neoadjuvant pegylated liposomal doxorubicin in combination with cisplatin and infusional fluoruracil ccf with and without endocrine therapy in locally advanced primary or recurrent breast cancer

Abstract Purpose To explore the activity of pegylated liposomal doxorubicin (PLD) as neoadjuvant therapy of breast cancer. Methods The combination of PLD with cisplatin and infusional fluorouracil (CCF) for 8 courses was investigated in patients with primary or recurrent T2-T4a-d N0-3 M0 breast cancer. Patients with ER and/or PgR ≥10% tumors also received letrozole (±triptorelin). Results Forty patients entered the study. Four patients had recurrent tumors and 13 had cT4d tumors. Overall, clinical response rate was 77.5% whereas a pathological complete response (pCR) was obtained in 3 patients (7.7%), 4 when considering bilateral tumors. Noticeably 3 pCR were observed among the 10 patients with T4d ER positive tumors (33%). Eleven patients discontinued treatment before completion of the 8 planned courses. Conclusions Our results indicated that CCF yielded an appreciable rate of clinical responses in a series of very locally advanced tumors and an unusually high rate of pCR in T4d ER positive tumors, suggesting an enhanced cutaneous activity of PLD

Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer

International audiencePatients with large ER positive tumors candidate to preoperative chemotherapy may also benefit from a concurrent endocrine intervention, but this issue has been scarcely investigated due to concerns arising from unfavorable results emerged from an adjuvant trial of concurrent tamoxifen and chemotherapy. We retrospectively investigated the activity of letrozole plus GnRH analogue (GnRH-a) administered concurrently with preoperative chemotherapy and as adjuvant treatment in premenopausal women with locally advanced ER positive breast cancer consecutively admitted at the European Institute of Oncology. Results were compared with those of a non-randomized unmatched control group of premenopausal women with locally advanced ER positive breast cancer receiving preoperative chemotherapy, followed by tamoxifen and GnRH-a after surgery. Primary endpoints were pathological complete response (pCR) rate, decrease of Ki67 and disease free survival (DFS). One-hundred and nineteen women constituted the study group, while 95 patients served as controls. The pCR rate was 5.0 vs 1.1% in the study and control group, respectively. A statistically significant greater suppression of Ki67 was observed in patients receiving chemoendocrine therapy as compared with controls ( = 0.003). At a median follow up of 59 months, 26 events occurred in the chemoendocrine group and 48 in the control group. Five-year DFS was 78 vs 41% in the study and in the control group, respectively [adjusted HR 0.46, 95% CI 0.27-0.79,  = 0.0047]. The concurrent administration of letrozole and GnRH-a with preoperative chemotherapy was highly effective in premenopausal women with large ER positive breast cancer in terms of decreased proliferation and of improved DFS. Randomized studies are warranted to establish the role of the addition of endocrine therapy to chemotherapy as standard preoperative approach for ER positive locally advanced breast cancer as well as of letrozole in combination with GnRH-a for the treatment of premenopauasal women with early breast cancer

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy

International audienceThe predictive role of the degree of endocrine responsiveness to preoperative chemotherapy (PCT) is unclear. We reviewed pretreatment biopsies of 553 patients with locally advanced breast cancer who were treated with PCT. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to the degree of estrogen (ER) and progesterone receptor (PgR) expression (ER and PgR absent, vs. ER or PgR 0–49%, vs. ER and PgR ≥50% of the cells positive). A statistically significant higher pCR rate was observed at the multivariate analysis for patients with ER and PgR absent tumors (17.7%) versus patients with tumors expressing high ER and PgR (0%) (OR 14.4  < 0.001). Despite the higher incidence of pCR, a statistically significant worse disease-free survival (DFS), and overall survival (OS) was observed for patients with ER and PgR absent tumors versus patients with tumors expressing high ER and PgR (HR 6.4, 95% CI 3.5–11.6, for DFS; HR 3.6 95% CI 2.4–5.6 for OS). Response and outcome after PCT are correlated with the degree of expression of steroid hormone receptors. Studies on tailored preoperative therapies are needed

Minimal residual disease-driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL

Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton's tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (&lt;10-4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax&nbsp;± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax&nbsp;± ibrutinib. Patients with uMRD4 at Cycle 12&nbsp;Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1&nbsp;discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7&nbsp;months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4&nbsp;restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035