s) with breast cancer, premenopausal or postmenopausal, unilateral or bilateral. TABLE 2: Ductal Carcinoma in Situ Versus Invasive s Ages Ages Ductal carcinoma in situ 28 (37) 29 (23) Invasive 47 (63) 99 (77) All cancers 75 (100) 128 (100)

3 AJR:164, May 1995 MAMMOGRAPHIC SCREENING 1101 TABLE 3: Size of Brea st Cance rs Detected at Mammographic 10 mm mm >20 mm Total Ductal carcinoma in situ Ages (68) 4 (14) 5 (18) 28 (100) Ages (79) 4 (1 4) 2 (7) 29 (100) Invasive Ages (40) 20 (43) 8 (1 7) 47 (100) Ages (37) 42 (43) 20 (20) 99 (100) All cancers Ages (51) 24 (32) 13 (1 7) 75 (100) Ages (47) 46 (36) 22 (1 7) 128 (100) TABLE 4: Axillary Lymph Node Status and Stage of Breast s Detected at Mammographic Status or Stage Axillary lymph node statusa Positive Negative Ages Ages (1 2) 63 (88) 15 (12) 1 08 (88) Distant metastasis at diagnosis 0 (0) 1 (1) Stage 0 I II Ill IV 28 (37) 33 (44) 13(18) 1 (1) 0(0) 29 (22) 66 (52) 30(23) 2 (2) 1(1) aaesults of axillary lymph node sampling or dissection are unknown for three invasive cancers in women ages and for five invasive cancers in women ages node sampling or dissection was undertaken for 44 invasive cancers in women ages and for 94 invasive cancers in women ages For some cases of DCIS, axillary lymph nodes were presumed to be free of metastasis (intentionally not sampled) on the basis of impalpability, small size, and noncomedo histologic subtype. The rest of our DCIS cases were found to be free of metastasis at axillary lymph node sampling regardless of age. There were no patients with distant metastasis in the younger age group, whereas one patient had metastatic disease in the older age group. Nineteen percent of women ages had advanced breast cancer (stage II or higher) compared with 26% of women ages This indicates a slightly more favorable prognosis in the younger age group but, again, the difference between the two age groups is not statistically significant (p =.25). Discussion This study compares the prognostic factors of breast cancers detected at screening in women years old with those of screening-detected cancers in women years old. The observed data, although lacking statistical significance, suggest that the prognosis of mammographically detected breast cancer is at least as favorable in women ages as in women ages As shown in Table 1, the cancer detection rate is higher for women ages than it is for women ages It is unlikely that this age-related disparity is due to decreased detection in younger women, because our cancer detection rate in this age group is much higher than those reported in other large-scale screening studies (Table 5). Rather, the disparity is fully consistent with and is likely due to the known increase in frequency of breast cancer with advancing age [18]. We plan to more directly address the issue of agedependent cancer detection when we are able to link our screening records with breast cancer cases listed in our regional tumor registry; this approach will permit identification of virtually all false-negative screening examinations. We detected proportionately more cases of DCIS (cornpared with invasive cancers) in women ages than in women ages 50-64, which is similar to findings reported in previous studies. DCIS accounts for 35-40% of impalpable mammographically detected breast cancers in women ages [1 9], but only 20% in the older age group [20]. The reason for this age-related difference is not fully understood, but a partial explanation may be that some cancers are being detected and excised as DCIS in women below age 50 before they develop into invasive cancers at age 50 and above. Although no statistically significant differences were found between women in the two age groups concerning the size, lymph node status, and stage of cancers, our data show a slight but consistent trend toward detection of smaller cancers and earlier stage at diagnosis in women ages Because our study lacks statistical power, we cannot rule out the existence of more than slight differences between the prognostic profiles of women in the two age groups. Nonetheless, our own observation is consistent with that made by Tab#{225}r et al. [21] in a study using data from the Swedish Two-County Trial, which indicated that the prognosis of tumors diagnosed in women ages was, if anything, better than that for older women. Others also have reported similar findings [22, 23]. However, a report on screening-detected breast cancers from a large-scale, population-based mammography program TABLE 5: Results Among Women Ages Comparing Selected Randomized Controlled Trials with the Current Study Result Swedish Two-County Triala CNBSS Current Study detection rate (per 1000, first screen)b Percentage node-negative Percentage stages 0 + I NA NA 81 Note.-CNBSS = Canadian National Breast Study (reference 7), NA = not available. areference 21. bsomewhat higher cancer detection rates are expected in the current study and in the CNBSS than in the Swedish Two-County Trial, because the Swedish study involved population-based screening and the other two studies involved self-selected women.

4 1102 CURPEN ET AL. AJR:164, May 1995 carried out from 1975 to 1990 in Nijmegen, the Netherlands, describes strikingly less favorable prognostic factors for women ages than for women ages [24]. This disparity with our results, summarized in Table 6, is limited almost entirely to women under age 50: for the Nijmegen study compared with ours, respectively, 19% versus 40% of invasive cancers were very small (10 mm), 39% versus 12% of cancers had positive axillary lymph nodes, and 35% versus 19% of cancers were advanced in stage (stage II or higher). One obvious difference between the two studies is that the Nijmegen study involves women ages 35-39, whereas ours does not. However, inclusion of these very young women is likely to have only a minor effect, if any, on the Nijmegen screening results as that study appears to involve a relatively small (albeit unspecified) number of women under age 40. Rather, we believe that the disparity in results between the Nijmegen study and our own is related to the intrinsic differences between the types of mammographic screening provided. Kopans has already identified four features of the mammography performed in the Nijmegen study that tend to diminish the effectiveness of screening [25]: the use of singleview (mediolateral oblique only) mammography has been shown to reduce the rate of screening-detected cancers by 10-11% [26, 27], thereby permitting some malignant lesions to grow until detected later, either at clinical examination or at the next scheduled mammographic screening; the use of single-radiologist interpretation (versus a double reading, in which two radiologists review each case) also decreases the number of screening-detected cancers, by 5-15% [4, 25, 28, 29], with similar consequences; the use by interpreting radiologists of high thresholds for intervention in an attempt to reduce the number of false-positive results, as is the policy in the Nijmegen study [30], also will decrease the number of screening-detected cancers because the false-positive rate can be reduced only at the expense of an increase in falsenegative cases [31, 32]; and the use of a 2-year interval between screenings for women ages also will diminish the effectiveness of screening, as the lead time for mammography in this age group is approximately 2 years [33, 34], and TABLE 6: Comparison of Selected Results from the Nljmegen Studya with Results from the Current Study Result Nijmegen Study Current Study Ages Ages Ages Ages Tumor sizeb lomm 11(19) 91(37) 19(41) 37(37) 11 mm 47 (81) 157 (63) 28 (59) 61(63) Nodal statusc Positive 17 (39) 37 (24) 9 (12) 15 (12) Negative 27 (61) 119 (76) 63 (88) 108 (88) Tumor stagec Stages 0 and I 34 (65) 127 (74) 61(81) 95 (74) Stage (35) 44 (26) 14 (19) 33 (26) a Reference 24. blnvasive cancers only. Clnvasive cancers and ductal carcinoma in situ. screening at such a long interval will increase the number of poorer-prognosis cancers detected during the interval while the number of less advanced, screening-detected cancers will decrease. To a certain extent, these four inherent limitations of the Nijmegen study mammography exist because the study was planned approximately 20 years ago, before the development of modern mammographic techniques and approaches. Our screening program, begun only 9 years ago, has used two-view mammography, double reading, lower thresholds for intervention, an annual screening interval, and more modern mammographic techniques (Nijmegen study dates are ; our study dates are ). We believe that these factors account for the improved ability of our mammographic techniques to detect early-stage, favorable-prognosis cancers. As shown in Table 6, the disparity in screening results between the Nijmegen study and our own is limited almost entirely to women under age 50. This suggests that the type of mammographic screening done in the Nijmegen study adversely affects clinical outcome primarily in younger women. This observation may partially explain why the randomized controlled trials, many of which are limited by Nijmegen-style mammography, do not show the same magnitude of screening benefit for women ages as they do for women ages In the report on the Nijmegen study, cross-classification of tumor size and axillary lymph node status (raw data not presented) showed that among women with small invasive cancers (10 mm), 40% of women younger than age 50 had positive nodes, whereas only 20% of women age 50 and older had positive nodes [24]. The investigators attributed these findings to age-related differences in tumor biology, suggesting that cancers in younger women disseminate early in their evolution, whereas cancers in older women progress to metastasis more slowly. We believe that the Nijmegen results do not serve as a basic indicator of tumor biology but simply are limited by relatively ineffective mammographic techniques and approaches. In our study the results are strikingly different, in thatfor women with small invasive cancers (1 0 mm), 0 (0%) of 18 women ages had positive axillary lymph nodes and two (6%) of 35 women ages had positive nodes. Tab#{225}r et al. have shown similar results [4]. We condude that advancing the time of diagnosis for invasive cancers does indeed diminish the propensity for axillary lymph node metastasis in women of all ages. Breast cancer is a disease of major significance among women ages years old. In the United States, among women in this decade of life, breast cancer is the most common malignant tumor and the leading cause of death from cancer [16, 32]. Although screening of women at ages appears to be somewhat less cost-effective than at ages [35], screening is still important in the younger age group because the impact of breast cancer is magnified by longer life expectancy. Furthermore, it is estimated that approximately 30% of the years of life lost to breast cancer is due to malignant disease found in women ages years old [2]. In our study, only 14 (19%) of the women years old in whom breast cancer was detected had a positive family history of breast cancer. Therefore, most of the cancers in this age group would have gone undetected had screening been

5 AJA:164, May 1995 MAMMOGRAPHIC SCREENING 1103 limited to women with a positive family history, as recommended by Kerlikowske et al. [36] and the recently changed guidelines of the National Institute [37]. In summary, data from randomized controlled trials establish the benefit of breast cancer screening for women ages but lack statistical power and are limited by experimental design and by older mammographic techniques for women ages Therefore, in the absence of conclusive data from the trials for women ages 40-49, it is also helpful to evaluate the efficacy of mammography for these women on the basis of indirect evidence. Since, as we show in this study, the major prognostic factors of cancers detected with modern mammographic screening appear to be at least as favorable for women ages as for women ages 50-64, and since screening already has been shown to be beneficial for the older group of women, one can infer that screening also should benefit women ages REFERENCES 1. 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