Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor-positive breast cancer, two major ...clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo. Furthermore, intact G1/S transition (Rb-positive and low-molecular-weight isoform of cyclin E (cytoplasmic)-negative) is a reliable prognostic biomarker in ER positive breast cancer patients, and predictive of preclinical sensitivity to this drug combination. Inhibition of CDK4/6 and autophagy is also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumours.
BACKGROUND AND OBJECTIVE:The early results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in locoregional recurrence for patients with positive ...sentinel lymph nodes (SLNs) randomized either to axillary lymph node dissection (ALND) or sentinel lymph node dissection (SLND) alone. We now report long-term locoregional recurrence results.
METHODS:ACOSOG Z0011 prospectively examined overall survival of patients with SLN metastases undergoing breast-conserving therapy randomized to undergo ALND after SLND or no further axillary specific treatment. Locoregional recurrence was prospectively evaluated and compared between the groups.
RESULTS:Four hundred forty-six patients were randomized to SLND alone and 445 to SLND and ALND. Both groups were similar with respect to age, Bloom-Richardson score, Estrogen Receptor status, adjuvant systemic therapy, histology, and tumor size. Patients randomized to ALND had a median of 17 axillary nodes removed compared with a median of only 2 SLNs removed with SLND alone (P < 0.001). ALND, as expected, also removed more positive lymph nodes (P < 0.001). At a median follow-up of 9.25 years, there was no statistically significant difference in local recurrence-free survival (P = 0.13). The cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (P = 0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P = 0.36).
CONCLUSION:Despite the potential for residual axillary disease after SLND, SLND without ALND offers excellent regional control for selected patients with early metastatic breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.
IMPORTANCE: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary ...because the majority of the patients had estrogen receptor–positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). OBJECTIVE: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. DESIGN, SETTING, AND PARTICIPANTS: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. INTERVENTIONS: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. RESULTS: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 1-sided 95% CI, 0-1.16; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 95% CI, 0.62-1.17; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. CONCLUSIONS AND RELEVANCE: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855
Background
Sentinel lymph node (SLN) dissection involves lymphatic mapping and selective removal of clinically negative lymph nodes at highest risk for harboring metastases. Lymphatic mapping is most ...often performed using radioisotope with or without blue dye (standard tracers). Sienna+
®
, a superparamagnetic iron oxide that can be detected using the Sentimag
®
magnetometer, is an alternative mapping agent to identify SLNs that has been investigated in five clinical trials. This meta-analysis was performed to determine if Sienna+
®
is non-inferior for SLN detection when compared to standard tracers.
Methods
Five clinical trials comparing Sienna+
®
to a standard technique were identified, and data from these studies were used to determine the agreement by Kappa statistic between Sienna+
®
and standard tracers in identifying SLNs and malignant SLNs. The trials included 1683 SLNs identified in 804 patients. Data from the studies were imbalanced, therefore additional agreement indices were utilized to compare techniques. The estimated difference between the techniques was analyzed and a margin of ≤5 % was used to determine non-inferiority.
Results
Agreement between the Sienna+
®
and standard tracers was strong for SLN detection by patient prevalence-adjusted bias-adjusted kappa (PABAK) 0.94, 95 % confidence interval (CI) 0.89–0.98, moderate to substantial for SLN detection by node (PABAK 0.68, 95 % CI 0.54–0.82), and strong for the detection of malignant SLNs by patient (PABAK 0.89, 95 % CI 0.84–0.95). Sienna+
®
demonstrated non-inferiority compared with standard tracers.
Conclusions
The Sienna+
®
mapping agent is non-inferior to the standard method for SLN detection in patients with clinically node-negative breast cancer.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Neoadjuvant systemic therapy in breast cancer treatment was initially utilized for inoperable disease. However, several randomized prospective studies have demonstrated comparable survival with ...adjuvant chemotherapy in early-stage, operable breast cancer while also decreasing tumor size facilitating breast conservation without significant increases in local recurrence. Response to therapy can predict outcome, with improved survival associated with pathologic complete response (pCR). Triple negative and HER2-positive subtypes show increased pCR rates. A multidisciplinary approach is necessary with neoadjuvant treatment. This can improve rates of breast conservation, provide insights into tumor biology and predict patient outcomes.
The evolution in axillary management for patients with breast cancer has resulted in multiple dramatic changes over the past several decades. The end result has been an overall deescalation of ...surgery in the axilla. Landmark trials that have formed the basis for the current treatment guidelines are reviewed herein.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
