Clinical Risk Factors for IBTR
• Young Age—Patient ages of 35 years or less and 40 years or less have been associated with an increased risk of IBTR following breast-conserving surgery and radiation in most series.[4,5,7,12-14,23,57-64] This finding may be due partly to the association of young age with other factors predictive of IBTR, including an extensive intraductal component and close or positive resection margins. Cowen et al reported a 55% rate of IBTR in women 40 years old or younger with positive margins, although this finding was not significant on multivariate analysis.
Freedman et al [unpublished data] conducted a recursive partitioning analysis to identify subgroups of patients at different levels of risk for IBTR. They found a significant dependence upon margin status in women aged 35 years or less with extensive intraductal component–negative tumors; the risk of developing IBTR at 10 years was only 3% with negative margins, compared with 34% for those with close or positive margins. Women £ 35 years old with extensive intraductal component–positive tumors had a 75% risk of IBTR, regardless of margin status. However, there is no evidence to suggest that women £ 35 years old have improved local control or disease-specific survival after mastectomy, as compared to breast-conserving surgery and radiation.
• Tumor Size—For clinical tumors £ 5 cm that are eligible for breast-conserving surgery and radiation, there is no significant difference in the risk of IBTR between T1 and T2 tumors.[4,8,12,13,61,63,65,66]
Little information is available on the risk of IBTR for operable T3 breast cancers treated with immediate breast-conserving surgery and radiation. In one series of 470 patients with operable stage III breast cancer, Toonkel et al reported IBTRs in 2 (6%) of 34 patients treated with breast-conserving surgery and radiation after a mean follow-up of 8 years. Khanna et al also reported that only 3 (8%) of 36 selected patients with T3 tumors developed an IBTR after a median follow-up of 46 months. Fortin et al reported a 16% IBTR rate for T3 tumors, compared to 10% for T1 or T2 tumors, with a median follow-up of 5.2 years.
More data are available on the use of neoadjuvant chemotherapy for T3 tumors with breast-conserving surgery and radiation offered to responding patients. In NSABP B-18, 13% of 1,523 patients had a T3 tumor size and were randomized to preoperative or postoperative chemotherapy. Following chemotherapy, 33% of the T3 tumors were treated with breast-conserving surgery and radiation, compared to only 9% of those randomized to postoperative chemotherapy.
The study showed a statistically significant increase in the rate of IBTR (14% vs 7%) for tumors that were downstaged by chemotherapy to become eligible for breast-conserving surgery and radiation, compared with those initially felt to be candidates for breast conservation prior to chemotherapy. Although the results for T3 tumors were not reported separately, it is likely that a significant portion of the group that was downstaged and rendered eligible for breast conservation were those with tumors that were initially staged as T3.
In contrast, Danforth et al reported no IBTRs in 18 patients treated with radiation after a clinical and pathologic complete response to induction chemotherapy from an initial group of 57 patients with stage IIIA disease. From a group of 84 women with tumors > 5 cm, Bonadonna et al treated 52 chemotherapy responders with quadrantectomy and radiation; at 8 years, the IBTR rate was 4%. After a median follow-up of 41 months, Ellis et al reported that there was a 7% risk of IBTR in responding patients treated with breast-conserving surgery and radiation after induction chemotherapy. However, Buzdar et al selected 15 patients who responded to induction chemotherapy for breast-conserving surgery and radiation (from an original group of 60 women with T3 tumors) and found a 20% rate of IBTR after a median follow-up of only 43 months.
In summary, the majority of T3 tumors remain ineligible for breast conservation, even after induction chemotherapy. Mastectomy should remain standard treatment for initial T3 tumors until the optimal selection factors, guidelines for treatment, and long-term rates of IBTR can be further defined.
• Gross Multifocal/Multicentric Disease—Clinically detected multifocal or multicentric disease, whether presenting as more than one palpable mass or as a mammographic abnormality, has been associated with nearly a 40% risk of IBTR.[75-77] A closer distance between separate clinically detected tumors has not been shown to be a predictor for a lower risk of recurrence. The risk of IBTR may not be increased by the presence of multifocal disease first detected by the surgeon intraoperatively. When detected by the pathologist on gross pathologic inspection, multifocal disease has generally been associated with a 20% to 36% risk of IBTR.[4,13,65,75,77] However, the risk of IBTR may be minimized after radiation with gross pathologic multifocal disease by selection of extensive intraductal component–negative tumors resected with negative margins.
• Genetic Factors—In contrast to findings in the mastectomy setting, data show that a genetic mutation does not increase the risk of IBTR at 5 years following breast-conserving surgery and radiation. Chabner et al reported on a series of 201 women aged 36 years or less treated by breast-conserving surgery and radiation, 29 of whom had a family history suggestive of inherited breast cancer but no documented BRCA1 or BRCA2 mutations. The crude 5-year local failure rate was lower in the subgroup with a strong family history (14% vs 3%), although this difference did not reach statistical significance.
Pierce et al reported a study of 73 women with known BRCA1 or BRCA2 mutations treated with breast-conserving surgery and radiation. There was no significant difference in the local failure-free survival at 5 years between these 71 patients and a matched similarly treated cohort of 219 patients with presumed sporadic breast cancer (99% vs 96%).
In another series of 28 Ashkenazi women with known BRCA1 and/or BRCA2 mutations, Robson et al reported IBTR rates of 15% at 5 years and 22% at 10 years, compared with rates in controls without the mutations of 5% and 7%, respectively. The difference in IBTR at 10 years did not reach statistical significance (P = .25). Women with mutations were more likely to be under the age of 50 years, which itself was the only significant variable associated with the risk of IBTR.
Seynaeve et al reported on the risk of IBTR following breast-conserving surgery and radiation in a series of 79 patients with hereditary breast cancer based on BRCA1 or BRCA2 mutations (18 patients) or a strong family history of three or more first-degree relatives with breast/ovarian cancer (61 patients). The risk of IBTR at 5 years was 14%, compared to a rate of 5% observed in 79 matched controls of presumed sporadic breast cancers. However, the magnitude of this difference continued to increase to 27% with longer follow-up at 10 years and to 48% at 13 years in hereditary cases, compared with only 18% in controls (P = .09).
Turner et al found that 8 (15%) of 52 patients with IBTR following breast-conserving surgery and radiation retrospectively tested positive for BRCA1 or BRCA2 mutations. The mean time to IBTR in these women was 8.7 years, compared with an interval of 4.3 years for the overall population. In addition, differences between relapse histology and location in the breast compared to the original tumors suggested that the majority of these IBTRs were actually new primaries in the treated breast. Therefore, 5-year rates of IBTR should be viewed with caution, and additional studies with 10-year follow-up will be needed to define the risk of IBTR—whether a true recurrence or a new breast primary—in patients with genetic mutations.
Histopathologic Risk Factors for IBTR
• Nodal Status—Compared with node-negative patients, patients with node-positive disease do not have an increased risk of IBTR following breast-conserving surgery and radiation and are generally at lower risk because of the combined use of adjuvant systemic therapy.[2,4,8,12,54,59,61]
• Extracapsular Extension—In patients undergoing breast-conserving surgery, axillary dissection, and radiation, extracapsular nodal extension is not associated with an increased risk of IBTR.[84,85] However, just as in the mastectomy setting, extracapsular extension is more prevalent in patients with a higher number of positive nodes but not an independent factor for axillary recurrence following breast-conserving surgery and radiation.[84,85]
• Margin Status—In most series, the presence of positive resection margins is associated with a two to three times increased risk of developing IBTR (compared to negative margins) following breast-conserving surgery and radiation.[5,7,54,62,65,86-90] There is controversy regarding the impact of a close margin on the risk of IBTR, with close margin defined variously as cancer cells within a distance of 1 mm[62,89,91] or 2 mm[86-88,90, 92,93] but not involving the resection edge. Obedian et al found the relapse-free survival rate was the same 98% at 10 years with close (£ 2 mm) or negative margins.
In a retrospective series from the Joint Center for Radiation Therapy, Park et al reported the same crude rate of IBTR (7%) at 8 years with close (£ 1 mm) or negative margins. However, in a prospective trial reported by Recht et al from the same institution, a close (£ 1 mm) margin was a significant predictor of IBTR in a randomized trial of sequencing chemotherapy before or after radiation following breast-conserving surgery. The overall crude 5-year risk of IBTR with close margins (£ 1 mm) was 11%, compared to 3% with negative margins, with a greater risk of IBTR observed in patients receiving chemotherapy before radiation (23% for £ 1 mm vs 0% for negative margins).
Peterson et al reported an 8-year actuarial IBTR risk of 17% with close (£ 2 mm) margins, compared to 8% with negative margins, although this did not reach statistical significance. Freedman et al reported no significant difference in the 5-year cumulative incidence of IBTR at 5 years with a close or negative margin, although by 10 years, a significant difference became apparent (14% vs 7%, respectively, P = .04). A long delay of 10 years or more until the rates of IBTR with close margins diverge from those of negative margins has also been shown in other series.[87,88]
• Extensive Intraductal Component—The presence of an extensive intraductal component–positive tumor has been associated with an increased risk of IBTR following breast-conserving surgery and radiation, although this effect is minimized by more extensive breast-conserving surgery and wide negative margins.[4,54,59,63,86,88,89]
• High Grade—High histologic grade has been variably associated with the risk of IBTR following breast-conserving surgery and radiation, with an increased risk reported by some series[65,94] but not others.[4,13,95]
• Lymphovascular Invasion—Lymphovascular invasion has been associated with an increased risk of IBTR in many [13,14,59,62,94] but not all [4,12,65] series.
• Oncogenes and Tumor-Suppressor Genes—Similar to the mastectomy setting, there is a paucity of data addressing the impact of HER2/neu or p53 expression on the risk of local failure. Haffty et al reported a case-control study in which 56% of patients with IBTR had overexpression of HER2/neu in the original tumor, compared with only 18% of matched control patients without IBTR. However, Pierce et al reported a series of 107 patients with known c-erbB-2 expression treated with either breast-conserving surgery and radiation or mastectomy. The risk of IBTR was 8% with overexpression, compared to 24% with no overexpression. Silvestrini et al found p53 overexpression was associated with a higher risk of IBTR following breast-conserving surgery alone but not following breast-conserving surgery with radiation.
• Estrogen-Receptor Status—Estrogen-receptor–negative tumors have not had a higher risk of IBTR following breast-conserving surgery and radiation in most series.[7,13,57,62,66]
• Adjuvant Systemic Therapy—The risk of IBTR has been reported to decrease with the use of adjuvant chemotherapy in subgroups of patients with node-positive disease[2,8,54,59] or focally positive margins following breast-conserving surgery and radiation. Adjuvant tamoxifen(Drug information on tamoxifen) has also been associated with a significant decrease in the rate of IBTR following conservative surgery and radiation.[5,12,55,98-101]
Cowen et al[13,65] reported that adjuvant hormone use increased local recurrence-free survival with positive margins but not with negative margins up to 10 years following breast-conserving surgery and radiation without chemotherapy. Freedman et al, using a cumulative incidence methodology, also showed no significant decrease in IBTR at 5 or 10 years with adjuvant systemic therapy in patients with negative margins. However, in patients with positive margins, adjuvant systemic therapy was associated with a lower rate of IBTR at 5 years (compared with no adjuvant systemic therapy) but no significant decrease in the ultimate 10-year cumulative incidence of IBTR.
Differences between the clinical and histopathologic risk factors associated with local recurrence following breast-conserving surgery and radiation or mastectomy are shown in Table 2. Significant factors contributing to an increased risk of local recurrence following either treatment are tumor size ³ 5 cm, close or positive margins, young age £ 35 to 40 years, and lymphovascular invasion.
Factors that increase the risk of chest wall recurrence but not IBTR include 4 or more positive axillary nodes, ER negativity, and p53 positivity. The few studies addressing high histologic grade suggest that there is an increased risk of chest wall recurrence but a variable association with IBTR. Extracapsular extension, particularly in those with 1 to 3 positive nodes, may also have an impact on chest wall recurrence but not on IBTR.
In contrast, gross multicentric disease or extensive intraductal component positivity increases the risk of IBTR but not chest wall recurrence. Patients with hereditary breast cancer are not at increased risk of developing IBTR within 5 years, but there are no data regarding its prognostic value for chest wall failure. Tumor size < 5 cm, adjuvant systemic chemotherapy, and HER2/neu overexpression are associated with a low risk of local recurrence after either treatment.