Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are now standard of care for hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study aims to examine physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. Methods: A retrospective chart review was conducted for consecutive MBC patients who received palbociclib between February 2015 and August 2017 at the Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. Results: Two-hundred patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). A majority of patients received palbociclib in the endocrine resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), the fraction of patients receiving palbociclib as the first- or second-line therapy increased in recent months (p=0.0428). The mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively (p<0.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to literature report. Among patients who progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane plus everolimus (n=12). The mPFS with hormonal therapy or combinations (n=32) post first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively (p=0.04). The mPFS with chemotherapy (n=70) was not-reached, 4.7, 4.1 months post first-line palbociclib, second-, and subsequent-line palbociclib, respectively (p=0.56). Conclusion: Palbociclib is effective for HR+HER2− MBC in real-world practice. Hormonal therapy or a combination with targeted agents remains an effective option following palbociclib progression.

Purpose: Patients with triple negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin, and to identify molecular alterations and/or immune gene signatures predicting pCR.Experimental Design: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole exome sequencing (WES) and immune pro ling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular pro les.Results: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-signi cant trend towards higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80, versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR.Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor in ammation signature, in ammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteosome were upregulated in pre-treatment samples from patients who achieved pCR.Conclusions: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune pro ling differentiated patients with and without pCR.

Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors of mesenchymal origin. The low response rate to cytotoxic chemotherapies has necessitated the need for development of either histologically driven or pathway-specific targeted therapies. As our understanding of the molecular mechanisms driving certain subtypes is rapidly advancing, the number of targeted therapies is also increasing. Recently identified novel druggable targets include the MDM2 amplifications in well-differentiated and dedifferentiated liposarcomas, the new translocation NAB2:STAT6 of solitary fibrous tumors, the angiopoeitin-TIE2 pathway in angiosarcoma, the suppression of Mcl1 in X:18/synovial sarcomas, the mTOR pathway in malignant peripheral nerve sheath tumors, CDK4 in alveolar rhabdomyosarcoma, cMET regulation in alveolar soft parts sarcoma, the metabolic abnormalities in wild-type/SHD GIST, and the lack of argininosuccinate synthetase 1 expression seen in most sarcomas. It is through a fundamental understanding of sarcoma biology that clinical trials based on molecular targets can be developed.

Background:Neoadjuvant Therapy (NAT) permits less aggressive breast and axillary surgery and better assessment of systemic response. Establishing accurate and early predictors of NAT response would help limit morbidity of ineffective regimens through modi cation of treatment regimens and thereby optimize clinical outcomes. The purpose of the study was to assess the utility of tumor biomarkers, ultrasound (US) and US-guided diffuse optical tomography (DOT) in early prediction of breast cancer response to NAT. MethodsThis prospective HIPAA compliant study was approved by the institutional review board. Forty one patients were imaged with US and US-guided DOT prior to NAT, at completion of the rst three treatment cycles, and prior to de nitive surgery from February 2017 to January 2020. Miller-Payne grading was used to assess pathologic response. Receiver operating characteristic curves (ROCs) were derived from logistic regression using independent variables, including: tumor biomarkers, US maximum diameter, percentage reduction of the diameter (%US), pretreatment maximum total hemoglobin concentration (HbT) and percentage reduction in HbT (%HbT) at different treatment time points. Resulting ROCs were compared using area under the curve (AUC). Statistical signi cance was tested using two-sided two-sample student t-test with P<0.05 considered statistically signi cant. ResultsThirty-eight patients (mean age =47, range 24-71 years) successfully completed the study, including 15 HER2+ of which 11 were ER+; 12 ER+ or PR+/HER2-, and 11 triple negative. The combination of HER2 and ER biomarkers, %HbT at the end of cycle 1 (EOC1) and %US (EOC1) provided the best early prediction, AUC = 0.941 (95% CI: 0.869-1.0). Similarly an AUC of 0.910 (95% CI: 0.810-1.0) with %US (EOC1) and %HbT (EOC1) can be achieved independent of HER2 and ER status. The most accurate prediction, AUC = 0.974 (95% CI: 0.933-1.0), was achieved with %US at EOC1 and %HbT (EOC3) independent of biomarker status. ConclusionThe combined use of tumor HER2 and ER status, US, and US-guided DOT may provide accurate prediction of NAT response as early as the completion of the rst treatment cycle.

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2−) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2− MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6–43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2–36.1%) without G4 in C1, and 40.7% (95% CI: 27.9–54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5–89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11–34.89), 33.5 (17.25–not reached [NR]), and 11.96 (10.43–NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 10−4, 0.001, 0.007, respectively). sTK1 decreased on C1D15 (p = 4.03 × 10−7), indicating target inhibition. Rise in sTK1 predicted progression, with the median lead time of 59.5 (inter-quartile range: −206.25–0) days. Palbociclib, 5-days-on/2-days-off weekly, met its primary endpoint with reduced G3 + ANC, without compromising efficacy. sTK1 is prognostic and shows promise in monitoring the palbociclib response. ClinicalTrials.gov#: NCT3007979.