Nonpalpable Breast Cancer in Women Aged Years: A Surgeon s View of Benefits From Screening Mammography

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1 Nonpalpable Breast Cancer in Women Aged Years: A Surgeon s View of Benefits From Screening Mammography Helena R. Chang, Bernard Cole, Kirby I. Bland* While mammography screening among women aged 50 years or older has proven to reduce breast cancer mortality, screening in younger women has been repeatedly scrutinized. To test the effect of screening among younger women, we examined 84 consecutive patients aged at the time of breast cancer diagnosis: 27 (32.1%) were diagnosed solely by mammography, and 57 (67.9%) had a palpable mass. The mean tumor sizes were 1.3 cm and 3.6 cm for the two groups respectively. While 68.8% nonpalpable invasive tumors were classified as Stage I cancer, only 34% of patients with palpable breast cancer had Stage I disease. None of the patients with nonpalpable breast cancer had disease beyond Stage II. In contrast, 28.3% of the patients with palpable invasive breast cancer presented with advanced disease. In addition, 6.3% versus 41.5% of patients with nonpalpable and palpable breast cancer respectively had nodal metastases. The five-year survival rates for the two groups were 100% and 73% respectively, favoring breast cancer detected mammographically. Screening of women aged also resulted in more breast-conserving surgery and less chemotherapy. We conclude that screening in this age group should be continued, although individual assessment is needed. [Monogr Natl Cancer Inst 1997:22: ] The beneficial effect of screening mammography among women aged 50 and older has been consistently demonstrated worldwide (1 6). Indeed, screening has been recognized as the most effective tool against breast cancer in this age group, and it has been firmly recommended for all women aged 50 and older. Meanwhile, the debate regarding its usefulness for women aged remains unsettled (7 13). Recently, however, a metaanalysis of seven randomized trials studying women aged years has demonstrated a statistically significant 24% reduction in breast cancer mortality due to screening intervention (14). It has been suggested that this outcome may be further improved by annual two-view screening with high-resolution mammography (15,16). These results, together with the significant breast cancer incidence in young women and the subsequent loss of life, make any negative recommendation for screening an extremely serious public health concern. It is estimated that a 40-year-old woman has a 1 in 63 chance of developing breast cancer before age 50 (17). Approximately 18% of all breast cancers (18), 20% of all breast cancer deaths, and one-third of all years of life expectancy lost due to breast cancer are in women of this age group (5). Any guidelines recommended by health professionals should therefore target improvements in the diagnosis, survival, and quality of life after diagnosis for this age group. While all the randomized trials to date have focused on the reduction of cancer death by screening programs, each has overlooked important quality-of-life issues, such as whether a woman must undergo adjuvant therapy and whether breastconserving surgery is a treatment option. The purpose of this paper, therefore, is to evaluate not only mortality benefits due to screening, but also subsequent improvements in quality of life. Specifically, we compare tumor size, cancer staging, surgical treatment, adjuvant therapy, and disease control between women aged years with palpable tumors and women of this age with nonpalpable breast cancer detected by mammography. Patients and Materials Eighty-seven breast cancer patients aged were identified in a single institution between 1983 and Patients with mammographically detected nonpalpable breast cancer were identified by reviewing the operative notes, specimen mammography, and pathology reports. Specimen mammography was performed after tissue was removed by the hook-wire method to ensure inclusion of the concerned area. When patients were either biopsied or surgically treated elsewhere, the pathologic confirmation of breast cancer diagnosis was achieved by institutional review. In these cases, the palpability of the original tumor was determined from the treating physician s notes and categorized as either nonpalpable (removed by needle localization) or palpable. The palpability of one tumor was uncertain, and it was excluded from the analysis. Since this study was aimed at examining the value of screening mammography, two cases with nonpalpable but nonmammographically detected breast cancer were also excluded: one patient had Paget s disease of the nipple, and the other patient had an incidental finding of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) from breast-reduction specimen. Mean size of invasive primary cancer, cancer staging, nodal *Affiliations of authors: H. R. Chang, Department of Surgery, Roger Williams Medical Center, Brown University, Providence, Rhode Island; B. Cole, Center for Statistical Sciences, Brown University, Providence, Rhode Island; K. I. Bland, Rhode Island Hospital and Department of Surgery, Roger Williams Medical Center, Brown University, Providence, Rhode Island. Correspondence to: Helena R. Chang, M.D., Ph.D., Department of Surgery, Roger Williams Medical Center, Brown University, 825 Chalkstone Avenue, Providence, RI See Note following References. Oxford University Press Journal of the National Cancer Institute Monographs No. 22,

2 status, types of surgical treatment, need for adjuvant treatment, overall survival, and disease-free survival were compared in the two groups. Tumor size was defined as the maximal diameter of the gross lesion or the microscopic measurement of the nonapparent lesion. The choice of surgical treatment was jointly decided by the treating surgeon, the radiation oncologist, and the patient. When needed, adjuvant therapy was recommended by a multidisciplinary team at the institution after team members reviewed the complete pathologic findings of the primary breast cancer and axillary lymph nodes. The statistical significance of differences of all parameters between the two groups was analyzed by Fisher s exact test or by chi-square analysis. Survival time was measured from the date of diagnosis. The survival curves were generated using the Kaplan-Meier method, and the survival curves were compared by the log-rank test. Results Eighty-four women aged years with breast cancer were identified between 1983 and Eighty-two percent were found to have invasive cancer, and the remaining had in situ disease. Approximately one-third of young patients (n 27) had mammographically detected breast cancers, which were surgically removed by needle-guided breast biopsy. Of these 27 patients, 40.7% were found to have in situ breast cancer. In contrast, only 5.2% of patients with palpable breast cancer had the same premalignant condition. A palpable mass was strongly associated with invasive breast cancer (Table 1). The size of the primary invasive cancer was compared between mammographically detected cancers and those diagnosed palpably. The mean size of the tumors in the mammographically diagnosed group was 1.3 cm, with a median tumor diameter of 0.8 cm. This was much smaller than the mean tumor diameter of 3.6 cm (P 0.059) and the median diameter of 2.5 cm (P 0.003) in patients with palpable cancers (Table 2). Forty-four percent of the nonpalpable breast cancers were 1 cm or less, compared to 16% of palpable breast cancers. The difference in distribution of tumor size in the two groups was significant (P 0.049), with the group having nonpalpable tumors dominated by Table 1. Comparison of characteristics of women aged years with palpable versus mammographically detected () nonpalpable breast cancer in 84 patients ( ) Characteristics (nonpalpable) Mean age 45 years 46 years Race White Nonwhite 0 1 Unknown 3 4 Invasive cancer Ductal Lobular 1 2 Ductal and lobular 0 1 Other 10 3 DCIS 4 11 Total cases Nonpalpable breast cancer diagnosed by needle-localization guided breast biopsy. Table 2. Mean size of palpable vs. mammographically detected () nonpalpable invasive breast cancer in women aged years Tumor size Invasive breast cancer Statistical difference small cancers (Table 3). Five of the palpable cancers had no definitive size due to diffuse involvement of the breast or metastatic disease. Tumor diameter was not available in three patients with nonpalpable breast cancer, all of whom had either malignant microcalcifications or fragmented specimens, and hence the exact sizes could not be correctly calculated. In addition to being smaller tumors, mammographically detected cancers also tended to be early-stage cancers. More than two-thirds of the mammographically detected cases had Stage I disease, and none had disease beyond Stage II. In contrast, only one-third of the patients with palpable tumors had Stage I breast cancer, and approximately one-third had Stage III and Stage IV breast cancer (Fig. 1). The difference in stage distribution between the two groups of patients was statistically significant (P<0.001). The incidence of nodal metastasis in the two groups also differed significantly, with 6.3% in the former group and 41.5% in the latter group (P 0.046) (Table 4). The mean numbers of metastatic nodes were 3.34 for patients with palpable breast cancer and 0.05 for patients with nonpalpable breast cancer (P ). Breast conservation was the most common form of surgical treatment for mammographically discovered breast cancer (Table 5). The mean tumor size was 1.4 cm for those who received lumpectomy and 1.3 cm for patients who received mastectomy. It is possible that all these patients were candidates for breast-conserving surgery. In comparison, the majority of patients with palpable breast cancer were treated with mastectomy. The mean tumor size of those who received a mastectomy for a palpable cancer was 4 cm, which appeared to justify the choice of mastectomy. Postoperative chemotherapy was less frequently employed in treating patients with mammographically detected breast cancer. While 67% of the women with palpable invasive breast cancer had chemotherapy, only 31% of the group with nonpalpable breast cancer received multidrug chemotherapy (P 0.01). More conservative surgery and less chemotherapy did not pose any adverse effect on the excellent outcome of patients with Mean 3.6 cm 1.3 cm P Median 2.5 cm 0.8 cm P Table 3. Distribution of tumor size in women aged with palpable vs. mammographically detected invasive breast cancer Tumor size 1 cm (T1a,b) 8 (15.0%) 7 (43.8%) cm (T1c) 15 (28.3%) 3 (25.1%) cm (T2) 19 (35.8%) 3 (12.5%) >5.0 cm (T3) 6 (11.3%) 0 Unknown 5* (9.4%) 3 (18.8%) P *Five of the palpable cancers had no definitive size due to diffuse involvement of the breast or metastatic. 146 Journal of the National Cancer Institute Monographs No. 22, 1997

3 Table 4. Axillary metastases in women aged with palpable vs. mammographically detected invasive cancer Nodal status + 22 (41.5%) 1 (6.3%) 28 (52.8%) 14 (87.5%) Unknown 3 (5.7%) 1 (6.3%) Fig. 1. Distribution of cancer stage in women aged years with either palpable or mammographically detected () nonpalpable invasive breast cancer (P<0.001). Table 5. Type of surgery received by women aged with either palpable or mammographically detected breast cancer Surgery palpable/mean tumor size /mean tumor size Lumpectomy 19 (33.4%)/2.6 cm 14 (51.8%)/1.4 cm Mastectomy 33 (57.3%)/3.9 cm 12 (44.4%)/1.3 cm Neither/unknown 5 (9.3%) 1 (3.8%) mammographically discovered breast cancer. Their five-year overall survival and disease-free survival rates were both 100% (Fig. 2). In contrast, the five-year overall and disease-free survival rates were 70% and 62% respectively among patients with palpable breast cancer. However, the five-year survival rates associated with women with local disease, regional disease, and distant metastases in this latter group were 89.7%, 68.9%, and 17.9% respectively, suggesting that the survival rates were stage specific and were not adversely affected by tumor palpability alone. A significant proportion of women aged in the study had mammographically detected breast cancer. The breast cancer detected by this mode resulted in 40% of in situ disease. Among those patients aged with invasive breast cancers, 94% were free of nodal metastasis. Mammographically detected cancers among these young women tend to be small in size and early in cancer stage. Young women with mammographically discovered breast cancer were more likely to receive breast conservation surgery and less likely to require chemotherapy. The excellent survival rate and disease control simply reflect that screening mammography detects breast cancer at a favorable stage. Discussion is the leading cause of death in women in their forties in the United States (19). Two screening methods mammography and clinical breast examination are thought to be life saving for women over 50 years of age, but the same techniques have been suggested by some to be ineffective for women aged years. Therefore, women in the younger age group are not screened routinely and must often wait for breast cancer to appear clinically before being treated. The opponents of universal screening for women in their forties have been supported by the report of the Canadian National Breast Screening Study (NBSS). The NBSS reported that more node-positive breast cancer cases and more patients with four or more positive lymph nodes were found in a mammographically Fig. 2. Five- and ten-year overall survival rates in women aged years with either palpable or mammographically detected () nonpalpable invasive breast cancer. (P 0.060). Journal of the National Cancer Institute Monographs No. 22,

4 screened group than in controls. This study implied that screening mammography caused more advanced breast cancer locally and regionally, hence a higher breast cancer mortality. According to our findings, this implication is misleading and unfounded. Our study focused on the characterization of breast cancers that were detected by mammography in asymptomatic women aged years. Approximately one-third of young women in our study had nonpalpable cancer. The majority of these nonpalpable breast cancers found by mammography were either in situ tumors or small invasive breast cancers. The mean size of invasive cancers detected as nonpalpable, mammographic abnormalities was 1.3 cm, and 94% of these patients had negative lymph nodes. The five-year survival rate was 100%, which is significantly better than 70% observed in patients with palpable breast cancer. Patients rarely had recurrent disease, which was reflected by an excellent disease-free survival rate at five years. Furthermore, only 31.3% received adjuvant chemotherapy. In contrast, 67% of patients with palpable breast cancer required chemotherapy. None of the patients with nonpalpable breast cancer had either Stage III cancer or metastasis at the time of diagnosis. On the contrary, 14 of the 53 patients with palpable breast cancers were found to have advanced disease. Our findings therefore support the cautious continuation of screening for women in their forties. This conclusion is supported by several previous studies, including of the Health Insurance Plan (HIP) trial, the first randomized controlled trial (RCT) of breast cancer screening. Although an initial, short follow-up of the HIP study reported no survival benefits to screening among women aged years (5,20), an 18-year follow-up demonstrated a 24% reduction in the mortality of women who entered the study at ages years (21). A second U.S. study, the Breast Cancer Detection and Demonstration Project (BCDDP), has been remarkable for demonstrating superior detection of breast cancer not only among postmenopausal women, but also women aged 40 to 49. In the BCDDP study, the breast cancers detection rate by screening mammography was 90% for young women and 92% for women aged years. The improved mammographic capability resulted in detecting smaller breast cancer, and 80% of all breast cancers detected by screening mammography were free of nodal metastases (22, 23). The overall 14-year adjusted survival rate for women aged years with invasive breast cancer was 81.8%. In 1993, Fletcher reported that screening mammography was not beneficial for women aged years based on a follow-up of five to nine years from previously conducted RCTs (24). More recently, however, an analysis of the five Swedish trials, which included 282,777 women who were followed for 5 to 13 years, showed a 13% reduction of breast cancer mortality among screened women aged years (25), although the beneficial effect did not emerge until after eight years of follow-up. The Edinburgh trial also revealed no benefit for the first seven years of follow-up. However, the relative risk (RR) the breast cancer mortality rate of screened women relative to nonscreened women decreased significantly at the 10-year follow-up (26). Kerlikowske et al. notes that in those clinical trials in which women aged years underwent two-view mammography and had 10 to 12 years of follow-up, the RR of screened to nonscreened women decreased significantly (RR 0.73) (27). Another meta-analysis of the seven prospective randomized trials included women aged years, reporting a 24% reduction of breast cancer mortality by breast cancer screening (14). Taken together, then, these studies suggest a beneficial effect from screening, at least after about 8 to 10 years. In addition to suggesting a benefit from screening mammography for young women, analysis of the National Cancer Institute s Surveillance, Epidemiology, and End Result Program data showed that the breast cancers detected solely by mammography were mainly DCIS and lesions less than 1.9 cm in diameter with no axillary nodal involvement (30). The BCDDP study further showed that the rates of breast cancer detected by mammography in women aged and women aged were similar. Kopans et al. found that the positive predictive value of breast biopsy performed as a result of mammography does not abruptly change at age 50 years (29). Thus, it is inappropriate to assume that screening mammography in women aged years is ineffective. Studies directed to examine the outcome of needle-localized breast biopsies in women aged are few. Lein et al. (30) recently examined 207 patients in this age category who underwent needle-guided biopsies. Fifteen percent of these patients were found to have breast cancer. Although the mean tumor diameter of this particular age group was not specified, the mean tumor size of all age groups was 1.46 cm. Others found that a high percentage of young women with occult, grouped microcalcifications had early-stage or noninvasive ductal carcinoma detected by screening mammography (31,32). Wilhelm et al. demonstrated that patients with nonpalpable breast cancer detected by mammography tended to have small tumors, fewer nodal metastases, and better survival (33 35). Even the NBSS study pointed out that the best survival was found in young women whose breast cancers could only be detected by mammography. Aside from favorable size, nodal status, and survival outcomes of patients with mammographically detected breast cancer, Haffty et al. has demonstrated excellent local control and overall survival in patients with nonpalpable breast cancer who are treated by breast-conserving surgery and radiation. These authors further point out that none of these patients received adjuvant chemotherapy (36). One would assume that the quality of the patient s life is likely to be improved when breastconserving treatment is an option, and when it is possible to avoid chemotherapy among women with mammographically detected breast cancer. Based on our study and the work of others, then, we believe that there is insufficient evidence to discontinue the practice of screening mammography in women aged years. References (1) Tabar L, Fagerberg G, Duffy SW, Day NE, Gad A, Grontoft O. Update of the Swedish two-county program of mammographic screening for breast cancer. 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