Abstract
Despite the introduction of modern therapeutics, overall survival (OS) in metastatic breast cancer (MBC) has not changed in 20 ys. In the 1990s a major effort was made to improve the situation through the use of high dose chemotherapy with autologous stem cell transplantation (HD-ASCT). Although OS was not affected in randomized trials, which led to near abandonment of this therapy, some studies suggested that progression-free survival (PFS) can be improved with HD-ASCT. To identify distinct transplant-, disease- and patient-related characteristics predictive of survival in patients with MBC who received HD-ASCT, we reviewed records of all patients in the bone marrow transplant registry at UCSD treated with HD-ASCT for MBC between 1989 and 2000.
METHODS: Age, race, stage at diagnosis, histology, estrogen receptor (ER) and menopausal status, body mass index (BMI) in kg/m2, time to transplant and death, site of metastasis, disease status prior to and after transplant, and days in hospital were extracted from medical records. Brookmeyer & Crowley’s 95% confidence intervals were used for median survival times, Cox models for predictors of a time-to-event variable and Schoenfeld tests for proportional hazard assumptions, respectively.
RESULTS: Of 96 patients with MBC 21, 43, 23, 8 and 1 had stage I, II, III, IV or unknown disease at diagnosis, respectively. Histologies were: infiltrating ductal, lobular, inflammatory or unknown in 79, 10, 6 and 1 of the cases, respectively. ER status was positive in 59.4% of patients and 29.2% of patients were post-menopausal. 84.4%, 4.2% and 11.5 % of patients were of caucasian, black or other ethnicity, respectively. Mean ages at diagnosis and at transplant were 43.7 ys (SD 8.6) and 47.4 ys (SD 8.7), respectively, with a median time to transplant of 29 months (range 3.8–180.8). When progression of disease (PD) was diagnosed, primary sites were visceral (39.6%), bone (29.2%), local (16.7%) or nodal (14.6%). Mean BMI at transplant was 26 (SD 5.9); 24% of patients were obese (BMI ≥ 30). Mean length of hospitalization after transplant was 17 days (SD 9.5 days); 33% of patients were hospitalized ≥ 18 days. Pre-transplant, 30.2% of patients were in complete remission; after HD-ASCT, this percentage increased to 41.7%. Median PFS and OS were 3.9 ys (CI 2.9–5.4) and 5.6 ys (CI 4.1–7.4) after initial diagnosis and 0.6 ys (CI 0.5–0.8) and 1.7 ys (CI 1.36–2.07) after transplant, respectively. As opposed to ER+ patients the rate of death events in ER− patients slowed down substantially after 5 ys from diagnosis. Although not statistically significant, at 12 ys, survival after HD-ASCT was 18.5% in ER− patients and 2.6% in ER+ patients. Stratified by ER status, stage at diagnosis was an independent predictor of length of PFS and OS. At diagnosis, stage I patients were at lowest risk of death when compared to stage II–IV patients with HRs of 2.7 (II vs I CI 1.4–5.2), 4.6 (III vs I CI 2.1–10) and 17 (IV vs I CI 6.1–47.8) disease; lower risk of death persisted for patients with initial stage I after PD was diagnosed with HRs of 2.4 (II vs I CI 1.3–4.6), 2.8 (III vs I CI 1.3–5.7) and 3.9 (IV vs I CI 1.6–9.9). Death risks were increased with infiltrating lobular carcinoma when compared with infiltrating ductal carcinoma (HR 2.5; CI 1.1–5.38) or when BMI was ≥ 30 (HR 3.1; CI 1.8–5.4); PFS in patients with a BMI ≥ 30 was significantly shorter after PD was diagnosed (death HR 3.1 [CI 1.8–5.5] when compared to BMI < 30). Visceral when compared to bone metastasis was a negative predictor of OS (HR 2.3; CI 1.3–4.1). Hospitalization ≥ 18 days after HD-ASCT was the strongest predictor of time to death after transplant (HR 2.2; CI 1.4–3.6).
DISCUSSION: The survival rate at 12 ys after HD-ASCT was 8.2% for patients with MBC. Survival was higher for ER- compared to ER+ patients. Negative prognostic factors for OS and PFS were higher stages of disease at initial diagnosis, but also once PD was diagnosed, infiltrating lobular histology and obesity. Since all transplants were carried out prior to routine assessment of Her-2 neu receptor status, this information was not part of our analysis. At PD, visceral metastasis translated into poorer OS and after HD-ASCT, length of hospitalization became the most important outcome predictor. Although HD-ASCT in MBC has lost favor because of no improvement in global OS, our analysis may provide a rationale for selection criteria to determine which patients could benefit from future trials of HD-ASCT.
Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support