Patient and tumor characteristics
A total of 197 women met inclusion criteria, with a median age of 54 years (range 22-86). Race was predominantly black (64%), 41% were married, and 64% of patients treated had private insurance. Comprehensive patient, tumor and treatment characteristics stratified by failure status are outlined in Table 1.
In total, thirty-two patients (16%) in our cohort experienced treatment failure. Insurance type (p=0.002) and active smoking (p=0.002) differed between the two groups, but race and marital status were not found to be significantly different between the patients who failed treatment and those who did not (p=0.36 and 0.94, respectively). The tumor histology was predominately (99%) IDC, the vast majority (85%) were grade 3, and LVSI was present in 28% of patients. Clinical (self-palpation) detection occurred in 73% of women. On Chi-square testing, presence of LVSI (p=0.036) and the method of tumor detection (p=0.003) were both significantly different between failure and non-failure groups. Grade and histology were not associated with an increased risk of treatment failure in our patient cohort (p=0.19 and 0.37, respectively) (Table 1).
According to AJCC 7th edition, the most common clinical stage was II (47%), followed by stage I (32%). Prevalence of failure increased with increasing stage: 15% in stage I, 18% in stage II, and 24% in stage III patients. Of patients who failed treatment, 28% were stage I, 47% were stage II, and 25% were stage III.
There was a significant difference in pathologic staging between those who failed and those who did not fail treatment (p<0.001). Largest tumor size was also documented and was stratified into 2 cm and 2 cm. Forty-nine percent of tumors were 2 cm, and increasing tumor size was significantly associated with treatment failure (p<0.001). Pathologic tumor stage was significantly different between the two groups (p=0.005); 35% of pT3/T4 patients failed compared to only 16% of pT1/T2 patients. Pathologic nodal stage was highly prognostic (p<0.001) with 36% of treatment-failure patients having either pN2 or pN3 pathologic nodal status compared to only 8% of the non-failure group.
Almost all patients (95%) underwent surgical resection with lumpectomy performed in 53% of patients. Rates of sentinel lymph node biopsy and axillary dissection were not different between groups (p=0.76). Thirty-one percent of women received neoadjuvant chemotherapy while 63% of women received adjuvant chemotherapy. Adjuvant radiation was given in 62% of patients to a median dose of 60 Gy (range 10.8-70.4), and there was no difference in failure for those receiving <60 Gy (p=0.14). Radiation treatment modality (3D-CRT vs IMRT) did not differ between those who failed and did not fail treatment.
Patterns of Failure
Table 2 outlines comprehensive details for the 32 patients who failed treatment including site and pattern of failure, as well as subsequent treatments rendered. Patterns of failure in our TNBC cohort were varied and complex. The largest proportion of patients (53%) failed in distant and locoregional sites simultaneously, whereas 34% of patients developed local breast or chest wall recurrence only. Of those patients who had any distant failure, median OS was 23.5 months. Failure patterns did not differ by race (p=0.41). The most common sites of failure were the lungs (28%), followed by the liver (25%), bone and brain (22% each). Eight patients (25%) received further surgery for locoregional recurrences, while 17 (53%) received salvage chemotherapy at the time of relapse. The most common salvage chemotherapy regimens included carboplatin/gemcitabine, eribulin, and ixabepilone. Median OS from time of initiation of treatment for all patients who failed was 30 months while median OS from time of failure for these patients was 8 months. Black patients had a median OS of 32 months compared to 23 months for white patients, but this was not significant (p=0.23).
Median follow-up for our entire cohort was 46 months (range 1-353 months). The median, 2-year and 5-year overall survival (OS) for the entire cohort was 45 months, 86.3% and 76.4%, respectively (Figure 1). Median, 2-year and 5-year freedom from recurrence (FFR) was 16 months, 88.1% and 83.8%, respectively (Figure 2). Median, 2- and 5-year OS rates for the patients who did not fail treatment was 46 months, 93.3% and 86.7%, respectively. Median, 2- and 5-year survival rates for patients with documented failures was 30 months, 55.4% and 35.3%, respectively. (log rank p<0.001 comparing OS of failure vs non-failure patients) (Figure 3).
On univariate analysis, insurance status was associated with treatment failure (p=0.048). Specifically, patients with private insurance were significantly less likely than uninsured patients (OR 0.068, 95% CI 0.006-0.810, p=0.033) or Medicare patients (OR 0.051, 95% CI 0.004-0.699, p=0.026) to experience failure. We also found smoking status had a statistically significant impact on treatment failure (p=0.011), with current smokers more likely to experience treatment failure than nonsmokers at the time of TNBC diagnosis (OR 5.212, 95% CI 1.950-13.929, p=0.001) (Table 3).
In terms of tumor characteristics, presence of LVSI (OR 2.566, 95% CI 1.043-6.309, p=0.04) and clinical detection (OR 6.944, 95% CI 1.597-30.206, p=0.01) were associated with treatment failure. Increasing pathologic tumor stage (p=0.020), pathologic nodal stage (p=0.001), and overall pathologic stage (p<0.001) were also associated with treatment failure. In addition, patients with tumor size 2cm had significantly higher rates of failure (OR 6.996, 95% CI 2.293-21.342, p=0.001). Treatment modalities including receipt of chemotherapy (both neoadjuvant and adjuvant), type of surgery, and radiation therapy dose were not found to be associated with an increased risk of treatment failure (Table 3).
On MVA, pathologic nodal staging was most strongly associated with treatment failure (p=0.017). Pathologic N2 stage, specifically, had a significant association with treatment failure (OR 25.0, 95% CI 3.454-180.972, p=0.001) (Table 4).