Marcel Mravunac

Histologic multifocality of Tis, T1-2 breast carcinomas: implications for clinical trials of breast-conserving surgery

Breast cancer multifocality was studied in mastectomy specimens by correlated specimen radiography and histologic techniques. The patients chosen for study were comparable to those eligible for breast‐conserving surgical therapy. Two study groups, one with 282 invasive cancers (T1‐2) and the other with 32 intraductal cancers, were selected from a group of 399 consecutive cases by omitting patients who were clearly, or very probably, not candidates for breast‐conserving surgical therapy according to current trial criteria. Omitted patients included those with clinically and/or radiologically multifocal cancers and patients with tumor extension into the chest wall or skin (7%). Also excluded were the socalled diffuse invasive cancers (8%), the clinically and radiologically occult tumors (3%), and the invasive cancers larger than 5 cm (3%). Of the 282 invasive cancers, 105 (37%) showed no tumor foci in the mastectomy specimen around the reference mass. In 56 (20%) tumor foci were present within 2 cm, and in 121 (43%) tumor was found more than 2 cm from the reference tumor. In 75 (27%) the tumor foci beyond 2 cm were histologically noninvasive cancers, and in 46 cases (16%) they contained invasive cancers as well. A comparison between the group with reference tumors less than 2 cm and the group with reference tumors more than 2 cm in size showed no significant difference between the groups in terms of presence or absence of tumor foci or distance of tumor foci from the reference tumor. If the 264 invasive cancers in this series that were 4 cm or less in diameter had been removed with a margin of 3 to 4 cm, 7% to 9% of the patients would have had invasive cancer left in the remaining breast tissue, and 4% to 9% would have had foci of noninvasive cancer left in the remaining breast tissue. On the basis of the data on the distribution of tumor at different distances from the reference tumor, the current study estimates the expected rates of local recurrences after breast‐conserving surgical procedures relative to the extensiveness of the excision. The possible impact of postoperative local radiation therapy on the rates of expected local recurrence is discussed.

Mammographically occult breast cancer: A pathologic and radiologic study

Fifteen mammographically occult breast cancers, 3 of which were preinvasive and 12 invasive, and 52 breast cancers, which presented only microcalcifications mammographically without an associated tumor shadow (33 preinvasive and 19 invasive), were reviewed pathologically and radiologically. This study suggests that most of the preinvasive cancers, without mammographically significant calcifications, are, and some of the invasive cancers situated in dense breasts may be, mammographically occult. The mean diameter of the five mammographically occult invasive ductal carcinomas and the five invasive lobular carcinomas was 20 mm and 50 mm, respectively. Histologic characteristics, which may explain why invasive lobular carcinomas could be occult mammographically, even in an advanced stage, include a diffuse invasive pattern and, frequently, a poor desmoplastic reaction in contrast to the invasive ductal carcinomas. The implications of mammographically occult cancers on management of symptomatic and asymptomatic patients are discussed.

So‐called interval cancers of the breast: Pathologic and radiologic analysis of sixty‐four cases

Within a population‐based breast cancer screening program, 209 cancers were detected by regular mammographic screening. Additionally, 66 cancers were discovered between two consecutive screenings after one, two, or three negative screening examinations (interval cancers). The study group consisted of 25,920 women who have been participating since 1975 in a breast cancer screening program in Nijmegen, the Netherlands. In this program, single view mammography (lateromedial projection) was administered as the sole screening examination every two years. Physical examination was not part of the screening program. All previous histologic and radiologic material from 64 of those “interval” patients was available and was reviewed. In 19 of the 64 patients, direct or indirect signs of tumor were seen on the previous screening mammogram on review (observers error). In four cases, the site of the tumor lay outside the imaging field (technical error). In 41 cases, no signs of tumor could be seen on the mammograms even on review. By calculated tumor doubling times, 20 of these 41 cases were probably too small to be detected at the last screening (“real” interval cancers). However, 21 cases were probably large enough but were somehow masked from radiologic detection. The main reasons for this “masking” proved to be: 1) dense breast, 2) poorly outlined tumor mass of diffuse infiltrative type, mainly invasive lobular carcinomas, and 3) intraductal localization. The authors suggest that women with dense breasts be screened more frequently, using more views and modalities and with broader criteria for advising surgical biopsy. They also note that in general the two‐year interval between screenings is probably longer than the optimal interval.

Long term breast cancer screening in Nijmegen, The Netherlands: the nine rounds from 1975-92.

STUDY OBJECTIVE: To assess the performance of breast cancer screening in different age categories over two decades. DESIGN: Important determinants of reduced breast cancer mortality such as attendance, mammography performance, cancer detection, and disease stage were recorded. SETTING: Nijmegen, The Netherlands, 1975-92. SUBJECTS: Since 1975 more than 40,000 women aged 35 years and older have been invited biennially for breast screening in a population based project in Nijmegen. MAIN RESULTS: Rates of attendance, referral, detection, and disease stage were calculated, as well as the specificity of screening mammography and the predictive value of referral and biopsy. From round 3 onwards, the attendance rate of women younger than 50 years stabilised at 70%, in women of 50-69 years it was 62%, and in women aged 70 and over it was 22%. In these three age categories, the referral rates of a positive screening mammography per 1000 screened women were 4.9, 6.2, and 11.8, respectively. Specificity rates were between 99% and 100%. Current predictive values of referral were high: in the specific age categories 39%, 59%, and 68% of the referred women had cancer. Detection rates remained fairly stable over the rounds 4-9, at 1.9, 3.6, and 8.0 cancers per 1000 screened women. In the two year period between screening the numbers of interval cancers per 1000 screened women were 2.2, 2.2, and 2.9, for the three age categories respectively. With regard to invasive cancers detected during screening, the percentage of small tumours (< or = 20 mm on the mammogram) was 84% in each age category. For women younger than 50 years, the proportion of intraductal carcinoma in all the cancers detected at screening was 40%, while it was 15% in the other age categories. CONCLUSION: Throughout the nine rounds, the screening outcomes were found to be adequate, particularly considering the high specificity rate and the predictive value of referral without the interference of a low detection rate. Although the occurrence of interval cancers seemed high, it was similar to other screening programmes. Despite a relatively low referral rate, the ratios of screen detected versus interval cancer cases were favourable. Well organised screening programmes can achieve good mammography results without too many false positives. It is important that women continue to participate in a screening programme because cancer can still be detected even after several successive negative screening examinations.

Mammographic screening after the age of 65 years : Evidence for a reduction in breast cancer mortality

We evaluated whether regular mammographic screening of women aged 65 years or older affected breast cancer mortality. In Nijmegen, a population‐based screening program for breast cancer was started in 1975, with biennial mammography for women aged 35–64 years. Since 1977, elderly women have also been participating. For the present case‐control study, women were selected who were over 64 years of age at the most recent invitation. Eighty‐two of them had died from breast cancer. For these cases, 410 age‐matched population controls were selected. The ratio of breast cancer mortality rates of the women who had participated regularly (i.e., in the 2 most recent screening rounds prior to diagnosis) vs. the women who had not participated in the screening was 0.56 (95% Cl = 0.28−1.13). The rate ratio was 0.45 in the women aged 65–74 years at the most recent invitation (95% Cl = 0.20−1.02), whereas it was 1.05 in the women aged 75 years and older (95% Cl = 0.27−4.14). While the breast cancer survival rate of the non‐participant patients was fairly equal to that of patients from a control population, the underlying incidence rate of breast cancer was higher in the participants than in the no‐participants. Therefore, we conclude that bias was present, but that it had decreased our effect estimate. The real reduction in breast cancer mortality due to regular screening will be even larger. Regular mammographic screening of women over age 65 (at least up to 75 years) can reduce breast cancer mortality by approximately 45%.

Breast-cancer mortality in a non-randomized trial on mammographic screening in women over age 65.

Recent case‐referent studies in the Nijmegen breast‐screening programme have shown a reduction in breast‐cancer mortality of approximately 50% due to screening of women aged 65 years and older. In this type of study, however, the results may be biased because of self‐selection. The purpose of our present study was to compare the breast‐cancer mortality rate in a population invited for screening with that of a reference population from an area without a screening programme. In 1977–1978, 6773 women aged 68–83 years were enrolled in the mammographic screening programme in Nijmegen, The Netherlands. The women were followed up until 31 December, 1990. The reference population consisted of women from the same birth cohort from Arnhem, a neighbouring city without mass screening, for whom the entry date was 1 January, 1978. The ratios of the Nijmegen and Arnhem breast‐cancer mortality rates with 95% confidence intervals (CI) were calculated. In the study period, 173 patients were diagnosed with primary breast cancer in Nijmegen vs. 183 in Arnhem; 40 Nijmegen patients had died of breast cancer vs. 51 Arnhem patients. The cumulative mortality‐rate ratio was 0.80 (95% CI = 0.53–1.22). In the periods 1978–1981, 1982–1985 and 1986–1990, the mortality rate ratios were 1.44 (95% CI = 0.67–3.10), 0.81 (95% CI = 0.37–1.79) and 0.53 (95% CI = 0.27–1.04), respectively. After adjustment for the difference in incidence rate that existed between the Nijmegen and Arnhem populations, mammographic screening of women older than 65 can be expected to yield a 40% reduction in breast‐cancer mortality after 10 years. Int. J. Cancer, 70:164–168, 1997.

Prognosis of younger and older patients with early breast cancer

The use of mammography in recent years has resulted in an increase in the detection of small breast cancers. The beneficial effects of early detection on breast cancer mortality seem to differ with age. To obtain more insight into this matter we studied the long-term prognosis of patients with early invasive breast cancers (T1) in three age groups: 144 patients of age 40-49, 402 patients of age 50-69 and 192 patients 70 years or older at diagnosis. In all age groups, patients with a tumour of 1 cm or less have a longer breast cancer specific survival than patients with a tumour larger than 2 cm. The survival advantage in the case of tumours of a size rounded to 1.5 cm compared with tumours larger than 2 cm in the under age 50 group was marginal (and not significant). However, older patients with tumours of this size do have a significantly improved survival. It is more difficult to improve survival in younger patients through early detection, partly because of an apparent early metastatic potential of their tumours. A reduction in breast cancer mortality might be expected in women younger than 50 years of age only if a substantial proportion of the invasive cancers are detected before their size exceeds 1 cm.

Mammographic screening after the age of 65 years: early outcomes in the Nijmegen programme.

We studied outcomes of mammographic screening in women older than 65 years. In 1975, breast cancer screening was started in Nijmegen, The Netherlands, for women aged 35-65 years. Since 1977, approximately 7700 older women have also been invited for biennial one-view mammography. This report is based on ten screening rounds from 1975 to 1994. The results of the subsequent screening rounds in the age groups 65-69 years, 70-74 years and 75 years and older were: participation rates 55%, 39% and 15%; screen-detected cancer rates 5.6%, 6.9% and 7.8%; interval cancer rates 2.0%, 1.8%, and 3.5%; and predictive values of referral 62%, 64% and 62% respectively. In all age groups, screen-detected patients had smaller tumours and a lower prevalence of axillary lymph node involvement than unscreened patients. Our conclusion is that, in women aged 65 years, and older, breast cancer can be detected at an earlier stage by mammographic screening.