OBJECTIVE:To evaluate the feasibility of hybrid intensity-modulated radiotherapy (IMRT) technique in patients with esophageal and breast cancer within a high-patient volume setup. MATERIALS AND METHODS:A total of 36 patients with carcinoma of the left breast and esophagus were retrospectively studied with 3D-CRT, IMRT and Hybrid techniques. 3D-CRT plans for esophageal cancer consisted of one anterior-postertior (AP) and two oblique beams, while IMRT consisted of seven beams. The hybrid plan consisted of AP and PA static beams combined with five conformal beams, with a weighting ratio of 5:5 and 4:6. In breast cases, hybrid planning involved two tangential static beams and three conformal beams with a weighting ratio of 7:3. Dosimetric parameters of the hybrid-IMRT plans were then compared with those of the 3D-CRT and IMRT plans. RESULTS:In esophageal cancer patients, there was a significant difference found in the PTV coverage and conformity. The V20 and Dmean of left lung showed significant differences between IMRT and Hybrid IMRT. V25 and Dmean for heart showed reduced values in IMRT plan. The maximum dose to the spinal cord was higher in Hybrid IMRT compared to IMRT and 3D-CRT. In breast cancer patients, V20 and Dmean for the left lung were 23.77±4.28% and 11.09±1.70 Gy in hybrid plans; 26.50±5.06 % and 12.44±1.62 Gy in IMRT; and 25.47±5.07% and 11.52±1.54 Gy in 3D-CRT. The dose to the contralateral breast was higher in the IMRT plans. CONCLUSION:Considering its comparable planning time to IMRT and the added benefit of reduced OAR doses, hybrid planning could be a valuable option in high-patient-volume settings.
We evaluate therapy-induced molecular heterogeneity in longitudinal samples from high-risk, hormone-receptor positive/HER2-negative breast cancer patients with residual tumor after neoadjuvant chemotherapy from the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic subtypes are prognostic in pre-therapeutic (Tx) samples (n = 629, p < 0.0001) and post-Tx residual tumors (n = 782, p < 0.0001). After neoadjuvant chemotherapy, a shift of intrinsic subtypes is observed from pre-Tx luminal (Lum) B to post-Tx LumA, with reverse transition back to LumB in metastases. In a combined analysis of 540 paired pre-Tx and post-Tx samples, we identify five adaptive clusters (AC-1-5) based on transcriptomic changes before and after neoadjuvant chemotherapy. These AC-subtypes are prognostic beyond classical intrinsic subtyping, categorizing patients into groups with excellent prognosis (AC-1 and AC-2), poor prognosis (AC-3 and AC-4), and very poor prognosis (AC-5, enriched for basal-like subtype). Our analysis provides a basis for an extended molecular classification of breast cancer patients and improved identification of high-risk patient populations.
BACKGROUND:Breast cancer is the most frequently diagnosed cancer in women. Survival is generally considered favourable, yet some patients remain at risk of early death. We aimed to assess whether comprehensive whole-genome sequencing (WGS) linked to mortality data could add prognostic value to existing clinical measures and identify patients who might respond to targeted therapeutics. METHODS:In this integrative, retrospective analysis, we analysed 2445 breast cancer tumours (any stage and molecular subtype) collected from 2403 patients recruited through 13 National Health Service Genomic Medicine Centres or hospitals in England affiliated to the 100 000 Genomes Project (100kGP) between 2012 and 2018. We linked 2208 (90%) cases with clinical data; mortality data were obtained for 1188 patients. Following high-depth WGS of tumour and matched normal DNA, we performed comprehensive WGS profiling seeking driver mutations, mutational signatures, and compound algorithmic scores for homologous recombination repair deficiency (HRD), mismatch repair deficiency, and tumour mutational burden. Data from 1803 additional patients with breast cancer from three independent cohorts were used to validate various findings. To evaluate the prognostic value of WGS features, we performed univariable and multivariable Cox regression on data from patients with stage I-III, ER-positive, HER2-negative breast cancer with a cancer-specific mortality endpoint (around 5-year follow-up). FINDINGS:Among 2445 tumours in the 100kGP breast cancer cohort, we observed genomic characteristics with immediate personalised medicine potential in 656 (26·8%), including features reporting HRD (298 [12·2%] total cases and 76 [6·3%] ER-positive, HER2-negative cases), highly individualised driver events, mutations underpinning resistance to endocrine therapy, and mutational signatures indicating therapeutic vulnerabilities. 373 (15·2%) cases had WGS features with potential for translational research, including compromised base excision repair and non-homologous end-joining dependency. Structural variation burden (hazard ratio 3·9 [95 CI% 2·4-6·2]; p<0·0001), high levels of APOBEC signatures (2·5 [1·6-4·1]; p<0·0001), and TP53 drivers (3·9 [2·4-6·2]; p<0·0001) were independently prognostic of customary clinical measures (age at diagnosis, stage, and grade) in patients with ER-positive, HER2-negative breast cancer. We developed a prognosticator for ER-positive, HER2-negative breast cancer capable of identifying patients who require either increased intervention or therapy de-escalation, validating the framework in the independent Swedish Cancerome Analysis Network-Breast (SCAN-B) dataset. INTERPRETATION:We show that breast cancer genomes are rich in predictive and prognostic value. We propose a two-step model for effective clinical application. First, the identification of candidates for targeted therapies or clinical trials using highly individualised genomic markers. Second, for patients without such features, the implementation of enhanced prognostication using genomic features alongside existing clinical decision-making factors. FUNDING:National Institute of Health Research, Breast Cancer Research Foundation, Dr Josef Steiner Cancer Research Award 2019, Basser Gray Prime Award 2020, Cancer Research UK, Sir Jeffrey Cheah Early Career Fellowship, the Mats Paulsson Foundation, the Fru Berta Kamprads Foundation, and the Swedish Research Council.
BACKGROUND:Inavolisib is a potent and selective PI3Kα inhibitor that promotes degradation of mutated p110α. We report safety from a phase I/Ib dose-escalation/-expansion study (GO39374; NCT03006172) of inavolisib alone or in combination therapies in PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative advanced breast cancer. PATIENTS AND METHODS:Patients received inavolisib [oral once daily (od)] alone, with letrozole (2.5 mg od) or fulvestrant (500 mg intramuscularly 4 weekly) ± palbociclib (125 mg od for 21/28 days); metformin was included in one arm. PRIMARY ENDPOINT:safety and tolerability. RESULTS:At data cutoff (1 January 2024), 190 patients had been treated, of which 179 (94.2%) had discontinued study treatment, mainly due to progressive disease [146 (76.8%)]. Treatment-related any-grade and grade 3-5 adverse events (AEs) occurred in 181 (95.3%) and 107 (56.3%) patients, respectively. Inavolisib-related AEs led to inavolisib withdrawal in 5 (2.6%) and dose reductions/interruptions in 103 (54.2%) patients. Hyperglycemia, diarrhea, stomatitis (grouped terms), and rash (grouped terms) occurred in 129 (67.9%), 124 (65.3%), 93 (48.9%), and 47 (24.7%) patients, respectively. Hyperglycemia, diarrhea, and stomatitis mainly occurred early in treatment, and were manageable with supportive measures (including oral antihyperglycemic agents, common antidiarrheal medications, and dexamethasone mouthwash, respectively) and/or inavolisib dose modifications (dose interruptions with or without dose reductions). Hyperglycemia remained frequent in patients with risk factors, despite early metformin treatment. Rash was mostly grade 1 and required no treatment. Patients treated for ≥1 year [n = 65 (34.2%)] demonstrated encouraging long-term tolerability. CONCLUSIONS:Inavolisib alone or in combination with HR-positive breast cancer therapies demonstrated a manageable safety and tolerability profile, which supports its ongoing development.
To evaluate the feasibility and diagnostic accuracy of indocyanine green (ICG)-guided pelvic lymph node dissection (PLND) during laparoscopic radical prostatectomy, and compare the lymph node detection rate and 3-year biochemical recurrence (BCR) rate between PLND and ICG-guided PLND. Sixty-eight patients were randomly divided into intervention and control groups (1:1). The intervention group underwent standard pelvic lymph node dissection (sPLND) and fluorescent visible sentinel lymph node dissection (SLND) after an ultrasound-guided injection of ICG (25 mg), while the control group received sPLND without ICG injection. Kaplan–Meier survival curves were used to compare the two groups of patients for BCR at a point three years post-surgery. In the intervention group, 284 lymph nodes were removed, and 58 lymph nodes were visualized by ICG, including 4 positive lymph nodes. In the control group, 205 lymph nodes were removed. There were three cases of ICG leakage and six cases of lymphocele in the intervention group and one case of lymphocele in the control group. The sensitivity and specificity of ICG-guided lymph node dissection was 80.00
