The Effect of Diet on Breast Cancer Recurrence: The DIANA-5 Randomized Trial.

PURPOSE: The DIANA-5 randomized controlled trial assessed the effectiveness of a diet based on Mediterranean and macrobiotic traditions (macro-Mediterranean diet) in reducing breast cancer recurrence. PATIENTS AND METHODS: The DIANA-5 study involved 1,542 patients with breast cancer at high risk of recurrence because of estrogen receptor-negative cancer, or metabolic syndrome, or high plasma levels of insulin or testosterone. Women were randomly assigned to an active dietary intervention (IG) or a control group (CG). Both groups received the 2007 American Institute for Cancer Research/World Cancer Research Fund recommendations for cancer prevention. The intervention consisted of meetings with kitchen classes, community meals, and dietary recommendations. Recommended foods included whole grain cereals, legumes, soy products, vegetables, fruit, nuts, olive oil, and fish. Foods to be avoided were refined products, potatoes, sugar and desserts, red and processed meat, dairy products, and alcoholic drinks. A compliance Dietary Index was defined by the difference between recommended and discouraged foods. RESULTS: Over the 5 years of follow-up, 95 patients of the IG and 98 of the CG developed breast cancer recurrence [HR = 0.99; 95% confidence interval (CI): 0.69-1.40]. The analysis by compliance to the dietary recommendations (IG and CG together) showed that the women in the upper tertile of Dietary Index change had an HR of recurrence of 0.59 (95% CI: 0.36-0.92) compared with women in the lower tertile. CONCLUSIONS: The DIANA-5 dietary intervention trial failed to show a reduction in breast cancer recurrence, although self-reported diet at year 1 in IG and CG combined showed a protective association with the higher Dietary Index change. See related commentary by McTiernan, p. 931.

Nutrition, aging and cancer: lessons from dietary intervention studies.

There is convincing epidemiological and clinical evidence that, independent of aging, lifestyle and, notably, nutrition are associated with development or progression of major human cancers, including breast, prostate, colorectal tumors, and an increasingly large collection of diet-related cancers. Mechanisms underlying this association are mostly related to the distinct epigenetic effects of different dietary patterns. In this context, Mediterranean diet has been reported to significantly reduce mortality rates for various chronic illnesses, including cardiovascular diseases, neurodegenerative diseases and cancer. Although many observational studies have supported this evidence, dietary intervention studies using a Mediterranean dietary pattern or its selected food components are still limited and affected by a rather large variability in characteristics of study subjects, type and length of intervention, selected end-points and statistical analysis. Here we review data of two of our intervention studies, the MeDiet study and the DiMeSa project, aimed at assessing the effects of traditional Mediterranean diet and/or its component(s) on a large panel of both plasma and urine biomarkers. Both published and unpublished results are presented and discussed.

Adherence to WCRF/AICR cancer prevention recommendations and metabolic syndrome in breast cancer patients.

Metabolic syndrome (MetS), conventionally defined by the presence of at least three out of five dismetabolic traits (abdominal obesity, hypertension, low plasma HDL-cholesterol and high plasma glucose and triglycerides), has been associated with both breast cancer (BC) incidence and prognosis. We investigated the association between the prevalence of MetS and a score of adherence to the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) recommendations for the prevention of cancer in a cross-sectional study of BC patients. The DIet and ANdrogen-5 study (DIANA-5) for the prevention of BC recurrences recruited 2092 early stage BC survivors aged 35-70. At recruitment, all women completed a 24-hour food frequency and physical activity diary on their consumption and activity of the previous day. Using these diaries we created a score of adherence to five relevant WCRF/AICR recommendations. The prevalence ratios (PRs) and 95% confidence intervals (CIs) of MetS associated with the number of recommendations met were estimated using a binomial regression model. The adjusted PRs of MetS decreased with increasing number of recommendations met (p < 0.001). Meeting all the five recommendations versus meeting none or only one was significantly associated with a 57% lower MetS prevalence (95% CI 0.35-0.73). Our results suggest that adherence to WCRF/AICR recommendations is a major determinant of MetS and may have a clinical impact.

Metabolic syndrome and breast cancer prognosis.

Metabolic syndrome (MS), conventionally defined by the presence of at least three out of five dysmetabolic traits (abdominal obesity, hypertension, low plasma HDL-cholesterol, high plasma glucose and high triglycerides), has been associated with an increased risk of several age-related chronic diseases, including breast cancer (BC). This may have prognostic implications for BC survivors. 2,092 early stage BC survivors aged 35-70, recruited in eleven Italian centres 0-5 years after surgical treatment (1.74 years on average), were followed-up over 2.8 years on average for additional BC-related events, including BC-specific mortality, distant metastasis, local recurrences and contralateral BC. At recruitment, 20 % of the patients had MS. Logistic regression models were carried out to generate OR and 95 % confidence intervals (CI) for new BC events associated with MS, adjusting for baseline pathological prognostic factors. New BC events occurred in 164 patients, including 89 distant metastases. The adjusted ORs for women with MS versus women without any MS traits were 2.17 (CI 1.31-3.60) overall, and 2.45 (CI 1.24-4.82) for distant metastasis. The OR of new BC events for women with only one or two MS traits was 1.40 (CI 0.91-2.16). All MS traits were positively associated with new BC events, and significantly so for low HDL and high triglycerides. MS is an important prognostic factor in BC. As MS is reversible through lifestyle changes, interventions to decrease MS traits in BC patients should be implemented in BC clinics.

Estimates of cancer burden in Sicily.

AIMS AND BACKGROUND: Estimates are complementary epidemiological measures which allow to present data on cancer burden, especially in geographical areas where measurements of cancer occurrence are not supported by exhaustive statistics on incidence, mortality and survival. The aim of this paper is to provide cancer incidence, mortality and prevalence estimates and projections for the major cancers in the period 1970-2015 for the entire region of Sicily. METHODS: The estimates were computed by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Published data from the Italian cancer registries were modeled in order to estimate the regional cancer survival. RESULTS: In 2012 the most common cancers were breast cancer in women, colorectal cancer in both sexes, and prostate cancer in men, with about 4,000, 3,500 and 3,000 estimated new cases, respectively. The highest crude mortality rates were estimated for lung cancer in men (63.6 per 100,000) and breast cancer in women (30.8 per 100,000) and the lowest for skin melanoma (both sexes) and cancer of the cervix uteri. For colorectal, lung and stomach cancer and skin melanoma, all the indicators were higher in men than women. The prevalence figures in women were more than 9 times the incidence figures for breast cancer and more than 10 times the incidence figures for skin melanoma. The prevalence was twice the incidence for lung cancer in both sexes. The prevalence increased for all the considered cancers except cervical cancer. CONCLUSION: According to our analyses in Sicily we expect about 14,000 new diagnoses and 5,500 deaths for the major cancer types in a year, while about 92,000 persons with a diagnosis of the considered cancers were alive in 2012. We expect an increase in cancer survival and contemporary aging of the population: both expectations will inflate the cancer prevalence, causing more demand for oncology facilities.

Consistency and inconsistency in testing biomarkers in breast cancer. A GRELL study in cut-off variability in the Romance language countries.

PURPOSE: Biological markers are crucial factors in order to differentiate female breast cancers and to determine the right therapy. This study aims at evaluating whether testing for biomarkers for female breast cancer has similar frequency and characteristics across and within countries. METHODS: Population-based cancer registries of the Association for cancer registration and epidemiology in Romance language countries (GRELL) were asked to complete a questionnaire on biomarkers testing. The data collected referred to invasive female breast cancer cases diagnosed between 2004 and 2009. The investigation focused on 1) the overexpression and amplification of the human epidermal growth factor receptor 2 oncogene (HER2); 2) the expression of oestrogen (ER) and progesterone (PgR) receptors; and 3) the proliferation index (PI). Weighted percentages, the heterogeneity among and within countries, and the correlation between responses and calendar years were evaluated. The study was based on 19,644 breast cancers. RESULTS: Overall, 85.9% of the cases were tested for HER2, 91.8% for both ER and PgR, and 74.1% for proliferative markers. For HER2 and ER-PgR, the frequency of testing increased from 2004 to 2009. Testing varied among countries (HER2 from 82.0% to 95.9%, ER-PgR from 89.3% to 98.9%, PI from 10% to 92%) and also within the same country (e.g. HER2 in Italy from 51% to 99%) as well as within single cancer registries. The most relevant differences were in the scores for positive/negative/not clearly defined HER2 (e.g. HER2 was defined positive if IHC 3+ in 21/33 registries), and in the cut-off of positive cells for ER/PgR (from >0% to >30%) and PI positivity (from >0% to >20%). CONCLUSIONS: Biological markers are widely tested in the Romance language countries; however, the parameters defining their positivity may vary, raising concerns about homogeneity in breast cancer classification and treatment.

Breast cancer survival in the US and Europe: a CONCORD high-resolution study.

Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment.

Cancer prevalence in Italy: an analysis of geographic variability.

PURPOSE: Statistics on cancer prevalence are scanty. The objectives of this study were to describe the cancer prevalence in Italy and to explore determinants of geographic heterogeneity. METHODS: The study included data from 23 population-based cancer registries, including one-third of the Italian population. Five-year cancer prevalence was observed, and complete prevalence (i.e., all patients living after a cancer diagnosis) was estimated through sex-, age-, cancer site-, and observation period length-specific completeness indices by means of regression models. RESULTS: In 2006, 3.8 % of men and 4.6 % of women in Italy were alive after a cancer diagnosis, with a 5-year prevalence of 1.9 % and 1.7 % in men and women, respectively. A relevant geographic variability emerged for all major cancer sites. When compared to national pooled estimates, crude cancer prevalence proportions were 10 % higher in the north and 30 % lower in the south of Italy. However, these variations were consistently reduced after age adjustment and, in both sexes, largely overlapped those of incidence rates, with correlations >0.90 between variations of prevalence and incidence for all cancer sites and areas. CONCLUSIONS: Magnitude of the cancer prevalence and the geographic heterogeneity herein outlined in Italy will help in meeting the needs of specific population of survivor patients.

Regional inequalities in cancer care persist in Italy and can influence survival.

BACKGROUND: Population-based cancer registry studies of care patterns can help elucidate reasons for the marked geographic variation in cancer survival across Italy. The article provides a snapshot of the care delivered to cancer patients in Italy. METHODS: Random samples of adult patients with skin melanoma, breast, colon and non-small cell lung cancers diagnosed in 2003-2005 were selected from 14 Italian cancer registries. Logistic models estimated odds of receiving standard care (conservative surgery plus radiotherapy for early breast cancer; surgery plus chemotherapy for Dukes C colon cancer; surgery for lung cancer; sentinel node biopsy for >1mm melanoma, vs. other treatment) in each registry compared to the entire sample (reference). RESULTS: Stage at diagnosis for breast, colon and melanoma was earlier in north/central than southern registries. Odds of receiving standard care were lower than reference in Sassari (0.68, 95%CI 0.51-0.90) and Napoli (0.48, 95%CI 0.35-0.67) for breast cancer; did not differ across registries for Dukes C colon cancer; were higher in Romagna (3.77, 95%CI 1.67-8.50) and lower in Biella (0.38, 95%CI 0.18-0.82) for lung cancer; and were higher in Reggio Emilia (2.37, 95%CI 1.12-5.02) and lower in Ragusa (0.27, 95%CI 0.14-0.54) for melanoma. CONCLUSIONS: Notwithstanding limitations due to variations in the availability of clinical information and differences in stage distribution between north/central and southern registries, our study shows that important disparities in cancer care persist across Italy. Thus the public health priority of reducing cancer survival disparities will not be achieved in the immediate future.

Differences in stage and treatment of breast cancer across Italy point to inequalities in access to and availability of proper care.

AIMS AND BACKGROUND: Population-based cancer registry studies of patterns of care can help elucidate reasons for differences in breast cancer survival across Italy documented by previous studies. The aims of the present study were to investigate across-country variation in stage at presentation and standard care for breast cancer cases diagnosed in Italy in the early 2000s. METHODS: Samples of adult (≥ 15 years) women with breast cancer diagnosed in 2003-2005 were randomly selected in 9 Italian cancer registries. Logistic regression models were used to estimate the odds of receiving breast-conserving surgery plus radiotherapy (BCS + RT) in each cancer registry, age group, and disease stage category compared with the entire sample (reference); the z test was used to evaluate differences in proportions of stage at diagnosis, employment of chemotherapy in node-positive (N+) disease, and use of endocrine treatment in estrogen-receptor positive (ER+) and negative (ER-) tumors across Italy. RESULTS: Stage at diagnosis was earlier in northern/central registries than in southern areas. Compared with the reference, the odds of receiving BCS + RT was significantly lower in Trapani, Sassari and Naples (southern Italy) after adjusting for age and stage at diagnosis. Among N+ patients, 73% received adjuvant chemotherapy (range, 51% [Biella, northern Italy] to 87% [Ragusa, southern Italy]). Eighty percent of ER+ cancers (range, 50% [Biella, northern Italy] to 97% [Ragusa, southern Italy]) and 18% of ER- cancers (range, 6% [Modena, northern Italy] to 28% [Umbria, central Italy]) were treated with hormonal therapy. CONCLUSIONS: Disparities in stage distributions and conservative surgery in breast cancer persist across Italy. On a positive note, we found lower variations in the use of systemic treatment between Italian regions.

Lifestyle and breast cancer recurrences: the DIANA-5 trial.

AIMS AND BACKGROUND: The DIANA (Diet and Androgens)-5 study is a multi-institutional randomized controlled trial of the effectiveness of a diet based on Mediterranean and macrobiotic recipes and principles, associated with moderate physical activity, in reducing additional breast cancer events in women with early stage invasive breast cancer at high risk of recurrence because of metabolic or endocrine milieu. The intervention is expected to reduce serum insulin and sex hormones, which were associated with breast prognosis in previous studies. METHODS: Between 2008 and 2010, the study randomly assigned 1208 patients to an intensive diet and exercise intervention or to a comparison group, to be followed-up through 2015. General lifestyle recommendations for the prevention of cancer are given to both groups, and the intervention group is being offered a comprehensive lifestyle intervention, including cooking classes, conferences, common meals and exercise sessions. Adherence assessments occurred at baseline and at 12 months and are planned at 36 and 60 months. They include food frequency diaries, anthropometric measures, body fat distribution assessed with impedance scale, one week registration of physical activity with a multisensor arm-band monitor, metabolic and endocrine blood parameters. Outcome breast cancer events are assessed through self report at semi annual meetings or telephone interview and are validated through medical record verification. RESULTS: The randomized groups were comparable for age (51.8 years), proportion of ER-negative tumors (22%), axillary node metastasis (42%), reproductive variables, tobacco smoking, blood pressure, anthropometric measurements and hormonal and metabolic parameters. CONCLUSIONS: DIANA-5 has the potential to establish whether a Mediterranean-macrobiotic lifestyle may reduce breast cancer recurrences. We will assess evidence of effectiveness, first by comparing the incidence of additional breast cancer events (local or distant recurrence, second ipsilateral or contralateral cancer) in the intervention and in the control group, by an intention-to-treat analysis, and second by analyzing the incidence of breast cancer events in the total study population by compliance assessment score.

Target therapy in HER2-overexpressing breast cancer patients.

The development of new therapeutic strategies, such as monoclonal antibodies directed against human epidermal growth factor receptor-2 (HER2), has offered new hopes for women with early breast cancer whose tumors overexpress HER2. We retrospectively analyzed the population-based data of Breast Cancer Registry of Palermo in 2004-2006, and selected 1401 invasive breast cancer cases, nonmetastatic at diagnosis, having HER2/neu oncogene expression determined. We have correlated this information to age, tumor stage at diagnosis (TNM), nodal involvement, and receptor status (ER and PgR). Survival analysis was conducted dividing the patients in two different groups according to date of diagnosis: one group diagnosed in 2004 and a second group in 2005-2006. In the 460 cases of 2004, nodal involvement, receptor status, age at diagnosis and TNM maintained a strong predictive value (p < 0.0001). In this group of patients, overall survival was significantly different according to the HER2 expression levels (p = 0.001). In the second group of patients (941 incident cases in 2005-2006) there was a statistically significant survival difference comparing patients with high levels of HER2 expression treated with trastuzumab versus those untreated (p = 0.006). Our data show that elevated levels of HER2 are a negative prognostic factor. In addition, patients overexpressing HER2 show a significant increase of overall survival when treated with trastuzumab.

Variation in 'standard care' for breast cancer across Europe: a EUROCARE-3 high resolution study.

On a population-based sample of 13,500 European breast cancer patients mostly diagnosed in 1996-1998 and archived by 26 cancer registries, we used logistic regression to estimate odds of conservative surgery plus radiotherapy (BCS+RT) versus other surgery, in T1N0M0 cases by country, adjusted for age and tumour size. We also examined: BCS+RT in relation to total national expenditure on health (TNEH); chemotherapy use in N+ patients; tamoxifen use in oestrogen-positive patients; and whether 10 nodes were examined in lymphadenectomies. Stage, diagnostic examinations and treatments were obtained from clinical records. T1N0M0 cases were 33.0% of the total. 55.0% of T1N0M0 received BCS+RT, range 9.0% (Estonia) to 78.0% (France). Compared to France, odds of BCS+RT were lower in all other countries, even after adjusting for covariates. Women of 70-99 years had 67% lower odds of BCS+RT than women of 15-39 years. BCS+RT was 20% in low TNEH, 58% in medium TNEH, and 64% in high TNEH countries. Chemotherapy was given to 63.0% of N+ and 90.7% of premenopausal N+ (15-49 years), with marked variation by country, mainly in post-menopause (50-99 years). Hormonal therapy was given to 55.5% of oestrogen-positive cases, 44.6% at 15-49 years and 58.8% at 50-99 years; with marked variation across countries especially in premenopause. The variation in breast cancer care across Europe prior to the development of European guidelines was striking; older women received BCS+RT much less than younger women; and adherence to 'standard care' varied even among countries with medium/high TNEH, suggesting sub-optimal resource allocation.

Oral contraceptive use and BRCA penetrance: a case-only study.

BACKGROUND: Women with deleterious mutations in BRCA genes are at increased risk of breast cancer. However, the penetrance of the genetic trait may be regulated through environmental factors. This multinational case-only study tested the interaction between oral contraceptive use and genetic susceptibility in the occurrence of breast cancer. METHODS: We recruited 3,123 patients diagnosed with breast cancer before the age of 45 years. Participants were classified according to their probability of carrying a BRCA mutation on the basis of their family history of breast and ovarian cancer. According to a case-only approach, the frequency of relevant exposures among breast cancer cases with high probability of BRCA mutation ("genetic cases") was compared with the frequency of the same exposures among breast cancer cases with a low probability of BRCA mutation ("sporadic cases"). The interaction odds ratios (OR) and 95% confidence intervals (CI) for oral contraceptive use were estimated by unconditional logistic regression, after controlling for potentially confounding variables. RESULTS: The analysis was carried out comparing 382 "genetic" and 1,333 "sporadic" cases. We found a borderline significant interaction between genetic breast cancer and oral contraceptive use for ever users compared with never users (OR, 1.3; 95% CI, 1.0-1.7). The greatest interaction OR was found for women who started using pill at 18 to 20 years (OR, 1.6; 95% CI, 1.1-2.3). CONCLUSION: These results suggest that BRCA mutation carriers, as well as women with a significant family history of breast and ovarian cancer are more vulnerable to exogenous hormones in oral contraceptives.

Application of a new classification to a breast tumor series from a population-based cancer registry: demographic, clinical, and prognostic features of incident cases, Palermo Province, 2002-2004 .

A new classification based on gene expression profiling or immunohistochemical (IHC) characteristics may replace current histopathological classifications and predict better clinical outcomes. We used IHC markers to classify incident cases ascertained by the Palermo Breast Cancer Registry (2002-2004) into four subtypes: luminal-A (ER+ or PgR+ and HER2/neu-); luminal-B (ER+ or PgR+, HER2/neu+); basal-like (ER-, PgR-, HER2/neu-); and HER2+/ER- (HER2/neu+, ER-, PgR-). We evaluated HER2/neu, ER and PgR in 1300/1985 (65%) cases. The most common IHC-subtype was luminal-A (68%), whereas luminal-B, basal-like, and HER2+/ER- accounted for 14%, 13%, and 5%, respectively. IHC-subtypes were not associated with tumor size, geographic location within the province, or menopause, but differed by NPI (P < 0.0001), grading (P < 0.0001), lymph-node involvement (P= 0.04), metastases (P= 0.04), and TNM stage (P= 0.04). Endocrine therapy was administered to 81% of 519 postmenopausal, luminal-A, and luminal-B cases and to 32% of 114 postmenopausal, basal-like, and HER2+/ER- cases.

Endocrine therapy in metastatic breast cancer: data from Breast Cancer Registry of Palermo, 1999-2005 .

This study compares the survival of breast cancer patients who are metastatic at diagnosis (DMBC) and of recurrent metastatic breast cancer (RMBC) patients. We analyzed retrospectively the population-based data of Breast Cancer Registry of Palermo and collected a total of 4459 breast cancer cases in the years 1999-2005. Survival analysis did not show statistically significant differences between DMBC and RMBC patients (P= 0.882). Endocrine manipulation is the treatment of choice in the case of hormone receptor-positive breast tumors. In 91 receptor-positive DMBC patients the endocrine treatment was associated with a prolonged overall survival (OS) (median survival 33.5 months compared to 29 months for receptor-positive patients who did not receive hormone treatment). Receptor-negative patients who underwent endocrine therapy (76% of cases) survived longer than receptor-negative patients who did not receive hormone treatment (median survival 28.5 months vs. 15 months, respectively). This evidence supports the concept that endocrine therapies impinging upon molecular targets other than hormone receptors may increase survival rates of breast cancer patients.

Dietary enterolactone affects androgen and estrogen levels in healthy postmenopausal women.

In this randomized dietary intervention study (DI) we analyzed levels of androgens, phytoestrogens, and estrogens in 12-h urine samples of 69 healthy postmenopausal women, 37 of whom followed a traditional Mediterranean diet for 6 months (intervention group) as compared to 32 women who followed their regular diet (control group). Circulating levels of both insulin and testosterone (T) were also assayed. Overall, enterolactone (ENL) was the most prominent phytoestrogen in urines of both control and intervention women, and its levels increased by a 20% after DI. At the baseline the ENL levels were seen to be significantly associated with both the total androgens (TOT-A) (r= 0.371, P= 0.002) and the TOT-A/total estrogen (TOT-E) ratio (r= 0.351, P= 0.005) in all 69 postmenopausal women. Furthermore, the DI resulted in a more pronounced negative association of both ENL with insulin (r=-0.321, P= 0.05) and insulin with TOT-A (r=-0.421, P= 0.01). Regarding urinary androgens, ENL associated with both 3alpha-androsterone (5alpha-androgen, r= 0.363, P= 0.002) and 3alpha-etiocholanolone (5beta-androgen, r= 0.295, P= 0.01) at baseline, while after DI, circulating insulin and T exhibited a significant negative association with the 5beta-androgen metabolite etiocholanolone (r=-0.487, P= 0.002; and r=-0.336, P= 0.042, respectively). We conclude that lignan components of the Mediterranean diet, notably ENL, are associated with urinary levels of products of androgen metabolism, including both 5alpha- and 5beta-reductase enzymes, in healthy postmenopausal women. Further studies are necessary to better understand the interplay of sex hormones with dietary phytoestrogens.

Breast screening: axillary lymph node status of interval cancers by interval year.

The aim of this study was to determine whether the excess risk of axillary lymph node metastases (N+) differs between interval breast cancers arising shortly after a negative mammography and those presenting later. In a registry-based series of pT1a-pT3 breast carcinoma patients aged 50-74 years from the Italian screening programmes, the odds ratio (OR) for interval cancers (n=791) versus the screen-detected (SD) cancers (n=1211) having N+ was modelled using forward stepwise logistic regression analysis. The interscreening interval was divided into 1-12, 13-18, and 19-24 months. The prevalence of N+ was 28% among SD cancers. With a prevalence of 38%, 42%, and 44%, the adjusted (demographics and N staging technique) OR of N+ for cancers diagnosed between 1-12, 13-18, and 19-24 months of interval was 1.41 (95% confidence interval 1.06-1.87), 1.74 (1.31-2.31), and 1.91 (1.43-2.54), respectively. Histologic type, tumour grade, and tumour size were entered in turn into the model. Histologic type had modest effects. With adjustment for tumour grade, the ORs decreased to 1.23 (0.92-1.65), 1.58 (1.18-2.12), and 1.73 (1.29-2.32). Adjusting for tumour size decreased the ORs to 0.95 (0.70-1.29), 1.34 (0.99-1.81), and 1.37 (1.01-1.85). The strength of confounding by tumour size suggested that the excess risk of N+ for first-year interval cancers reflected only their higher chronological age, whereas the increased aggressiveness of second-year interval cancers was partly accounted for by intrinsic biological attributes.

Estimate of overdiagnosis of breast cancer due to mammography after adjustment for lead time. A service screening study in Italy.

INTRODUCTION: Excess of incidence rates is the expected consequence of service screening. The aim of this paper is to estimate the quota attributable to overdiagnosis in the breast cancer screening programmes in Northern and Central Italy. METHODS: All patients with breast cancer diagnosed between 50 and 74 years who were resident in screening areas in the six years before and five years after the start of the screening programme were included. We calculated a corrected-for-lead-time number of observed cases for each calendar year. The number of observed incident cases was reduced by the number of screen-detected cases in that year and incremented by the estimated number of screen-detected cases that would have arisen clinically in that year. RESULTS: In total we included 13,519 and 13,999 breast cancer cases diagnosed in the pre-screening and screening years, respectively. In total, the excess ratio of observed to predicted in situ and invasive cases was 36.2%. After correction for lead time the excess ratio was 4.6% (95% confidence interval 2 to 7%) and for invasive cases only it was 3.2% (95% confidence interval 1 to 6%). CONCLUSION: The remaining excess of cancers after individual correction for lead time was lower than 5%.