Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer.

Background: Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed. Patients and methods: Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes. Results: Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P < 0.027] and are frequently polyclonal in ctDNA assays. Assessment of paired specimens shows that NF1 alterations arise in the setting of acquired resistance. An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4-hydroxy tamoxifen. Our study further identified a significant increase in tumor mutational burden (TMB) in mILCs relative to breast ILCs or metastatic IDCs (8.9% >20 mutations/mb; P < 0.001). Most TMB-high mILCs harbor an APOBEC trinucleotide signature (14/16; 88%). Conclusions: This study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibitor. Moreover, for an independent subset of mILC, TMB was elevated relative to breast ILC, suggesting possible benefit from immune checkpoint inhibitors.

Comparative evaluation of efficacy and safety of artesunate-lumefantrine vs. artemether-lumefantrine fixed-dose combination in the treatment of uncomplicated Plasmodium falciparum malaria.

OBJECTIVE: To establish efficacy and safety of artesunate/lumefantrine fixed-dose combination (FDC) in comparison with artemether/lumefantrine FDC in treatment of uncomplicated Plasmodium falciparum malaria. METHODS: Confirmed cases of uncomplicated P. falciparum malaria were randomly assigned to receive artesunate (100 mg)/lumefantrine (480 mg) (ASLF FDC) or artemether (80 mg)/lumefantrine (480 mg) (AMLF FDC) tablets for 3 days. Patients were followed up on Day 7, 14, 21 and 28. RESULTS: Of the 158 enrolled patients, 144 completed the study. Seventy-three patients (94.8%) from the ASLF group and 71 patients (94.7%) from the AMLF group showed parasite clearance within 48 h. The mean parasite clearance time was 25.40 ± 14.82 h in the ASLF group and 24 ± 13.32 h in the AMLF group (P = 0.542). All patients showed gametocyte clearance by Day 7 and remained gametocyte free till Day 28. Sixty-five patients (84.4%) from the ASLF group and 56 patients (74.7%) from the AMLF group were afebrile within 24 h. The mean fever clearance time was 17.38 ± 12.33 h in the ASLF group and 17.2 ± 12.01 h in the AMLF group (P = 0.929). There was one early treatment failure in the AMLF group as per WHO criteria. Improvement in haemoglobin and haematocrit was comparable in both the treatment groups. In the ASLF group, of the 25 (32.47%) patients anaemic at baseline, only seven (9.09%) reported anaemia on Day 28, while in the AMLF group, of the 14 (18.67%) patients anaemic at baseline, only four (5.33%) reported anaemia on Day 28. Both study medications were well tolerated. CONCLUSION: Artesunate (100 mg)/lumefantrine (480 mg) fixed-dose combination could add one more option to currently available artemisinin combinations in treatment of uncomplicated P. falciparum malaria.

AMPK promotes tolerance to Ras pathway inhibition by activating autophagy.

Targeted inhibitors of oncogenic Ras (rat sarcoma viral oncogene)-Raf signaling have shown great promise in the clinic, but resistance remains a major challenge: 30% of tumors with pathway mutations do not respond to targeted inhibitors, and of the 70% that do respond, all eventually develop resistance. Before cancer cells acquire resistance, they respond to initial drug treatment either by undergoing apoptosis ('addiction') or by surviving treatment albeit with reduced growth ('tolerance'). As these drug-tolerant cells serve as a reservoir from which resistant cells eventually emerge, inhibiting the pathways that confer tolerance could potentially delay or even prevent recurrence. Here, we show that melanomas and other cancers acquire tolerance to Ras-Raf pathway inhibitors by activating autophagy, which is mediated by the cellular energy sensor AMP-activated protein kinase (AMPK). Blocking this AMPK-mediated autophagy sensitizes drug-tolerant melanomas to Ras-Raf pathway inhibitors. Conversely, activating AMPK signaling and autophagy enables melanomas that would otherwise be addicted to the Ras-Raf pathway to instead tolerate pathway inhibition. These findings identify a key mechanism of tolerance to Ras-Raf pathway inhibitors and suggest that blocking either AMPK or autophagy in combination with these targeted inhibitors could increase tumor regression and decrease the likelihood of eventual recurrence.

The evolving portrait of cancer metastasis.

The phenomenon of cancer metastasis remains poorly understood. We discuss here various conceptual frameworks that attempt to rationalize the mechanisms by which tumors acquire metastatic ability. Portrayal of cancer as a somatic Darwinian process occurring within a tissue fails to fully explain the phenomenon of metastatic competence. The biology of pre-neoplastic cells also complicates this picture, since the phenotypes of normal cellular precursors are clearly relevant to metastatic behavior following transformation. Recent experimental results help to shed light on these and other considerations regarding the molecular mechanisms of malignant progression.

Survey of pharmacists: impact of the generic drug scandal and implications for marketing generic drugs.

The generic drug scandal that made headlines in 1989 shocked consumers, prescribers, pharmacists, insurers, the pharmaceutical industry, the FDA and Congress. Using data collected after the scandal was reported, this study investigates the impact of scandal on pharmacists' confidence in generics, and their attitudes, opinions and behavior toward generics. Based upon the findings, the author provides a set of recommendations for marketing generic drugs.

Decision making in health care institutions: the health care practice paradigm.

Based on research reported in the health care literature, this paper adapts Blake and Mouton's (1985) two dimensional Managerial Grid to develop a model called the Health Care Practice Paradigm. The paradigm postulates two primary dimensions to represent the behavior of health care providers and practitioners: (1) patient orientation and (2) task orientation. To illustrate the usefulness of this approach, a study of the decision making processes of dietitians with respect to a new product was conducted. Based on a national sample of dietitians, the findings suggest that health care orientation of the dietitians is a better predictor of attitudes toward trying a new product than traditional demographic factors such as hospital size. Key implications for health care providers targeting new products toward hospitals and other health care institutions are highlighted.