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Objective: To determine how commercial software platform upgrades impact on derived parameters for colorectal cancer.Materials and Methods: Following ethical approval, 30 patients with suspected colorectal cancer underwent Perfusion CT using integrated 64 detector PET/CT before surgery. Analysis was performed using software based on modified distributed parameter analysis (Perfusion software version 4; Perfusion 4.0), then repeated using the previous version (Perfusion software version 3; Perfusion 3.0). Tumour blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined for identical regions-of-interest. Slice-by-slice and 'whole tumour' variance was assessed by Bland-Altman analysis.Results: Mean BF, BV and PS was 20.4%, 59.5%, and 106% higher, and MTT 14.3% shorter for Perfusion 4.0 than Perfusion 3.0. The mean difference (95% limits of agreement) were +13.5 (-44.9 to 72.0), +2.61 (-0.06 to 5.28), -1.23 (-6.83 to 4.36), and +14.2 (-4.43 to 32.8) for BF, BV, MTT and PS respectively. Within subject coefficient of variation was 36.6%, 38.0%, 27.4% and 60.6% for BF, BV, MTT and PS respectively indicating moderate to poor agreement.Conclusion: Software version upgrades of the same software platform may result in significantly different parameter values, requiring adjustments for cross-version comparison. [ABSTRACT FROM AUTHOR]

The aim of this study is to quantify myocardial perfusion during coronary CT angiography using data from a modified timing test-bolus acquisition. Institutional review board approval and informed consent were obtained. Nineteen patients with suspected coronary artery disease underwent combined coronary CT angiography and cardiac (82)Rubidium-PET perfusion. Prior to the CT angiogram a retrospectively ECG-gated dynamic test bolus was obtained following 25 mls of IV contrast medium injected at 5 ml/s. Images were acquired every 1.5 s for 30 s using 4 x 1.25-mm slices at 120 kV, 35 mAs. Regions of interest were drawn to delineate the myocardium and aorta on the resulting transaxial images. Time density curves were created and perfusion calculated using two simple approaches: maximum-slope method and peak method. In patients with normal PET myocardial perfusion, the mean (SD) resting myocardial perfusion estimated by CT using the maximum-slope method was 0.89 (+/-0.27) ml/min/g and 0.93 (+/-0.21) ml/min/g at end-systole and end-diastole, respectively, and 0.69 (+/-0.11) ml/min/g and 0.79 (+/-0.19) at end-systole and end-diastole, respectively, for the peak method. Thus quantification of myocardial perfusion from a routine coronary CT angiography test bolus is possible. CT-derived myocardial perfusion values are consistent with published values derived from other techniques. [ABSTRACT FROM AUTHOR]

Many proteins populate partially organized structures during folding. Since these intermediates often accumulate within the dead time (2?5 ms) of conventional stopped-flow and quench-flow devices, it has been difficult to determine their role in the formation of the native state. Here we use a microcapillary mixing apparatus, with a time resolution of ∼150 μs, to directly follow the formation of an intermediate in the folding of a four-helix protein, Im7. Quantitative kinetic modeling of folding and unfolding data acquired over a wide range of urea concentrations demonstrate that this intermediate ensemble lies on a direct path from the unfolded to the native state. [ABSTRACT FROM AUTHOR]

Fast ion conducting glasses in the system xAgI−(1−x)AgSeO (0·5≤x≤0·75), prepared by melt quenching route have been investigated in detail. Spectroscopic, thermal and electrical properties including dielectric relaxation have been studied. An attempt is made to understand the variation in these properties by using a structural unpinning model. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy for locally advanced breast cancer improves survival and rates of breast-conserving surgery. Pathologic complete response (pCR) after neoadjuvant therapy strongly correlates with improved disease free survival (DFS) and provides an early indicator of treatment efficacy. The expected pCR rate with a standard taxane-containing combination is approximately 18%. Eribulin is a non-taxane synthetic analogue of halichondrin B that inhibits microtubule dynamics by a novel mechanism of action distinct from other tubulin-targeting agents. Eribulin is active against taxane and anthracycline pretreated metastatic breast cancer (MBC) and is well tolerated with a predictable toxicity profile. Substitution of eribulin for docetaxel in a neoadjuvant combination regimen may therefore improve efficacy. This study will evaluate the non-anthracycline eribulin/cyclophosphamide (ErC) and docetaxel/cyclophosphamide (TC) combinations as neoadjuvant therapy. The first ten patients (pts) will be evaluated for tolerability and feasibility of standard prescribed eribulin monotherapy dosing in combination with standard dose cyclophosphamide. Study Objectives: This randomized phase II trial is designed to determine the pCR rate of locally advanced, HER2-negative breast cancer treated with 6 cycles of ErC or TC. The secondary objectives are to evaluate the clinical response rate of ErC as neoadjuvant therapy and to determine the 2 year DFS of pts treated with ErC and TC. Eligibility: Females ≥18 years with untreated, locally advanced, HER2-negative breast cancer appropriate for neoadjuvant chemotherapy are eligible. Eligibility criteria include: adenocarcinoma histology; clinical T1-3, N0-2, M0 breast tumors; ECOG PS 0-2; known hormone receptor status at study entry; adequate bone marrow and organ function; willingness to provide archived biopsy specimen for correlative testing. Clinical N3, T1N0M0, and T4 tumors are excluded. Upfront axillary lymph node sampling and/or definitive nodal surgery is permitted, and demonstrated pN3a disease is allowed. Trial Design: A lead-in phase of the trial will enroll 10 pts to be treated with ErC to determine safety and feasibility of the combination. If the safety is confirmed, subsequent pts will be stratified by hormone receptor status (positive vs. triple- negative) and will be randomized in a 2:1 ratio to Arm 1: ErC or Arm 2: TC. Pts on Arm 1 will receive eribulin 1.4 mg/m ² IV (Days 1 & 8) and cyclophosphamide 600 mg/m ² IV (Day 1). Pts on Arm 2 will receive docetaxel 75 mg/m² IV (Day 1) and cyclophosphamide 600 mg/m² IV (Day 1). Both regimens are repeated every 21 days for a total of 6 cycles. After completion of neoadjuvant chemotherapy, pts will undergo definitive local surgery, as determined by the treating surgeon. Archival tumor samples and residual tumor tissue at surgery will be collected for biomarker evaluations. A total of 66 pts (Arm 1: 44; Arm 2: 22) will be enrolled to this study. A pCR rate ≥18% in patients treated with ErC is considered a study result that merits further evaluation. This trial is pending activation and has a total accrual goal of 76 pts. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is a poor prognosis subtype with treatment limited to chemotherapy. Over expression of epidermal growth factor receptor (EGFR) occurs in up to 70% of TNBC providing a potential targetable receptor for treatment. Panitumumab is an approved fully human, IgG2 monoclonal anti-EGFR antibody that inhibits intracellular growth signals dependent on receptor activation. The gemcitabine/platinum combination has demonstrated activity in metastatic as well as TNBC at various schedules and doses. We therefore investigated the efficacy and safety of panitumumab in combination with gemcitabine and carboplatin in patients (pts) with TNBC. Methods: Eligibility criteria included: females with metastatic TNBC, 0-1 prior chemotherapy regimen for metastatic disease, ECOG PS 0-1, no brain metastases, no previous EGFR inhibitors and adequate organ function. All pts received gemcitabine 1500 mg/m2 IV, carboplatin AUC = 2.5 IV, and panitumumab 6 mg/kg IV every 2 weeks. A prophylactic skin regimen consisting of moisturizer, sunscreen and topical steroid was to be used 24 hours prior to study treatment and continued until panitumumab was discontinued. Pts were restaged after 3 treatment cycles and continued treatment until unacceptable toxicity or disease progression. If treatment benefit was demonstrated, and pts were experiencing toxicity or intolerance to gemcitabine, carboplatin or both, pts were allowed to discontinue either one or both agents and continue study treatment with panitumumab as a single agent or in combination. The primary endpoint of this study is progression free survival (PFS) with accrual of 70 pts necessary to detect an improvement in median PFS from 3.6 to 5.4 months (80% power, 10% level of significance). Results: Between May 2010 and May 2012, 61 patients were enrolled with an accrual goal of 70 pts. This analysis is based on 47 pts. Pt characteristics include: median age 56, prior hormonal therapy 4%, no prior chemotherapy for metastatic disease in 87% (28% de novo stage IV), 1 prior chemotherapy for metastatic disease in 13%. Sites of metastatic disease included local regional/lymph nodes 70%, lung 57%, liver 32%, bone 26%, and others 23%. Best response to treatment was as follows: CR - 1 (2%), PR - 14 (30%), SD - 20 (43%), PD - 11 (23%), UE - 1 (2%). As 1st line TNBC therapy, the ORR was 34%. The most common grade 3/4 heme toxicities were neutropenia - 12 (25%), leucopenia - 7 (15%), anemia - 3 (6%) and thrombocytopenia - 2 (4%). Grade 3/4 non-hematologic toxicities were rash - 4 (9% with 1 grade 4), fatigue - 3 (6%) and DVT - 3 (6%). Grade 1 and 2 rash was present in 19 and 9 pts respectively. Archival tumor tissue was collected for correlative biomarker analysis to include PI3KCA, p53, PTEN, EGFR, and K-ras status. Conclusions: The addition of panitumumab to gemcitabine and carboplatin in metastatic TNBC was active with an ORR of 32%. No new safety signals were identified and treatment was generally well tolerated with easily manageable toxicity. Full study results and correlative biomarker assessments will be reported. [ABSTRACT FROM AUTHOR]

Background: Sorafenib (S) is an oral multi-kinase inhibitor with effects on tumor proliferation and angiogenesis, targeting VEGFR1 and VEGFR2. It has modest activity as a single agent in breast cancer. In combination with capecitabine, S demonstrated a significant improvement of 2.3 months in progression free survival (PFS) in patients (pts) with metastatic breast cancer (MBC) and added benefit when combined with paclitaxel. Ixabepilone (Ixa) is a semi-synthetic analog of epothilone B with excellent single agent activity in MBC. The phase I portion of this trial identified the MTD of the Ixa and S combination. We now report the initial results of the phase II trial with this novel combination. Methods: Eligibility criteria included: HER2-negative MBC previously untreated with chemotherapy; measurable disease; ECOG PS 0-2; normal LVEF; and adequate bone marrow and organ function. Prior hormonal therapy for MBC was permitted. Pts received Ixa 32mg/m2 IV on day 1 of each 21-day cycle and S 400mg PO BID. Following a minimum of 4 cycles of the combination, responding pts could discontinue Ixa and remain on study treatment with S monotherapy. Granulocyte-stimulating growth factors were permitted after cycle one. Tumor assessments were performed every 9 weeks. Pts continued study treatment until disease progression or unacceptable toxicity. The primary endpoint of this trial was PFS; the addition of S to Ixa was hypothesized to improve PFS from 4.2 month to 6.2 months in this patient population. The total enrollment goal is 85 pts, and the trial is currently open to accrual. Results: Between 5/2010 and 4/2012, 76 pts have been enrolled, and 57 pts (56 females, 1 male) are included in this analysis. Baseline characteristics included: median age 58; 61% were ER and/or PR positive; 39% were triple-negative; 39% received neoadjuvant therapy. Anthracycline exposure was noted in 34 pts and prior taxane exposure in 39 pts. 29 pts received prior hormonal therapy, 7 of these for MBC. Sites of metastatic disease included lymph nodes 42%, lung 35%, liver 30%, bone 30%, and 23% other. 19 pts (33%) had 3 or more sites of metastatic disease. Median treatment duration was 3 cycles (9 weeks), range 1-11+ cycles with 9 pts discontinuing Ixa after a median of 6 cycles and continuing on S monotherapy. 12 pts (21%) had objective responses (1 CR, 11 PR); 3 of the 22 (14%) triple-negative patients had responses (1 CR, 2 PR). An additional 24 patients (42%) had stable disease at first reevaluation. Neutropenia was the most common grade 3/4 toxicity (26%) with growth factor use reported in 35%. Grade 3/4 non-hematologic toxicity occurring in > 5% of patients consisted of: rash (12%), fatigue (11%), hypersensitivity reaction (7%, Ixa= 3 pts and S= 1 pt), and neuropathy (7%). Discontinuation due to adverse events occurred in 11%. Conclusion: The combination of Ixa and full dose S was well tolerated with no new observed toxicities. Adverse events were manageable and consisted primarily of G3/4 neutropenia and rash. Study is ongoing and updated results will be presented. [ABSTRACT FROM AUTHOR]

Background: S is an oral, small molecule, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, stem cell factor receptor, and colony-stimulating factor-1 receptor with demonstrated single agent activity in multiple tumor types including breast cancer. S's anti-proliferative and anti-angiogenic activity stimulated interest in combining it with a variety of chemotherapy regimens. In the previously reported Phase I portion of this trial, S 25mg PO daily was determined feasible in combination with weekly P and C, an active regimen for TNBC. We now report the feasibility and efficacy of the phase II evaluation of this combination as neoadjuvant therapy with pathologic complete response (pCR) as the primary endpoint. Methods: Eligibility criteria included: invasive adenocarcinoma, triple negative histology defined as ER/ PR negative (<10% IHC staining) as well as HER2-negative (IHC 0-1+ or FISH neg), clinical T1-3, N0-1, M0 with clinical N3, T4 and T1 N0 M0 tumors excluded, ECOG PS 0-2, normal LVEF, and adequate organ function. All pts received P 70mg/m² (Days 1,8, 15) + C AUC=5 (Day 1) with S 25mg PO daily q 28 days for 6 cycles. Response assessments were performed after 3 cycles, and in the absence of disease progression or unacceptable toxicity, study treatment continued for 3 additional cycles. Postoperatively, pts resumed S 25 mg qd until 52 weeks from D1. Definition of pCR was an absence of invasive cancer in both breast and lymph nodes. A pCR rate of ≥30% would warrant additional evaluation of this regimen. Results: The phase II portion of this trial enrolled 36 pts from 2/2011 to present. This analysis is based on 22 pts evaluable for toxicity and efficacy. Median tumor size was 4 cm with 68% designated T2 and 27% as T3 and 63% with clinical N1 or N2 disease. A median of 3 preoperative cycles was delivered. Best clinical response was; cCR - 1 (5%), cPR - 9 (41%), cSD - 6 (27%), PD - 1 (5%), UE - 5 (22%). Pathologic responses are as follows: ypCR -2 pts (9%), PR2 (residual invasive cancer in breast, negative lymph nodes -1 pt, PR3 (residual invasive cancer in breast and lymph nodes) -1 pt. 3 pts of the 4 with surgical outcomes completed all 6 cycles of treatment; 2 of which had pCR. Poor tolerance/toxicity resulted in 8 pts proceeding to surgery early/or discontinuation and 2 pts experienced progression; data is pending in 8 pts. Grade 3/4 hematologic toxicity consisted of neutropenia-15 pts (68%) with fever in 2 (9%), anemia -9 pts (41%), and thrombocytopenia-8 pts (36%). No G3/4 non-hematologic toxicity was present in >5% of pts. Conclusions: The addition of sunitinib to paclitaxel and carboplatin was accompanied by significant hematologic toxicity resulting in the inability to deliver the planned study therapy. Treatment discontinuations were frequent as was the need for dose adjustments and modifications. The sunitinib-paclitaxel/carboplatin combination evaluated in this study is not recommended for further use in locally advanced breast cancer. [ABSTRACT FROM AUTHOR]

Opinion Statement: It has become clear that patients whose cancers have progressed post-CDK4/6 inhibitor therapy (CDK4/6i) are not deriving the same magnitude of benefit to subsequent standard endocrine therapy as historical studies would suggest. For example, anticipated duration of benefit to fulvestrant prior to CDK4/6i historically was ~ 5-6 months, and data from the VERONICA and EMERALD trials report less than 2 months. This has magnified our need for novel endocrine agents. Some have argued that patients post-CDK4/6i may just have more endocrine-resistant tumors and perhaps should just receive chemotherapy. While this may be appropriate for some, we do not currently have an assay that reliably predicts whose cancers remain endocrine sensitive and whose are endocrine resistant. ESR1 mutations can enrich for patients whose tumors are more likely to be heavily dependent on estrogen, but this is certainly not the whole answer and many patients without ESR1 mutations continue to derive benefit from subsequent endocrine agents. Most patients would strongly prefer the side effect profile of endocrine agents compared to chemotherapy, and thus, premature use of cytotoxic agents when subsequent ER targeting can control disease is not preferred. These novel ER targeting agents (PROTAC, SERD, SERCA, CERAN) hold great promise to not only outperform standard agents like fulvestrant, but also offer the promise of agents with a different side effect profile that may be more advantageous when compared to menopausal symptoms, hot flashes, arthralgias, and sexual side effects so commonly seen with AIs. We also are likely to see these novel agents move to earlier lines, whether that be 1st line in combination with CDK4/6i or even adjuvant disease., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Antibody-drug conjugates (ADCs) embody a simple, but elegant, vision for cancer therapy-the delivery of a potent cytotoxic agent to tumor cells with minimal damage to normal cells-so-called smart chemo. Although there were significant challenges in achieving this milestone culminating in the first Food and Drug Administration approval in 2000, subsequent advancements in technology have led to rapid drug development with regulatory approvals for ADCs targeting a variety of tumor types. The most successful application for solid tumors has been in breast cancer, with ADCs becoming the standard of care across traditional human epidermal growth factor receptor 2 (HER2)+, hormone receptor+ (HR+) and triple-negative disease subtypes. Moreover, the improved features and gains in potency with the development of ADCs have expanded the treatment-eligible population to those with low/heterogeneous expression of the target antigen on the tumor with trastuzumab deruxtecan or in the case of sacituzumab govitecan, agnostic to target expression. Despite their antibody-directed homing, these novel agents come with their share of toxicities obligating appropriate patient selection and vigilant monitoring while on treatment. As more ADCs are included in the treatment armamentarium, mechanisms of resistance need to be studied and understood for optimal sequencing. Modifying the payload to use immune-stimulating agents or combination therapies with immunotherapy and other effective targeted therapies may further extend the utility of these agents in the treatment of solid tumors.

The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system., (© 2022. Springer Nature Limited.)

Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. TROP-2 expression is higher in HER2-negative breast tumors (HR+/HR-) and is associated with worse survival. Sacituzumab govitecan (SG) is a first-in-class TROP-2-directed ADC with an anti-TROP-2 antibody conjugated to SN-38, a topoisomerase inhibitor via a hydrolysable linker. This hydrolysable linker permits intracellular and extracellular release of the membrane permeable payload enabling the "bystander effect" contributing to the efficacy of this agent. There was significant improvement in progression free survival (PFS) and overall survival (OS) with SG versus chemotherapy in pretreated metastatic triple negative breast cancer (TNBC), resulting in regulatory approval. Common adverse events (AE) reported were neutropenia and diarrhea. SG also demonstrated clinical activity versus chemotherapy in a phase III trial of HR+/HER2-metastatic breast cancer (MBC) and is under evaluation in first-line metastatic and early stage TNBC as well. Datopotamab deruxtecan (Dato-DXd) is a TROP-2 ADC that differs from SG in that it has a cleavable tetrapeptide linker and a more potent topoisomerase inhibitor payload. This construct is highly stable in circulation with a longer half-life than SG, and undergoes cleavage in presence of intracellular lysosomal proteases. Dato-DXd demonstrated preliminary efficacy in unselected metastatic TNBC, with common AEs of low-grade nausea and stomatitis. Dato-DXd is being investigated in phase III studies in metastatic TNBC and HR+/HER2- MBC. These novel TROP-2 ADCs have the potential to deliver enhanced efficacy with reduced toxicity in MBC and possibly in early stage breast cancer (EBC)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Erika Hamilton's institution has received research funding from multiple entities (see below). Erika Hamilton's institution has received consulting fees from multiple entities (see below). Hope S Rugo reports the following: Institutional research support from Pfizer, Novartis, Eli Lilly, Genentech/Roche, OBI, Merck, Gilead Sciences, Daiichi Sankyo, Seattle Genetics, Sermonix, AstraZeneca, Astellas, Veru, GSK, Taiho, AMBRX and Pionyr. Travel support to academic meetings from Merck, Astra Zeneca, GE Healthcare and Gilead. Consultancy/advisory support from Puma, NAPO and Blueprint., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC)., Methods: Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint., Results: Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%)., Conclusions: Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results., Methods: We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019. A total of 2,635 NGS reports from 2,316 unique breast cancer patients were assessed. Hormone receptor and human epidermal growth factor receptor 2 statuses were abstracted from patient medical records. Comparative gene amplification and mutation frequencies were analyzed using Pearson's correlation and Lin's concordance statistics., Results: The number of physicians ordering NGS tests for patients with breast cancer increased more than six-fold from 2014 to 2019. Tissue- and plasma-based tests were ordered roughly equally by 2019, with plasma-based testing ordered most frequently in hormone receptor-positive subtypes. Patients with triple-negative breast cancer were most likely to receive NGS testing. Gene amplifications including ERBB2 were detected less frequently in our real-world data set as compared to previous genomic landscape studies, whereas the opposite was true for gene mutations including ESR1 . Pathogenic mutations in the PI3K pathway (38.6%) and DNA damage repair pathway (11.0%) were frequently reported. Alterations were also reported across other cellular pathways., Conclusion: Overall, we found that an increasing number of physicians in community settings are adopting NGS in the care of patients with breast cancer. Discrepancies between our real-world NGS data and previous genomic landscape studies are likely owed to the prevalence of plasma-based testing in community oncology clinics, as the reference data were from tissue-based NGS alone., Competing Interests: Emma G. SturgillEmployment: HCA/Sarah CannonStock and Other Ownership Interests: HCA Healthcare Rebecca LachsEmployment: Sarah Cannon Research InstituteTravel, Accommodations, Expenses: Sarah Cannon Research Institute Carissa C. JonesEmployment: HCA/Sarah Cannon Dan SchlauchEmployment: Sarah Cannon Research InstituteStock and Other Ownership Interests: HCA Healthcare Suzanne F. JonesEmployment: HCA/Sarah CannonStock and Other Ownership Interests: HCA HealthcareConsulting or Advisory Role: Amgen Mythili ShastryEmployment: Sarah Cannon Research Institute Denise A. YardleyConsulting or Advisory Role: Novartis, Biotheranostics, Bristol Myers Squibb, G1 Therapeutics, Athenex, Immunomedics, Sanofi/Aventis, R-Pharm, LillySpeakers' Bureau: Novartis, Genentech/RocheResearch Funding: Genentech/Roche, Novartis, MedImmune, Lilly, Medivation, Pfizer, Tesaro, Macrogenics, AbbVie, Merck, Clovis Oncology, Amgen, Biomarin, Biothera, Dana Farber Cancer Hospital, Incyte, Innocrin Pharma, Nektar, NSABP Foundation, Odonate Therapeutics, PolyphorTravel, Accommodations, Expenses: Novartis, Genentech/Roche Howard A. Burris IIIEmployment: HCA HealthcareLeadership: HCA HealthcareStock and Other Ownership Interests: HCA HealthcareConsulting or Advisory Role: AstraZeneca, FORMA Therapeutics, Celgene, Incyte, NovartisResearch Funding: Roche/Genentech, Bristol Myers Squibb, Incyte, AstraZeneca, MedImmune, Macrogenics, Novartis, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, BioMed Valley Discoveries, TG Therapeutics, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, BioAtla, CicloMed, Harpoon therapeutics, Archer, Arvinas, Revolution Medicines, Array BioPharma, Bayer, BIND Therapeutics, Kymab, miRNA Therapeutics, Pfizer, Takeda/Millennium, Foundation Medicine, EMD SeronoExpert Testimony: NovartisUncompensated Relationships: Daiichi Sankyo, Pfizer, Bayer, GRAIL, Novartis, Vincerx PharmaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/201030/summary David R. SpigelLeadership: ASCOConsulting or Advisory Role: Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, AstraZeneca, Pfizer, GlaxoSmithKline, Merck, Nektar, Takeda, TRM Oncology, Evelo Therapeutics, Illumina, PharmaMar, Aptitude Health, Bayer, Dracen, EMD Serono, Iksuda Therapeutics, Molecular Templates, Seattle Genetics, TRIPTYCH Health Partners, Amgen, Curio Science, Intellisphere, Ipsen, Jazz Pharmaceuticals, Mirati Therapeutics, Puma Biotechnology, Sanofi/Aventis, Exelixis, Novocure, RegeneronResearch Funding: Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Lilly, AstraZeneca, University of Texas Southwestern Medical Center—Simmons Cancer Center, Merck, G1 Therapeutics, Neon Therapeutics, Takeda, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Astellas Pharma, GRAIL, Transgene, Aeglea Biotherapeutics, Ipsen, BIND Therapeutics, Eisai, ImClone Systems, Immunogen, Janssen Oncology, MedImmune, Molecular Partners, Agios, GlaxoSmithKline, Tesaro, Cyteir, Apollomics, Novocure, Elevation Oncology, Calithera BiosciencesTravel, Accommodations, Expenses: AstraZeneca, Genentech, Novartis Erika P. HamiltonConsulting or Advisory Role: Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics, Black Diamond Therapeutics, CytomX Therapeutics, Dantari, H3 Biomedicine, Merck, Seattle Genetics, Eisai, Deciphera, ArvinasResearch Funding: AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millennium, TapImmune Inc, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Takeda, Macrogenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon Pharmaceuticals, Black Diamond Therapeutics, Orinove, Molecular Templates, Silverback Therapeutics, Seattle Genetics, Puma Biotechnology, Compugen, G1 Therapeutics, Karyopharm Therapeutics, Torque, Dana Farber Cancer Hospital, Infinity Pharmaceuticals, Onconova Therapeutics, Shattuck Labs, Merck, PharmaMar, Olema Pharmaceuticals, Polyphor, Immunogen, Plexxikon, Amgen, AkesobioNo other potential conflicts of interest were reported.

The identification of Human epidermal growth factor receptor 2 (HER2) as a target in breast cancer and the subsequent development of HER2-targeted therapies has revolutionized the treatment of patients with HER2-positive breast cancer. However, there is an increasing awareness of how frequently tumors have low or heterogeneous expression of HER2. It is now recognized that this impacts the degree of benefit from HER2-targeted therapies. With the advent of novel and more potent antibody drug conjugates, targeting HER2 in traditional HER2-negative tumors with "HER2-low" expression is becoming possible. It is essential to refine the nomenclature around HER2 expression to enable clinicians to optimize treatment for patients across the HER2 expression spectrum in breast cancer. HER2 heterogeneity can be detected by conventional IHC, gene expression profiling or other methods and numerous studies have documented the correlation between the presence of HER2 heterogeneity and shorter disease-free survival (DFS) and overall survival (OS). Validation of techniques to identify HER2 heterogeneity in the clinic and concurrent development of agents to effectively treat tumors with non-uniform HER2 expression is needed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Falls are a major health problem with one in three people over the age of 65 falling each year, oftentimes causing hip fractures, disability, reduced mobility, hospitalization and death. A major limitation in fall detection algorithm development is an absence of real-world falls data. Fall detection algorithms are typically trained on simulated fall data that contain a well-balanced number of examples of falls and activities of daily living. However, real-world falls occur infrequently, making them difficult to capture and causing severe data imbalance. People with multiple sclerosis (MS) fall frequently, and their risk of falling increases with disease progression. Because of their high fall incidence, people with MS provide an ideal model for studying falls. This paper describes the development of a context-aware fall detection system based on inertial sensors and time of flight sensors that is robust to imbalance, which is trained and evaluated on real-world falls in people with MS. The algorithm uses an auto-encoder that detects fall candidates using reconstruction error of accelerometer signals followed by a hyper-ensemble of balanced random forests trained using both acceleration and movement features. On a clinical dataset obtained from 25 people with MS monitored over eight weeks during free-living conditions, 54 falls were observed and our system achieved a sensitivity of 92.14%, and false-positive rate of 0.65 false alarms per day.

Purpose: Women with residual invasive breast cancer at the primary site or axillary lymph nodes following neoadjuvant chemotherapy have a high risk of recurrence. Eribulin improves survival in patients with metastatic breast cancer who progress after anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of postoperative eribulin in breast cancer patients who did not achieve a pCR following standard neoadjuvant chemotherapy., Methods: Women with localized breast cancer who had residual invasive cancer following ≥ 4 cycles of standard anthracycline and/or taxane-containing neoadjuvant chemotherapy received adjuvant eribulin treatment. HER2-positive patients also received trastuzumab for 1 year. Adjuvant hormonal therapy and locoregional radiotherapy were administered as per institutional guidelines. Primary endpoint was the 2-year DFS rate. Three patient cohorts were analyzed: TNBC (Cohort A), HR+/HER2- (Cohort B), and HER2+ (Cohort C)., Results: One hundred twenty-six patients (Cohort A-53, Cohort B-42, and Cohort C-31) were enrolled. Neoadjuvant chemotherapy included a taxane and an anthracycline in 70%. Eribulin was well tolerated; 84% of patients received the planned 6 cycles. After a median follow-up of 28 months, the 24-month DFS rates were 56% (95% CI 42, 69), 83% (95% CI 67, 91), and 73% (95% CI 53, 86) for Cohorts A, B, and C, respectively. The most common grade 3/4 treatment-related adverse events were neutropenia (26%), leukopenia (13%), and neuropathy (7%)., Conclusion: Administration of adjuvant eribulin after neoadjuvant chemotherapy was feasible and well tolerated. The 24-month DFS rate did not reach the study target levels in any of the cohorts and was similar to DFS previously described in these cohorts following neoadjuvant chemotherapy alone.

Background: Therapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR + ) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR + /HER2 - MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR + /HER2 - MBC., Patients and Methods: Patients with HR + MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%)., Results: Forty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures., Conclusion: After progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR + /HER2 - MBC., (Copyright © 2019. Published by Elsevier Inc.)

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with backbone endocrine therapy have markedly improved progression-free survival and overall survival over endocrine therapy alone in advanced hormone receptor-positive, HER2-negative (HR + /HER2 - ) breast cancer and are the standard of care in the first- or second-line setting. There are few data to drive decision making for subsequent treatment strategies after inevitable disease progression after CDK4/6i. Information about the genomic landscape of CDK4/6i-resistant disease is emerging. Resistance mechanisms appear to be varied, but mutations in PIK3CA and ESR1, which can be acquired while receiving treatment, are frequent. Activating PIK3CA mutations are present in up to 35% of patients and are now the most actionable genomic alteration in HR + /HER2 - advanced breast cancer with the recent approval of alpelisib and fulvestrant. Everolimus-based combinations and chemotherapy appear to have continued efficacy after progression while receiving CDK4/6i, although historical data on benefit include CDK4/6i-naive patients. Use of selective estrogen down-regulators over aromatase inhibitors is best once the patient has an acquired ESR1 mutation. Tumor biopsy with genomic sequencing and repeat biomarker analysis in patients with CDK4/6i- and endocrine-resistant disease will be integral to guide subsequent treatment strategies and to inform clinical trial eligibility. Promising novel therapeutics in CDK4/6i-resistant disease including oral selective estrogen down-regulators, fibroblast growth factor receptor antagonists, and immunotherapy will be discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Current bevacizumab-based regimens have failed to improve survival in patients with recurrent glioblastoma. To improve treatment efficacy, we evaluated bevacizumab + BKM120, an oral pan-class I PI3K inhibitor, in this patient population., Methods: A brief phase I study established the optimal BKM120 dose to administer with standard-dose bevacizumab. BKM120 60 mg PO daily + bevacizumab 10 mg/kg IV every 2 weeks in 28-day cycles was then administered to patients with relapsed/refractory glioblastoma in the phase II portion., Results: Eighty-eight patients enrolled (phase I, 12; phase II, 76). In phase I, BKM120 80 mg PO daily produced dose limiting toxicity in 3 of 6 patients; a BKM120 dose of 60 mg PO daily was established as the maximum tolerated dose. In phase II, the median progression-free survival (PFS) was 4.0 months (95% CI 3.4, 5.4), PFS at 6 months was 36.5%, and the overall response rate was 26%. Forty-two patients (57%) experienced one or more serious treatment related toxicities. The most common CNS toxicities included mood alteration (17%) and confusion (12%); however, these were often difficult to classify as treatment- versus tumor-related., Conclusions: The efficacy seen in this study is similar to the efficacy previously reported with single-agent bevacizumab. This regimen was poorly tolerated, despite the low daily dose of BKM120. Further development of this combination for the treatment of glioblastoma is not recommended.

Background: Eribulin mesylate is a non-taxane microtubule inhibitor effective in the treatment of metastatic breast cancer refractory to anthracyclines and taxanes. In preclinical studies, additional mechanisms of eribulin included reversal of epithelial mesenchymal transition and tumor vascular remodeling. The present study compared the safety and efficacy of eribulin plus cyclophosphamide (ErC) to docetaxel plus cyclophosphamide (TC) as neoadjuvant therapy for operable HER2 - breast cancer., Patients and Methods: Women with invasive HER2 - breast adenocarcinoma with no distant metastases were eligible. After a 10-patient safety lead-in, the patients were randomized 2:1 to receive either ErC (eribulin 1.4 mg/m 2 on days 1 and 8 plus cyclophosphamide 600 mg/m 2 on day 1) or TC (docetaxel 75 mg/m 2 plus cyclophosphamide 600 mg/m 2 on day 1) administered every 21 days for 6 cycles, followed by surgery. The pathologic complete response (pCR) rate was the primary endpoint. Tumor samples collected at baseline and at surgery were assayed for select epithelial mesenchymal transition and vascular density markers: E-cadherin, vimentin, and CD31 expression., Results: A total of 76 patients were enrolled. Of the 76 patients, 10 received ErC in the lead-in phase and 66 were randomized to ErC (n = 44) or TC (n = 22). The pCR rates with ErC and TC were 13% and 9%, respectively. Both regimens produced frequent neutropenia and peripheral neuropathy. Both regimens increased vascular density as measured by CD31 staining., Conclusion: The neoadjuvant regimens of ErC and TC resulted in relatively low pCR rates in this patient population. No unexpected toxicities were observed. Our results also provided no suggestion that ErC is a neoadjuvant treatment with greater efficacy than that of standard regimens., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood-brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood-brain barrier. The present phase II study (ClinicalTrials.gov identifier, NCT01934894) evaluated the combination of these agents to treat HER2 + MBC patients with CNS metastases., Materials and Methods: Patients with HER2 + MBC and ≥ 1 untreated or progressive, measurable CNS metastasis were eligible. Using a 3+3 dose escalation design, patients were treated with escalating doses of intravenous cabazitaxel every 21 days and oral lapatinib daily in 21-day treatment cycles. Intracranial disease restaging was performed every 2 cycles for the first 8 cycles and then every 3 cycles until progression or unacceptable toxicity., Results: Eleven patients were treated at 2 dose levels. Six patients were treated at dose level 1 (intravenous cabazitaxel 20 mg/m 2 plus oral lapatinib 1000 mg daily), and five were treated at dose level 2 (intravenous cabazitaxel 25 mg/m 2 plus oral lapatinib 1000 mg daily). The most common treatment-related adverse events were myelosuppression, diarrhea, fatigue, and skin toxicity. A total of 5 dose-limiting toxicity events occurred. No intra- or extracranial objective responses were observed., Conclusion: The combination of cabazitaxel plus lapatinib was not feasible because of toxicity and because no objective CNS activity was seen in the 5 evaluable patients. The role of cabazitaxel to treat breast cancer patients with CNS metastases remains undefined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Meningiomas that progress after standard therapies are challenging with limited effective chemotherapy options. This phase II trial evaluated the efficacy of everolimus plus bevacizumab in patients with recurrent, progressive meningioma after treatment with surgical resection and local radiotherapy when appropriate. Patients with recurrent meningioma (WHO grade I, II, or III) following standard treatments with surgical resection and radiotherapy received bevacizumab (10 mg/kg IV days 1 and 15) and everolimus (10 mg PO daily) each 28 day cycle. Evaluation of response occurred every 2 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, overall survival and safety. Seventeen patients with a median age of 59 years (29-84) received study treatment. WHO grades at study entry included: I, 5 (29 %); II, 7 (41 %); III, 4 (24 %); unknown, 1 (6 %). Patients received a median of 8 cycles (1-37); all patients are off study treatment. A best response of SD was observed in 15 patients (88 %), and 6 patients had SD for >12 months. Overall median PFS was 22 months (95 % CI 4.5-26.8) and was greater for patients with WHO grade II and III compared to grade I tumors (22.0 months vs 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1). However, other grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The combination of everolimus and bevacizumab was well-tolerated, and produced stable disease in 88 % of patients; the median duration of disease stabilization of 10 months (2-29). The median PFS from this prospective trial was similar to previous retrospective reports of bevacizumab in the treatment of recurrent meningioma.

Ixabepilone and the taxanes have similar activity in the first-line treatment of metastatic breast cancer, and ixabepilone is sometimes effective in taxane-refractory patients. We conducted a phase 2 trial to evaluate ixabepilone in combination with cyclophosphamide as neoadjuvant treatment for patients with locally advanced HER2-negative breast cancer. Response to neoadjuvant treatment was correlated with the baseline 21-gene Recurrence Score® (Oncotype DX; Genomic Health Inc, Redwood City, CA). Eligible women with HER2-negative locally advanced breast cancer received ixabepilone 40 mg/m(2) plus cyclophosphamide 600 mg/m(2) on day 1 of each 21-day cycle. Following 6 cycles, patients underwent definitive surgery. Primary endpoint was rate of pathologic complete response (pCR). Breast biopsy tumor samples were obtained at pretreatment and at surgery in patients with residual disease. Tumor specimens were analyzed using the 21-gene assay. One hundred sixty-eight patients (median age 52 years; 45 % triple-negative) were enrolled; 161 (96 %) underwent definitive surgery following neoadjuvant ixabepilone/cyclophosphamide. Overall, 27 patients (17 %) achieved pCR, including 19 of 73 (26 %) triple-negative patients. The most frequently occurring grade 3/4 toxicity was neutropenia (98 patients; 58 %). Recurrence Scores were highly correlated with achievement of pCR (0/36 with low or intermediate Recurrence Scores vs. 19/72 with high Recurrence Scores; p = 0.002). There was high concordance between baseline and post-treatment Recurrence Scores in the 72 patients with paired samples. The combination of ixabepilone and cyclophosphamide yielded a pCR rate of 17 %, similar to other neoadjuvant chemotherapy regimens. Pathologic complete responses occurred only in patients with high-risk baseline Recurrence Scores.

The purpose of the study is to evaluate the feasibility and efficacy of adding sunitinib to paclitaxel/carboplatin in the neoadjuvant therapy of patients with triple-negative breast cancer (TNBC). Patients had histologically proven, previously untreated, triple-negative adenocarcinoma, with disease limited to the breast and axilla (clinical T1-T3, N0-N2, M0; T1N1M0 excluded). Following determination of the maximum tolerated doses in the phase I portion, patients in the phase II study received paclitaxel 70 mg/m(2) IV days 1, 8, and 15; carboplatin AUC 5.0 IV day 1; sunitinib 25 mg orally daily; treatment was administered for six 28-day cycles followed by definitive surgery. Sunitinib was resumed postoperatively to complete a 52-week course. Pathologic complete response (pCR) rate was the primary endpoint. Fifty-four patients enrolled; 41 received treatment in the phase II study. Sixteen patients (39 %) were able to complete six cycles of neoadjuvant therapy; 18 additional patients had surgery after completing 2-5 cycles of treatment. The pCR rate in these 34 evaluable patients was 35 %. The toxicity of the regimen was considerable, with myelosuppression resulting in numerous dose reductions and/or omissions of paclitaxel and carboplatin. Eleven patients (27 %) discontinued sunitinib during neoadjuvant therapy, and six patients (14 %) completed 52 weeks of single-agent sunitinib. In the neoadjuvant treatment of patients with TNBC, the combination of paclitaxel, carboplatin, and sunitinib was difficult to administer, and produced a pCR rate comparable to other less toxic regimens. This combination is not recommended for further evaluation. At present, sunitinib has no defined role in the treatment of breast cancer.

Purpose: We prospectively examined the role of tumor textural heterogeneity on positron emission tomography/computed tomography (PET/CT) in predicting survival compared with other clinical and imaging parameters in patients with non-small cell lung cancer (NSCLC)., Experimental Design: The feasibility study consisted of 56 assessed consecutive patients with NSCLC (32 males, 24 females; mean age 67 ± 9.7 years) who underwent combined fluorodeoxyglucose (FDG) PET/CT. The validation study population consisted of 66 prospectively recruited consecutive consenting patients with NSCLC (37 males, 29 females; mean age, 67.5 ± 7.8 years) who successfully underwent combined FDG PET/CT-dynamic contrast-enhanced (DCE) CT. Images were used to derive tumoral PET/CT textural heterogeneity, DCE CT permeability, and FDG uptake (SUVmax). The mean follow-up periods were 22.6 ± 13.3 months and 28.5± 13.2 months for the feasibility and validation studies, respectively. Optimum threshold was determined for clinical stage and each of the above biomarkers (where available) from the feasibility study population. Kaplan-Meier analysis was used to assess the ability of the biomarkers to predict survival in the validation study. Cox regression determined survival factor independence., Results: Univariate analysis revealed that tumor CT-derived heterogeneity (P < 0.001), PET-derived heterogeneity (P = 0.003), CT-derived permeability (P = 0.002), and stage (P < 0.001) were all significant survival predictors. The thresholds used in this study were derived from a previously conducted feasibility study. Tumor SUVmax did not predict survival. Using multivariable analysis, tumor CT textural heterogeneity (P = 0.021), stage (P = 0.001), and permeability (P < 0.001) were independent survival predictors. These predictors were independent of patient treatment., Conclusions: Tumor stage and CT-derived textural heterogeneity were the best predictors of survival in NSCLC. The use of CT-derived textural heterogeneity should assist the management of many patients with NSCLC., (©2013 AACR.)

Purpose of Review: Triple-negative breast cancer (TNBC) is clinically characterized by the lack of expression of the estrogen receptor/progesterone receptor and the human epidermal growth factor receptor 2. It is highly heterogeneous and exhibits considerable overlap with basal-like and BRCA-related breast cancers. Constituting 15-20% of breast cancers, TNBC exhibits an aggressive phenotype with a poor prognosis. This review summarizes recent progress and studies in TNBC and discusses some of the ongoing clinical trials and emerging therapies for the treatment of TNBC., Recent Findings: Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay for treatment of this disease. The use of targeted agents such as bevacizumab, epidermal growth factor receptor and polyadenosine diphosphate-ribose polymerase inhibitors have led to conflicting results. However, recent research has prompted evaluation of additional drugs targeting multiple signaling pathways and epigenetic modifications for the treatment of this disease., Summary: TNBC remains a challenging disease to treat with recent trials having demonstrated only modest improvements in outcomes. Increased understanding of the heterogeneity of this complex subtype may help tailor therapies to specific patient subgroups.

Objective: The purpose of this article is to assess the effect of observers on combined metabolic-vascular parameters in colorectal cancer., Subjects and Methods: Twenty-five prospective patients (12 men and 13 women; mean age, 66.9 years) with proven primary colorectal adenocarcinoma underwent integrated (18)F-FDG PET/perfusion CT to assess tumor metabolism (mean and maximum standardized uptake value [SUV(mean) and SUV(max), respectively]) and vascularization (blood flow [BF], blood volume [BV], permeability surface-area product, and standardized perfusion value). Intra- and interobserver agreement for PET, perfusion CT, and combined metabolic-flow parameters were determined by Bland-Altman statistics and intraclass correlation coefficients (ICCs)., Results: The mean tumor size was 3.8 ± 1.6 cm; there were five stage IA/B, six stage IIA/B, eight stage IIIA/B, and six stage IV tumors. Intra- and interobserver agreement for individual parameters was fair to good, with mean differences between observers of -0.74 for SUV(max), -0.16 for SUV(mean), 9.72 for BF, 0.15 for BV, -0.76 for permeability surface-area product, and 0.09 for standardized perfusion value. ICCs were 0.44-0.99 and 0.38-0.89 for intra- and interobserver agreement, respectively. Interobserver agreement was variable for combined metabolic-flow parameters but better for metabolic-flow difference than for metabolic-flow ratio: ICCs were 0.69-0.88 for the metabolic-flow difference and 0.44-0.94 for the metabolic-flow ratio., Conclusion: Combined parameters to assess the metabolic-flow relationship are influenced by observer variation. Intra- and interobserver agreement are better for the metabolic-flow differences than for the ratios, suggesting that metabolic-flow differences may be a more robust parameter for clinical practice.

We applied modern molecular and functional imaging to the pretreatment assessment of lung cancer using combined dynamic contrast-enhanced computed tomography (DCE-CT) and (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) to phenotype tumors. Seventy-four lung cancer patients were prospectively recruited for (18)F-FDG-PET/DCE-CT using PET/64-detector CT. After technical failures, there were 64 patients (35 males, 29 females; mean age [± SD] 67.5 ± 7.9 years). DCE-CT yielded tumor peak enhancement (PE) and standardized perfusion value (SPV). The uptake of (18)F-FDG quantified on PET as the standardized uptake value (SUV(max)) assessed tumor metabolism. The median values for SUV(max) and SPV were used to define four vascular-metabolic phenotypes. There were associations (Spearman rank correlation [rs]) between tumor size and vascular-metabolic parameters: SUV(max) versus size (rs  =  .40, p  =  .001) and SUV/PE versus size (r  =  .43, p < .001). Patients with earlier-stage (I-IIA, n  =  30) disease had mean (± SD) SUV/PE 0.36 ± 0.28 versus 0.56 ± 0.32 in later-stage (stage IIB-IV, n  =  34) disease (p  =  .007). The low metabolism with high vascularity phenotype was significantly more common among adenocarcinomas (p  =  .018), whereas the high metabolism with high vascularity phenotype was more common among squamous cell carcinomas (p  =  .024). Other non-small cell lung carcinoma tumor types demonstrated a high prevalence of the high metabolism with low vascularity phenotype (p  =  .028). We show that tumor subtypes have different vascular-metabolic associations, which can be helpful clinically in managing lung cancer patients to hone targeted therapy.

Objectives: To investigate how the histological scoring of microvessel density affects correlations between integrated (18)F-FDG-PET/perfusion CT parameters and CD105 microvessel density., Methods: A total of 53 patients were enrolled from 2007 to 2010. Integrated (18)F-FDG-PET/perfusion CT was successful in 45 patients, 35 of whom underwent surgery without intervening treatment. Tumour SUV(max), SUV(mean) and regional blood flow (BF) were derived. Immunohistochemical staining for CD105 expression and analysis were performed for two hot spots, four hot spots and the Chalkley method. Correlations between metabolic flow parameters and CD105 expression were assessed using Spearman's rank correlation., Results: Mean (SD) for tumour size was 38.5 (20.5) mm, for SUV(max), SUV(mean) and BF it was 19.1 (4.5), 11.6 (2.5) and 85.4 (40.3) mL/min/100 g tissue, and for CD105 microvessel density it was 71.4 (23.6), 66.8 (22.9) and 6.18 (2.07) for two hot spots, four hot spots and the Chalkley method, respectively. Positive correlation between BF and CD105 expression was modest but higher for Chalkley than for four hot spots analysis (r = 0.38, P = 0.03; r = 0.33, P = 0.05, respectively). There were no significant correlations between metabolic parameters (SUV(max) or SUV(mean)) and CD105 expression (r = 0.08-0.22, P = 0.21-0.63)., Conclusions: The histological analysis method affects correlations between tumour CD105 expression and BF but not SUV(max) or SUV(mean)., Key Points: • FDG-PET/perfusion CT offers new surrogate biomarkers of angiogenesis. • Microvessel density scoring influences histopathological correlations with CT blood flow. • Highest correlations were found with the Chalkley analysis method. • Correlations between SUV and CD105 are not affected by the scoring method.