Simple WT radiotherapy delivered in vDIBH achieves satisfactory coverage of the IMC while meeting heart and lung dose constraints. However, where higher isodose coverage is required, VMAT(vDIBH) is the optimal photon technique. The lowest OAR doses are achieved by PBT, in which the use of vDIBH does not improve dose statistics.

Quantitative computed tomography (QCT) was compared to dual X-ray absorptiometry (DXA) measured in the lumbar spine of 508 European women defined as normal without fracture (NoF), or osteoporotic (OP), with either vertebral fracture (VF), or peripheral fracture (PF). The correlations between QCT and DXA BMD measurements were significantly different in normal and in osteoporotic patients, indicating that the two exams do not measure the same bone aspects. According to ROC curves results, QCT Z-scores separate OP from NoF with better sensitivity than all other measurements. A threshold to differentiate OP from NoF was chosen at Z-score = -1 for DXA-BMD and -1.5 for QCT-BMD. VF patients showed a highly significant decrease in BMD by DXA or QCT. PF patients revealed measurements lower than those of normal subjects but greater than those of VF, calling into question the idea of a diffuse osteoporosis causing nonvertebral fractures that is measurable by spinal DXA or QCT. DXA is weakly dependent upon age, and T-score or Z-score are equivalent for evaluating osteoporosis. QCT depends greatly upon age, and Z-score appears to be more efficient.

Background: Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K), are highly prevalent in breast cancer and solid tumor malignancies. GDC-0077 is a potent p110α-selective inhibitor with a novel mechanism of action that degrades mutant p110α and anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with anti-estrogens with or without a CDK4/6 inhibitor. An open-label, Phase I dose-escalation study of GDC-0077 monotherapy and GDC-0077 combined with endocrine therapies and palbociclib is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the completed single agent dose escalation portion of the trial are presented herein. Methods: This study (NCT03006172) assesses the safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of single agent GDC-0077 administered daily (QD) orally at 6, 9, or 12 mg in 28-day cycles until intolerable toxicity or disease progression. Tumor and ctDNA samples are profiled for relevant signaling and pharmacodynamic (PD) biomarkers. Results: As of the clinical cut-off date of 29 March 2019, 20 pts were enrolled in the single agent arm, all with hormone receptor-positive breast cancer, except for 1 pt with colorectal cancer. Nineteen patients had received ≥ 2 prior lines of therapy for metastatic disease. GDC-0077 MTD was established at 9 mg QD. DLTs occurred in 2 pts at 12 mg (1 Grade 4 hyperglycemia, 1 Grade 3 fatigue). Adverse events (AEs) resulted in dose reduction in 6 pts (30%). The most frequent treatment-related (TR)AEs in ≥ 3 pts (15%) included hyperglycemia (14 pts, 70%), diarrhea (8 pts, 40%), decreased appetite and vomiting (4 pts each, 20%), and alopecia, fatigue, nausea, and weight decreased (3 pts each, 15%). Grade ≥3 TRAEs were hyperglycemia (4 pts, 20%) and lymphopenia, fatigue, nausea, weight loss, and asthenia (1 pt, 5% each). Hyperglycemia was generally manageable with oral anti-hyperglycemic medications. Stomatitis (grouped term) occurred in 4 pts (20%, all Grade 1) and responded to topical corticosteroid treatment. Rash (grouped term) occurred in 3 pts (15%) (1 unrelated Grade 2, otherwise Grade 1). No colitis was reported. Mean half-life (t1/2) of GDC-0077 was 18 hours, with the maximum concentration (Cmax) achieved 2-8 hours after dosing. The preliminary PK profile of GDC-0077 showed low-moderate variability in Cmax and area under the concentration-time curve, and dose proportionality across the tested dose levels. Accumulation with QD dosing regimen was 1.6-2.4 fold. All pts discontinued from treatment due to disease progression (radiographic or clinical). Median GDC-0077 treatment duration was 5.3 months (range 1.1-17.6) and cumulative dose intensity was 97%. Overall, partial response (PR) was observed in 5 pts (25%, range 2-10 lines of prior metastatic therapy), with confirmed PR in 4 pts (20%). The clinical benefit rate was 45% (9 of 20 pts). Decreased PI3K pathway effector expression in paired tumor biopsies and decreased PIK3CA mutant allele frequency were observed over time in the majority of specimens. In addition, 18F-fluorodeoxyglucose-positron emission tomography scans at baseline and after 2 weeks of GDC-0077 showed metabolic responses at all dose levels evaluated. Conclusion: The single agent dose escalation study of the p110α-selective and mutant-degrading inhibitor GDC-0077 demonstrated linear PK, a manageable safety profile, PD modulation of the PI3K pathway, and promising preliminary anti-tumor activity. GDC-0077 at the recommended Phase II dose of 9 mg in combination with endocrine therapies with or without the CDK4/6 inhibitor palbociclib is being investigated in this Phase I study and presented separately. Citation Format: Dejan Juric, Kevin Kalinsky, Mafalda Oliveira, Andres Cervantes, Philippe Bedard, Ian Krop, Erika Hamilton, Peter Schmid, Andrea Varga, Nick Turner, Antoine Italiano, Cristina Saura, Valentina Gambardella, Zachary Veitch, Leslie Dickmann, Naoki Kotani, Jill Fredrickson, Amy Kapp, Katie Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer Schutzman, Komal Jhaveri. A first-in-human phase Ia dose escalation study of GDC-0077, a p110a-selective and mutant-degrading PI3K inhibitor, in patients with PIK3CA-mutant solid tumors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-04.

Background: Dysregulation of the PI3K/AKT/mTOR signaling pathway occurs in solid tumor malignancies. GDC-0077 (G) is a potent p110α-selective, p110α-mutant degrading inhibitor with anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with endocrine therapies (ET) with or without a CDK4/6 inhibitor (i). An open-label, Phase I dose escalation study of Galone and in combination with ET and P is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the combinations of G and L with and without P in pts with PIK3CA-mutant HR+/HER2- breast cancer are presented herein. Methods: This study (NCT03006172) assesses the safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of G administered daily (QD) orally at 6 or 9 mg with L (G+L) or at 3, 6, or 9 mg in combination with P+L (G+P+L). L is administered QD orally at 2.5 mg. P is administered QD orally at 125 mg on Days 1-21 followed by 7 days off in 28-day cycles. For dose expansion, prior CDK4/6i was prohibited (G+P+L) and up to one prior metastatic chemotherapy allowed (G+L and G+P+L). Tumor and ctDNA samples (collected before and after 2 weeks of G) are profiled for relevant signaling and pharmacodynamic (PD) biomarkers. Results: As of 29 March 2019, 70 pts had enrolled (G+L: 37 pts [7 at 6 mg and 30 at 9 mg]; G+P+L: 33 pts [3 at 3 mg, 3 at 6 mg, and 27 at 9 mg]). Overall, 33 pts in G+L and 31 pts in G+P+L received ≥ 1 prior metastatic therapy; 70% and 21% of pts received prior CDK4/6i in G+L and G+P+L arms, respectively. No DLTs were reported in pts receiving either combination with G. In G+L, the most frequent treatment-related AEs (TRAEs) occurring in ≥10 (27%) pts included hyperglycemia (25 pts, 68%), nausea (14 pts, 38%), and diarrhea (10 pts, 27%). Grade ≥3 TRAEs in ≥2 (5%) pts included hyperglycemia (7 pts, 19%), and fatigue and hypokalemia (2 pts each, 5%). In G+P+L, the most frequent TRAEs occurring in ≥13 (41%) pts included neutropenia (25 pts, 78%), hyperglycemia (17 pts, 52%), anemia (17 pts, 52%), diarrhea (16 pts, 49%), and nausea and thrombocytopenia (13 pts each, 39%). Grade ≥3 TRAEs in ≥2 (6%) pts included neutropenia (21 pts, 64%), hyperglycemia (5 pts, 15%), lymphopenia (3 pts, 15%), and leukopenia and thrombocytopenia (2 pts each, 6%). Hyperglycemia was manageable with oral anti-hyperglycemic medication. Stomatitis (grouped term) occurred in 11 pts (30%) in G+L and 21 pts (64%) in G+P+L and responded to treatment with dexamethasone mouthwash. 46 pts discontinued treatment, mainly due to disease progression; one due to Grade 3 hyperglycemia in G+P+L (no discontinuation due to AE in G+L). Median G treatment duration: 5.7 months (range 0.2-14.5) in G+L and 9.7 months (range 1.3-23.1) in G+P+L, with a cumulative G dose intensity of 98% for both. In G+ L, PR was reported in 6 pts (16%), confirmed PR in 3 pts (8%) and CBR 35% (13 pts). In G+P+L, PR was reported in 14 pts (42%), confirmed PR in 12 pts (36%) and CBR 76% (25 pts). G PK parameters were similar to those observed as a single agent, and P and L showed exposures comparable with historical data, suggesting an absence of PK drug-drug interaction (DDI). Robust PD downregulation of PI3K pathway effectors (pAKT, pS6) was observed in available paired biopsies and PIK3CA mutant allele frequency decreased in ctDNA on-treatment in most patients. Conclusion: This Phase Ib study of GDC-0077 in combination with letrozole with and without pabocicilb demonstrated a manageable safety profile combining GDC-0077 at its single agent recommended Phase II dose of 9 mg with letrozole with and without palbociclib at standard doses, with no evidence for DDI, high GDC-0077 dose intensity, and promising preliminary anti-tumor activity. Citation Format: Komal Jhaveri, Kevin Kalinsky, Philippe Bedard, Andres Cervantes, Cristina Saura, Ian Krop, Erika Hamilton, Peter Schmid, Andrea Varga, Nick Turner, Antoine Italiano, Valentina Gambardella, Zachary Veitch, Mafalda Oliveira, Leslie Dickmann, Naoki Kotani, Amy Kapp, Katie Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer Schutzman, Dejan Juric. A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-46.

Objectives: Implement scripted automatic breast planning (AP) for breast techniques within Raystation. Methods: Manual plans (MP) were re-planned and compared with AP plans for whole breast (WB), partial breast (PB), hybrid VMAT SIB and VMAT nodal plans. Results: WB AP plans took 7 min comparing well to MP. One WB AP failed a mandatory dose constraint. Small statistically significant differences showed improved coverage for AP at expense of slightly hotter plans, however absolute differences were small (mean differences < 1% or D 0.5cc <0.2 Gy). PB AP plans took 9 min, showing improved coverage (V 24.7Gy97.6versus 96.4 %). One PB AP case failed a mandatory constraint. Other dosimetric differences were non-significant. SIB AP plans took 14 mins with one case failing a mandatory constraint with minor differences compared with MP except larger V 42.8Gy (3vs 1.5 %) and more μ. VMAT AP plans took 12 mins and were hotter for PTVp_4000 but had higher nodal coverage. Contra_Lung V 2.5Gy was higher (8.8 %) than MP plans (6.5 %). Conclusion: Automatic planning of modern breast techniques has been successfully introduced using a commercial planning system. AP plans are very similar to MP, requiring little manual interaction for most cases with significant timesaving potential. Advances in knowledge: Scripted breast plans produced within minutes for WB, PB, SIB and VMAT. Successfully introduced into large busy department. Plans similar to manual plans, requiring little manual interaction.

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Background: Prognosis for triple-negative breast cancer (TNBC) patients remains poor, due in part to the lack of effective targeted therapies in the advanced setting. Emerging clinical data indicates reduced efficacy of immune checkpoint inhibitors in heavily pre-treated TNBC, but the underlying mechanisms are poorly understood. To better understand the immune phenotypic evolution of paired TNBCs, we studied the genomic and transcriptomic profiles of tumors from patients undergoing treatment for TNBC. Methods: We analyzed primary and recurrent TNBCs from 55 poor-risk patients, including 44 paired primary-metastatic samples and 11 paired metastatic tumors. FoundationOne® and RNAseq was successful on 89 specimens and 97 specimens, respectively. In addition to somatic alterations, FoundationOne® provided tumor mutational burden (TMB). From RNAseq, we ascertained the TNBC molecular subtypes, and the mRNA expression of immune-related genes. Stromal tumor-infiltrating lymphocytes (stromal TILs), recurrence-free survival, and overall survival were also studied. Results: From FoundationOne® sequencing, a mutational landscape typical of TNBCs was observed across both primary and recurrent disease specimens, with TP53 mutated in 82.0% of specimens, and BRCA1 and BRCA2 mutated in 4.5% and 16.9% of specimens, respectively. Sample profiles revealed minimal shifts in copy number alterations and TMB over time, however, notable TNBC subtype shifts were observed between primary and recurrent tumors. These included an increase in the Lehmann/Pietenpol-defined basal-like 1 phenotype (BL1, 12.8% to 20.9%), an increase in the mesenchymal phenotype (M, 12.8% to 20.9%), and a significant decrease in the immunomodulatory phenotype (IM, 27.1% to 2.3%). Similarly, tumors exhibited a downward shift in gene expression delineating the Burstein-defined basal-like immune-activated phenotype (BLIA, 37.0% to 14.3%). Composite expression of immunomodulatory gene signatures representative of Th1/Th2 responses, IFNg-related inflammation, M1/M2 macrophage activation and suppression, etc., was decreased in the recurrent tumors compared to the primaries (p = 0.01), and histopathology-derived percent stromal TILs were significantly decreased in the recurrent TNBCs (p = 0.02). However, higher stromal TILs (≥30%) were not associated with improved overall survival when measured in primary specimens (p = 0.15), or with the time from relapse to death when measured in recurrent specimens (p = 0.65) in this cohort of immunotherapy-naïve patients. Conclusion: In this retrospective study of paired TNBCs, significant transcriptomic phenotype shifts were observed as patients progressed, while only minor genomic shifts were seen. Selective immune profiling showed significantly reduced TILs and immune-activating gene expression signatures in recurrent TNBCs, which may explain the lack of efficacy of immunotherapeutic agents in heavily pretreated TNBCs. Further studies are ongoing to understand the proteomic landscape shifts in TNBCs over time and to identify novel targeted agents appropriate for recurrent disease. Citation Format: Yuan Y, Yost SE, Chang C-W, Yoh KE, Johnson RM, Schmolze D, Liang J, Hutchinson KE. Comprehensive profiling of poor-risk paired primary and recurrent triple-negative breast cancers reveals immune phenotype shifts [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-07.

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