Background: This randomized, multicenter, phase III trial compared doxorubicin plus cyclophosphamide (AC), single-agent docetaxel (D), and an alternating regimen of AC and docetaxel (AC–D) as ...first-line chemotherapy in metastatic breast cancer (MBC).
Patients and methods: Patients with MBC resistant to endocrine therapy were entered in a randomized study to receive either six cycles of AC (doxorubicin 40mg/m2 plus cyclophosphamide 500mg/m2), D (60mg/m2), or alternating treatment with AC–D (i.e. three cycles of AC and three cycles of D). Treatment was administered every 3 weeks.
Results: A total of 441 patients were entered in a randomized study. Response rates were 30% for AC, 41% for D, and 35% for AC–D. The median times to treatment failure (TTFs) were 6.4, 6.4, and 6.7 months (one-sided log-rank test, P=0.13 for AC versus D, P=0.14 for AC versus AC–D) and median overall survival (OS) was 22.6, 25.7, and 25.0 months (P=0.09 for AC versus D, P=0.13 for AC versus AC–D) in the AC, D, and AC–D, respectively.
Conclusion: There was no difference in the TTF among the three arms. However, there was a trend toward a better response and better OS in the D than in the AC.
We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and ...pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % 95 % confidence interval (CI) 85–90. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %,
P
< 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %,
P
< 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage hazard ratio (HR) 2.63, 95 % CI 1.36–5.21,
P
= 0.004 for cN2–3 vs. cN0, histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15–2.91,
P
= 0.011), and non-pCR (HR 1.98, 95 % CI 1.22–3.24,
P
= 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43–4.90,
P
= 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16–4.20,
P
= 0.017 for cT3–4 vs. cT1–2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48–6.62,
P
= 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53–13.14,
P
= 0.005 for cN2–3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12–4.94,
P
= 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31–5.97,
P
= 0.006 and HR 3.86, 95 % CI 1.13–24.21,
P
= 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.
The FUTURE trial (UMIN000029294) demonstrated the safety and efficacy of adding palbociclib after fulvestrant resistance in patients with hormone receptor-positive (HR+)/human epidermal growth factor ...receptor 2-negative (HER2−) advanced and metastatic breast cancer (ABC/MBC). In this planned sub-study, cancer panel sequencing of cell-free DNA (cfDNA) was utilized to explore prognostic and predictive biomarkers for further palbociclib treatment following fulvestrant resistance.
Herein, 149 cfDNA samples from 65 patients with fulvestrant-resistant disease were analysed at the time of palbociclib addition after fulvestrant resistance (baseline), on day 15 of cycle 1, and at the end of treatment using the assay for identifying diverse mutations in 34 cancer-related genes.
During the course of treatment, mutations in ESR1, PIK3CA, FOXA1, RUNX1, TBX3, and TP53 were the most common genomic alterations observed. Analysis of genomic mutations revealed that before fulvestrant introduction, baseline PIK3CA mutations were marginally lower in metastatic aromatase inhibitor (AI)-treated patients compared to adjuvant AI-treated patients (P = 0.063). Baseline PIK3CA mutations were associated with poorer progression-free survival hazard ratio: 1.62, P = 0.04. Comparative analysis between baseline and early-changing gene mutations identified poor prognostic factors including early-changing MAP3K1 mutations (hazard ratio: 4.66, P = 0.04), baseline AR mutations (hazard ratio: 3.53, P = 0.04), and baseline PIK3CA mutations (hazard ratio: 3.41, P = 0.02). Notably, the relationship between ESR1 mutations and mutations in PIK3CA, MAP3K1, and TP53 weakened as treatment progressed. Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations.
Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2− ABC/MBC.
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•Trial: palbociclib’s effect on cfDNA genetic changes in fulvestrant-resistant BC.•Baseline PIK3CA and AR mutations reduced progression-free survival.•Early-changing MAP3K1 mutations reduced progression-free survival.•As treatment advanced, correlation between ESR1, PIK3CA, and TP53 mutations weakened.•Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations.
Abstract Introduction Mastectomy is the current standard surgical procedure for ipsilateral breast tumor recurrence (IBTR). However, there is little evidence about the prognostic impact of the ...surgical procedure (mastectomy versus repeat lumpectomy) for IBTR. Patients and methods A total of 271 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent definitive surgery for IBTR between 1989 and 2008 were included from eight institutions in Japan. The impact of the surgical procedure for IBTR on distant disease-free survival (DDFS) and overall survival (OS) was evaluated using and multivariable proportional hazards regression and propensity score matching methods. Results Of the 271 patients, 149 patients (55%) underwent repeat lumpectomy and 122 patients (45%) underwent mastectomy after IBTR. The median follow-up period from definitive surgery for IBTR was 55 months. There was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR, adjusted for various clinical and tumor characteristics. In addition, for the matched patient cohort, no difference in DDFS and OS was seen between the 2 groups. Conclusion In our study, both multivariate analysis and the propensity score matching method demonstrated that there was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR. Further studies are warranted (UMIN-CTR number UMIN000008136).
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