Profiling Determinants of Resting Energy Expenditure in Colorectal Cancer.

Background: Understanding resting energy expenditure (REE) is important for determining energy requirements; REE might be altered in individuals with cancer. The objective of this study was to characterize determinants of REE in patients with stages II-IV colorectal cancer (CRC).Methods: REE was measured via indirect calorimetry in patients with newly diagnosed CRC. Computerized tomography images from medical records ascertained skeletal muscle and total adipose tissue cross-sectional areas, which were then transformed to lean soft tissue (LST) and fat mass (FM) values (in kg). Linear regression assessed determinants of REE.Results: 86 patients were included (n = 55, 64.0% male; 60 ± 12 years old; median body mass index: 27.6, interquartile range: 24.3-31.2 kg/m2), with most (n = 40) having stage III disease. Age, sex, and weight were significant predictors of REE [R2 = 0.829, standard error of the estimate (SEE): 128 kcal/day, P < 0.001]. Replacing weight with LST and FM yielded a similar model, with age, sex, LST, and FM predictive of REE (R2 = 0.820, SEE: 129 kcal/day, p < 0.001).Conclusion: Age, sex, weight, LST, and FM were the main contributors to REE. Further investigation of REE changes over time and its relationship to total energy expenditure, dietary intake, and clinical outcomes should be explored.

Atypical reversible posterior leukoencephalopathy syndrome (RPLS) induced by cediranib in a patient with metastatic rectal cancer.

BACKGROUND: Reversible posterior leukoenecphalopathy syndrome (RPLS) is a rare clinicoradiologic syndrome characterized by neurologic symptoms such as seizures, headaches, visual abnormalities, confusion and encephalopathy, accompanied by vasogenic edema of posterior white matter seen on neuroimaging. It has been reported in association with many anti-angiogenic therapies, including bevacizumab, sunitinib, sorafenib, pazopanib and regorafenib. Cediranib is a potent, orally available small molecule tyrosine kinase inhibitor with anti-angiogenic activity, which has been shown to have activity against various solid tumors. CASE REPORT: We present a case of a 65 year old male with metastatic adenocarcinoma of the rectum who received cediranib as part of a phase I clinical trial. He developed confusion and fluctuations in his level of consciousness. MRI of the brain revealed diffuse low level T2 signal abnormality in the cerebral peduncles, pons, and medulla and patchy T2 signal in both thalami, consistent with RPLS. With conservative management, including tight blood pressure control, his symptoms improved and MRI findings resolved. CONCLUSION: RPLS is a rare, but serious, clinicoradiologic syndrome which has been described as an adverse effect of many anti-angiogenic agents and should also be considered in patients on cediranib who present with neurologic symptoms along with vasogenic edema seen on MRI. If RPLS is suspected, cediranib should be discontinued and blood pressure should be aggressively controlled.

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors.

INTRODUCTION: Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. METHODS: In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m(2)) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1-6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. RESULTS: Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. CONCLUSIONS: Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.

Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours.

AIM: To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. METHODS: This was a three-treatment, randomised, three-sequence cross-over study. Lapatinib was administered 1 h after a low- [B] or a high-fat [C] meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal [A]. RESULTS: In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low-fat and high-fat meals affected lapatinib exposure. Lapatinib AUC0-24 increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37-2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98-3.43). Lapatinib Cmax increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49-2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08-3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment-related grade ≥ 3 event occurred (fatigue grade 3, 4 %). CONCLUSIONS: Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal.

Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.

BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.

Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

Canadian Consensus Recommendations on the Management of Extensive-Stage Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive, neuroendocrine tumour with high relapse rates, and significant morbidity and mortality. Apart from advances in radiation therapy, progress in the systemic treatment of SCLC had been stagnant for over three decades despite multiple attempts to develop alternative therapeutic options that could improve responses and survival. Recent promising developments in first-line and subsequent therapeutic approaches prompted a Canadian Expert Panel to convene to review evidence, discuss practice patterns, and reach a consensus on the treatment of extensive-stage SCLC (ES-SCLC). The literature search included guidelines, systematic reviews, and randomized controlled trials. Regular meetings were held from September 2022 to March 2023 to discuss the available evidence to propose and agree upon specific recommendations. The panel addressed biomarkers and histological features that distinguish SCLC from non-SCLC and other neuroendocrine tumours. Evidence for initial and subsequent systemic therapies was reviewed with consideration for patient performance status, comorbidities, and the involvement and function of other organs. The resulting consensus recommendations herein will help clarify evidence-based management of ES-SCLC in routine practice, help clinician decision-making, and facilitate the best patient outcomes.

Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC.

Activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS), in particular, a point mutation leading to a glycine-to-cysteine substitution at codon 12 (G12C), are among the most frequent genomic alterations in non-small cell lung cancer (NSCLC). Several agents targeting KRAS G12C have recently entered clinical development. Sotorasib, a first-in-class specific small molecule that irreversibly inhibits KRAS G12C, has since obtained Health Canada approval. The emergence of novel KRAS-targeted therapies warrants the development of evidence-based consensus recommendations to help clinicians better understand and contextualize the available data. A Canadian expert panel was convened to define the key clinical questions, review recent evidence, and discuss and agree on recommendations for the treatment of advanced KRAS G12C-mutated NSCLC. The panel agreed that testing for KRAS G12C should be performed as part of a comprehensive panel that includes current standard-of-care biomarkers. Sotorasib, the only approved KRAS G12C inhibitor in Canada, is recommended for patients with advanced KRAS G12C-mutated NSCLC who progressed on guideline-recommended first-line standard of care for advanced NSCLC without driver alterations (immune-checkpoint inhibitor(s) [ICIs] +/- chemotherapy). Sotorasib could also be offered as second-line therapy to patients who progressed on ICI monotherapy that are not candidates for a platinum doublet and those that received first-line chemotherapy with a contraindication to ICIs. Preliminary data indicate the activity of KRAS G12C inhibitors in brain metastases; however, the evidence is insufficient to make specific recommendations. Regular liver function monitoring is recommended when patients are prescribed KRAS G12C inhibitors due to risk of hepatotoxicity.

Present and Emerging Biomarkers in Immunotherapy for Metastatic Non-Small Cell Lung Cancer: A Review.

Targeting the immune system, especially the PDL-1/PD-1 axis, has significantly improved the outcomes of metastatic lung cancer patients. However, only a portion of patients will benefit significantly from PD(L)1 therapeutics alone or in combination with either chemotherapy or anti-CTLA4 antibody. It is therefore important to study predictive biomarkers to help select the patients who will experience the most benefit from immunotherapy. In this paper, the current status of PDL-1 expression on tumour cells, the smoking status of patients, tumour mutational burden, gut microbiome and STK11 and KEAP1 mutations in the tumour as predictive biomarkers for PD(L)-1-based immunotherapy are summarized.

Bilateral Lung Transplant for Treatment of Idiopathic Pulmonary Fibrosis With Undetected Lung Adenocarcinoma: A Case Report.

BACKGROUND: Lung transplant has become a curative therapy for various forms of progressive lung disease refractory to medical management. Idiopathic pulmonary fibrosis (IPF) is a rare condition characterized by accumulation of activated fibroblasts and secretion of extracellular matrices within the lung parenchyma. End-stage IPF is a fatal condition, with limited medical therapies other than lung transplantation. IPF has been demonstrated as a known risk factor for the development of lung cancer, and current lung transplant standards define history of malignancy within the past five years as an absolute exclusion criterion. CASE REPORT: We present the case of a patient with biopsy-confirmed idiopathic pulmonary fibrosis treated with bilateral lung transplant, discovered to have stage four lung adenocarcinoma in the explanted lungs. The patient subsequently received pseudoadjuvant chemotherapy and remained recurrence-free until 23 months post-transplant. CONCLUSION: This case highlights the challenge of ruling out malignancy in patients with end-stage lung disease. There remains a paucity of clinical studies on lung transplantation for lung cancer and more evidence is required before supporting this clinical decision.

Consensus Recommendations to Optimize Testing for New Targetable Alterations in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) has historically been associated with a poor prognosis and low 5-year survival, but the use of targeted therapies in NSCLC has improved patient outcomes over the past 10 years. The pace of development of new targeted therapies is accelerating, with the associated need for molecular testing of new targetable alterations. As the complexity of biomarker testing in NSCLC increases, there is a need for guidance on how to manage the fluid standard-of-care in NSCLC, identify pragmatic molecular testing requirements, and optimize result reporting. An expert multidisciplinary working group with representation from medical oncology, pathology, and clinical genetics convened via virtual meetings to create consensus recommendations for testing of new targetable alterations in NSCLC. The importance of accurate and timely testing of all targetable alterations to optimize disease management using targeted therapies was emphasized by the working group. Therefore, the panel of experts recommends that all targetable alterations be tested reflexively at NSCLC diagnosis as part of a comprehensive panel, using methods that can detect all relevant targetable alterations. In addition, comprehensive biomarker testing should be performed at the request of the treating clinician upon development of resistance to targeted therapy. The expert multidisciplinary working group also made recommendations for reporting to improve clarity and ease of interpretation of results by treating clinicians and to accommodate the rapid evolution in clinical actionability of these alterations. Molecular testing of all targetable alterations in NSCLC is the key for treatment decision-making and access to new therapies. These consensus recommendations are intended as a guide to further optimize molecular testing of new targetable alterations.

Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer.

BACKGROUND: Palliative chemotherapy is aimed at increasing survival and palliating symptoms. However, the response rate to first-line chemotherapy in patients with nonsmall cell lung cancer (NSCLC) is less than 30%. Experimental studies have shown that supplementation with fish oil (FO) can increase chemotherapy efficacy without negatively affecting nontarget tissue. This study evaluated whether the combination of FO and chemotherapy (carboplatin with vinorelbine or gemcitabine) provided a benefit over standard of care (SOC) on response rate and clinical benefit from chemotherapy in patients with advanced NSCLC. METHODS: Forty-six patients completed the study, n = 31 in the SOC group and n = 15 in the FO group (2.5 g EPA + DHA/day). Response to chemotherapy was determined by clinical examination and imaging. Response rate was defined as the sum of complete response plus partial response, and clinical benefit was defined as the sum of complete response, partial response, and stable disease divided by the number of patients. Toxicities were graded by a nurse before each chemotherapy cycle. Survival was calculated 1 year after study enrollment. RESULTS: Patients in the FO group had an increased response rate and greater clinical benefit compared with the SOC group (60.0% vs 25.8%, P = .008; 80.0% vs 41.9%, P = .02, respectively). The incidence of dose-limiting toxicity did not differ between groups (P = .46). One-year survival tended to be greater in the FO group (60.0% vs 38.7%; P = .15). CONCLUSIONS: Compared with SOC, supplementation with FO results in increased chemotherapy efficacy without affecting the toxicity profile and may contribute to increased survival.

Canadian Consensus Recommendations on the Management of MET-Altered NSCLC.

In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition (MET) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET-altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET-targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET-altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations.

Skeletal muscle depletion is associated with reduced plasma (n-3) fatty acids in non-small cell lung cancer patients.

Upwards of 50% of newly diagnosed advanced lung cancer patients have severe muscle wasting (sarcopenia). Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in advanced cancer has been shown to attenuate lean tissue wasting. However, the relationship between muscle mass and plasma (n-3) fatty acids in the absence of supplementation is unclear. We aimed to determine how plasma phospholipid (n-3) fatty acids relate to sarcopenia and change in muscle mass in non-small cell lung cancer patients receiving chemotherapy. Computed tomography images were used to measure muscle mass. Patients were classified as sarcopenic or nonsarcopenic based on sex-specific cutpoints. Change in muscle mass during chemotherapy (2.5 mo) was calculated and patients were divided into quartiles based on the rate of muscle loss or gain. Patients with sarcopenia had lower plasma EPA (16.7 +/- 2.1 micromol/L vs. 31.6 +/- 4.4 micromol/L; P = 0.001), DHA (36.6 +/- 4.0 micromol/L vs. 55.3 +/- 4.0 micromol/L; P = 0.003), and Sigma(n-3) fatty acids (63.6 +/- 5.6 micromol/L vs. 95.0 +/- 7.7 micromol/L; P = 0.002) than nonsarcopenic patients. Patients with maximal muscle loss (mean - 3.5 kg) had lower plasma EPA (12.2 +/- 3.3 micromol/L vs. 35.0 +/- 7.1 micromol/L; P = 0.03), DHA (26.9 +/- 8.7 micromol/L vs. 59.6 +/- 5.3 micromol/L; P = 0.01), and Sigma(n-3) fatty acids (57.8 +/- 13.5 micromol/L vs. 104.6 +/- 11.1 micromol/L; P = 0.005) compared with patients who were gaining muscle (mean +1 kg). Plasma (n-3) fatty acids are depleted in cancer patients with sarcopenia, which may contribute to accelerated rates of muscle loss.

Satraplatin, an oral platinum, administered on a five-day every-five-week schedule: a pharmacokinetic and food effect study.

PURPOSE: The study aimed to assess the pharmacokinetic behavior of satraplatin under fasted and fed conditions, and its safety and preliminary antitumor activity in adults with advanced solid tumors. EXPERIMENTAL DESIGN: Satraplatin was administered orally at 80 mg/m(2) once daily with prophylactic antiemetics for 5 consecutive days every 5 weeks. Patients were randomized to receive day 1 and day 5 doses of satraplatin in either the fed or fasted state, the order being reversed for cycle 2. Pharmacokinetic sampling was done during the first two cycles. For all subsequent cycles, patients received satraplatin in the fasted state. RESULTS: Seventeen patients were treated with 60 total cycles of satraplatin. There was no dose-limiting toxicity during cycle 1. Severe hematologic toxicity was rare and the hematologic nadir occurred during week 4. Nausea, vomiting, and diarrhea were grade 1/2. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The hypothesis that food decreased ultrafiltrate platinum bioavailability could not be rejected, as the lower limit of the 90% confidence intervals for peak plasma concentration and area under the concentration-time curve from time 0 to 24 hours were 56.14% and 73.53%, respectively, both below the 80% bioequivalence acceptance criterion. One partial response (hormone refractory prostate cancer) and four durable stable diseases (breast, ovarian, parotid, and hormone refractory prostate cancer) were confirmed. CONCLUSIONS: There is an effect of food on the pharmacokinetics of satraplatin, the clinical significance of which is unclear. It is recommended that satraplatin be administered in the fasting state. This 5-week interval schedule of satraplatin was well tolerated in heavily pretreated patients.

Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion.

The identification of driver mutations in epidermal growth factor receptor, anaplastic lymphoma kinase, the BRAF and ROS1 genes and subsequent successful clinical development of kinase inhibitors not only significantly improves clinical outcomes but also facilitates the discovery of other novel driver mutations in non-small cell lung cancer. These driver mutations can be categorized into mutations in or near the kinase domain, gene amplification or fusion. In this review, BRAF V600E, EGFR and HER-2 exon 20 mutation, FGFR1-4, K-RAS, MET, neuregulin-1, NRTK, PI3K/AKT/mTOR, RET and ROS1 gene aberration and their therapeutics will be discussed.

Determinants of change in resting energy expenditure in patients with stage III/IV colorectal cancer.

BACKGROUND & AIMS: Resting energy expenditure (REE) is variable in cancer and might be influenced by changes in tumor burden, systemic inflammation, and body composition. The objective of this study was to assess REE change and the predictors of such in patients with stage III or IV colorectal cancer. METHODS: REE was measured via indirect calorimetry and fat mass and fat-free mass (FFM) were assessed using dual X-ray absorptiometry as part of a unique analysis of two studies. C-reactive protein (CRP) was measured as an inflammatory marker. Linear regression was used to assess the determinants of REE at baseline and REE change, with days between baseline and follow-up measures included as a covariate. RESULTS: One-hundred and nine patients were included at baseline (59.6% male; 67 ± 12 years; body mass index 24.1 ± 4.3 kg/m2); 49 had follow-up data (61.2% male; 65 ± 12 years; body mass index 25.4 ± 4.3 kg/m2), with median follow-up of 119 days (interquartile range: 113-127 days). At baseline, age, FFM, and CRP explained 68.9% of the variability in REE. A wide variability in REE change over time was observed, ranging from -156 to 370 kcal/day, or -13.0 to 15.7%/100 days. CRP change (1.7 ± 0.4 mg/L, p < 0.001) and stage (81.3 ± 38.7, p = 0.042) predicted REE change in multivariate analysis, controlling for age, FFM change, and days between visits (R2: 0.417 ± 88.2, p < 0.001). CONCLUSIONS: Age, FFM, and CRP predicted REE at a single time point. REE change was highly variable and explained by inflammation and stage. Future research should investigate the validity and feasibility of incorporating these measures into energy needs recommendations.

The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS, and AURKA-have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079.

A phase I and pharmacokinetic study of lapatinib in combination with letrozole in patients with advanced cancer.

PURPOSE: The main objectives of this phase I and pharmacokinetic, open-label study were to determine the optimally tolerated regimen (OTR), safety, pharmacokinetics, and clinical activity of lapatinib in combination with letrozole in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients with advanced breast cancer with immunohistochemically detectable estrogen or progesterone receptors or other cancers were eligible. Doses of lapatinib were escalated in cohorts of three subjects from 1,250 to a maximum of 1,500 mg/d based on dose-limiting toxicities in the first treatment cycle. The letrozole dose was fixed at 2.5 mg/d. Additional patients were enrolled at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. RESULTS: Thirty-nine patients were enrolled in the study: 12 in the dose-escalation group, 7 in the OTR safety group, and 20 in the pharmacokinetic group. The OTR dose level was identified as 1,500 mg/d lapatinib and 2.5 mg/d letrozole. The most common (>25% of patients) drug-related adverse events were diarrhea (77%), rash (62%), nausea (46%), and fatigue (26%). No significant differences were observed in the pharmacokinetic variables (C(max) and AUC) of lapatinib and letrozole when coadministered compared with single-agent administration. One patient with endometrial cancer had a confirmed partial response. CONCLUSIONS: Clinically relevant doses of lapatinib in combination with letrozole were well tolerated and did not result in a pharmacokinetic interaction, and clinical antitumor activity was observed.