Boni L

Dionigi G

Dionigi R.

Fachinetti A

Rausei S

Rovera F

Tornese D

ROVERA, FRANCESCA  ANGELA

DIONIGI, GIANLORENZO

BONI, LUIGI

DIONIGI, RENZO

Archivio istituzionale della ricerca - Università dell'Insubria

ORIGINAL ARTICLEPredictors of Loco-Regional Recurrence andCancer-Related Death after Breast Cancer SurgeryStefano Rausei, MD, Francesca Rovera, MD, Gianlorenzo Dionigi, MD, FACS,Deborah Tornese, MS, Anna Fachinetti, MS, Luigi Boni, MD, FACS, andRenzo Dionigi, MD, FACS, FRCS (Hon. Edin.)Department of Surgical Sciences, University of Insubria, Varese, Italyn Abstract: To determine which tumor-related factors might predispose the patient to loco-regional recurrence or deathand the impact of these factors on the different types of events. We retrospectively analyzed the data of 1991 womenbetween January 1998 and March 2010 for a first primary nonmetastatic breast cancer and treated with surgery and neo-adjuvant ⁄adjuvant therapy. The overall survival distribution was estimated using the Kaplan–Meier method. The prognosticimpact of several factors on cumulative overall and loco-regional recurrence free survival was evaluated by univariate (log-rank test) and multivariate analysis (Cox regression). At log-rank test, pT, nodal status, histotype, grading, lymphangioinva-sive growth, tumor diameter, estrogen receptors (ER) status, progesterone receptors (PR) status, expression of Ki67, andexpression of Her2 ⁄neu had a prognostic value on loco-regional recurrence or overall survival. In the multivariate analysisgrading remained the only independent predictor of loco-regional recurrences. With regard to overall survival, the Coxmodel selected grading along with nodal status and PR status. Loco-regional recurrences after breast cancer surgery arenot frequent events. They are markers of tumor aggressiveness and predictor of an increased likelihood of cancer-relateddeath. However, loco-regional recurrence and systemic tumor progression are partially independent events, since someprognostic factors differ. nKey Words: breast cancer, loco-regional recurrence, predictive factorsToday, in minimally invasive surgery era, outcomeof breast cancer patients after breast-conservingsurgery seems better than outcome after mastectomy:actually, this effect is due to many early-stage diseasestreated by conservative excision (1–4). However, whilesurgical procedure cannot be considered a prognosticfactor for these patients, there is the need to detectreliable predictors of loco-regional recurrence, a mar-ker of tumor aggressiveness linked to an increased riskof distant metastases and death (5–11). In fact, byidentification of stronger pathologic and molecularpredictors of loco-regional recurrence and more effec-tive treatment strategies, the risk of local failure afterbreast surgery could decrease.In this study, we analyzed data on 1991 womenunderwent surgery for breast cancer in order todetermine which tumor-related factors might predisposethe patient to loco-regional recurrence or death and todetermine the impact of these factors on the differenttypes of events.PATIENTS AND METHODSStudy PopulationWe retrospectively analyzed the data of 1991women hospitalized at the University of Insubria Hos-pital in Varese between 1 January 1998 and 30 March2010 for a first primary nonmetastatic breast cancerand treated with surgery and neo-adjuvant ⁄adjuvanttherapy. Women were usually followed up by physicalexamination every 6 months and mammography withbreast ultrasound (US) annually; in symptomatic casesor when clinically indicated, bone scan, chest x-ray,liver US or computed tomography scan were carriedout.Definitions of End PointsLoco-regional recurrence was defined as recurrencein the original tumor bed or in the ipsilateral axillary,Address correspondence and reprints request to: Stefano Rausei, MD,Department of Surgical Sciences, University of Insubria, Viale L. Borri 57,21100 Varese, Italy, or e-mail: s.rausei@libero.it.DOI: 10.1111/j.1524-4741.2010.01000.x 2010 Wiley Periodicals, Inc., 1075-122X/10The Breast Journal, Volume 16 Suppl. 1, 2010 S29–S33internal mammary or supraclavicular or infraclavicularnodes with the same histopathologic features of theprimary tumor. Regarding to end point of death, weconsidered only deaths for breast cancer.Statistical MethodsThe overall survival distribution was estimatedusing the Kaplan–Meier method (12). New ipsilateralbreast tumor, contralateral breast tumor, distantmetastases onset and other nonbreast primary tumorwere considered as censoring events for loco-regionalrecurrence free survival and death for other causes ascensoring event for overall survival. In the absence ofany of these events, the observation time was censoredat the last follow-up visit. The prognostic impact ofseveral factors on cumulative overall and loco-regionalrecurrence free survival was evaluated by log-rank test(13). Continuous variables were categorized accordingto the median value. In order to consider only tumor-related factor, we excluded from analysis any patient-and treatment-related factors. Variables reaching ap value <0.1 in the univariate analysis were regressedon the cause-specific hazard, using multivariate Coxproportional hazards model (14). The stepwise (back-ward elimination) procedure was used. The effect ofeach factor was expressed as hazard ratio (HR) with95% confidence intervals (CIs). The proportionalhazard assumption was controlled using goodness offit tests. The statistical analysis was performed withSPSS software for Windows. All reported p-valueswere two-sided.RESULTSMedian age was 61.1 years (range 24–96). Medianfollow-up was 53 months (range 1–148), with 44.7%of patients having a follow-up >5 years. Table 1shows the tumor-related factors of the cohort consid-ered for analysis.We observed 144 loco-regional recurrences and 55cancer-related deaths as events, corresponding to a5-year cumulative overall survival of 96.4% (Fig. 1)and a 5-year cumulative loco-regional recurrence freesurvival of 91.5% (Fig. 2).Table 2 shows the univariate analysis of prognosticfactors. pT, nodal status, grading, lymphangioinvasivegrowth, tumor diameter, ER status, PR status, andexpression of Her2 ⁄neu had a prognostic value onloco-regional recurrence. At the univariate analysis ofoverall survival the histotype and the expression ofKi67 also were associated with outcome (but not thelymphangioinvasive growth).In the multivariate analysis, reported in Table 3,grading remained the only independent predictor ofloco-regional recurrences. With regard to overall sur-vival, the Cox model selected grading along withTable 1. Study Population Tumor-Related Fac-tors Considered for AnalysisVariable Category No. (%)Tumor diameter* <15 mm 784 (50.1)‡15 mm 782 (49.9)pT* pT0–1 1356 (68.8)pT2 524 (26.6)pT3 36 (1.8)pT4 55 (2.8)pN* pN0 1385 (72.7)pN1 354 (18.6)pN2 119 (6.2)pN3 48 (2.5)Histotype* Ductal 1478 (74.4)Lobular 214 (10.8)Other 294 (14.8)Estrogen receptors* Negative 275 (15.0)Positive 1556 (85)Progesterone receptors* Negative 427 (23.1)Positive 1419 (76.9)Grading* G1–2 1379 (75.4)G3 449 (24.6)Her2 ⁄ neu* Overexpressed 569 (36.5)Not expressed 989 (63.5)Ki67* <20% 777 (49.9)‡20% 779 (50.1)p53* Overexpressed 857 (56.6)Not expressed 658 (43.4)Lymphoangioinvasive growth* Absent 422 (76.2)Present 132 (23.8)*Data not available for all patients.Figure 1. Cumulative overall survival for study patients.S30 • rausei et al.nodal status and PR status as statistically significantindependent prognostic factors.DISCUSSIONThe revolution of breast cancer treatment duringthe past decades has led to the progressive reductionof the surgical extent (1–4,15,16). Consequently, thequality of life has improved and women are now moremotivated to follow screening programs for early diag-nosis of the disease. The most relevant problem inbreast-conserving surgery remains the loco-regionalrecurrence, which can nullify the aim of conservationfor subsequent mastectomy.In the present series, we verify the predictive factorsof loco-regional recurrence and survival in a large ser-ies of patients treated by surgery. In this all-stagespatients sample we observed a low incidence of loco-regional recurrences (8.5% at 5 years). This importantresult highlights the clear improvement of the surgicalapproach in local control obtained in the last fewyears. With this regard, the distinction between trueloco-regional recurrences and new primary tumorsarising in the ipsilateral breast is important, since theymay have different biologic behavior and prognosisand a true recurrence might denote a persistent, radio-resistant, drug-insensitive and potentially more dan-gerous disease (17,18).Even if local failure has been linked to an increasedrisk of distant metastases and death (5–11), in ourstudy the 5-year cumulative rate of loco-regionalrecurrences was significantly higher than 5-year rateof cancer-related death (8.5% versus 3.6%). There-Figure 2. Cumulative loco-regional recurrence free survival forstudy patients.Table 2. Univariate Analysis ofPredictive Factors for EventsVariable Category5-year loco-regionalrecurrence freesurvival (%) p-value5-year overallsurvival(%) p-valueTumor diameter <15 mm 96.0 <0.001 98.5 0.004‡15 mm 89.0 95.6pT pT0–1 95.7 <0.001 99.0 <0.001pT2 86.3 93.9pT3 75.3 85.4pT4 74.9 86.9pN pN0 94.5 <0.001 98.5 <0.001pN1 92.0 95.8pN2 77.8 90.6pN3 52.3 71.9Histotype Ductal 91.1 0.168 95.6 0.018Lobular 93.4 98.4Other 92.5 98.7EstrogenreceptorsNegative 84.9 0.021 92.6 0.002Positive 92.4 97.2ProgesteronereceptorsNegative 85.6 0.002 92.2 <0.001Positive 93.2 98.0Grading G1–2 94.2 <0.001 97.9 <0.001G3 82.4 91.1Her2 ⁄ neu Overexpressed 87.7 0.034 94.7 0.052Not expressed 93.9 97.4Ki67 <20% 93.9 0.057 98.0 0.016‡20% 90.1 95.1p53 Overexpressed 91.7 0.951 96.3 0.760Not expressed 93.3 97.0Lymphoangioinvasive growth Absent 92.8 0.016 94.0 0.07Present 75.3 91.2Loco-Regional Recurrence and Cancer-Related Death after Breast Cancer Surgery • S31fore, loco-regional recurrence should not be consid-ered as a failure of surgical approach (conservative ornot) or responsible for systemic progression by itself:in fact, previous trials have shown that patients with ahigh incidence of local recurrences have the same sur-vival rate as patients with a low local recurrence rate(1,2). Hence, loco-regional recurrence can be evalu-ated as a marker of tumor aggressiveness and a pre-dictive factor for distant metastases and death(6,11,19–21), but as a condition still susceptible ofcure.By identification of loco-regional recurrence tumor-related predictors, we could identify a subset ofpatients, who might be curatively treated with a fur-ther therapy (surgical or not), allowing a good localcontrol.According to the results of univariate analysis, theloco-regional recurrence and the distant recurrence (orcancer-related death) shared some prognostic factorsamong the tumor characteristics, such as pT, nodalstatus, grading, tumor diameter, ER status, PR status,and overexpression of Her2 ⁄neu. In contrast, histotypeand an expression of Ki67 were predictors of systemicprogression only, specifically denoting a greater meta-static capacity.Similarly, the multivariate models for loco-regionalrecurrence free survival and overall survival were dif-ferent. In fact, for loco-regional recurrence free survivalthe Cox regression selected the grading as the onlyindependent prognostic factor, like a more specificmarker of local aggressiveness. In contrast, for overallsurvival the regression model selected grading alongwith nodal status and PR status: the nodal status asa measure of invasive potential and the PR status as arelevant feature for therapy.Last result highlights a limitation of our study: infact, the sample included patients underwent adjuvant(and neo-adjuvant) therapy which could favorablyaffected prognosis and, hence, our analysis results.Further limitation of this study regards the durationof follow-up with the subsequent (not ever reliable)actuarial survival rates. A substantial proportion ofevents occurred after 5 years of follow-up, supportingthe need for longer follow-up (1,6,11).In conclusion, loco-regional recurrences after breastcancer surgery are not frequent events. 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Predictors of loco-regional recurrence and cancer-related death after breast cancer surgery

Predictors of loco-regional recurrence and cancer-related death after breast cancer surgery

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