To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes.
The American Society of Clinical Oncology, American Society for ...Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process.
Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria.
Patients with newly diagnosed BC and
/
mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in
/
or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in
/
carriers. Radiation therapy should not be withheld in
carriers. For patients with germline
mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in
carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in
/
carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.
"What is Literature? A Critical Anthology" explores the most fundamental question in literary studies. 'What is literature?' is the name of a problem that emerges with the idea of literature in ...European modernity. This volume offers a cross-section of modern literary theory and reflects on the history of thinking about literature as a specific form. "What is Literature?" reveals how ideas of the literary draw on the foundations of Western thought in ancient Greece and Rome, charting the emergence of modern literature in the eighteenth century, and including selections from the present state of the art. The anthology includes the work of leading writers and critics of the last two thousand years including Plato, Henry James, Virginia Woolf, Edward Said, Gayatri Chakravorty Spivak, Jacques Rancière, and many others. The book is an insightful examination of the nature of literature, its meanings and values, functions and forms, provocations and mysteries. "What is Literature?" brings together in one volume influential and intriguing essays that show our enduring fascination with the idea of literature. This important guide: (1) Contains a broad selection of the most significant texts on the topic of literature; (2) Includes leading writers from ancient times to the most recent thinkers on literature and criticism; and (3) Encourages readers to reflect on the varied meanings of "literature." "What is Literature? A Critical Anthology" is a unique collection of texts that will appeal to every student and scholar of literature and literary criticism in the European tradition. This book contains the following chapters: (1) Hamburg Dramaturgy (1769) (G. E. Lessing); (2) Of the Standard of Taste (1777) (David Hume); (3) Critique of Judgment (1790) (Immanuel Kant); (4) On the Aesthetic Education of Man (1795) (Friedrich Schiller); (5) On the Study of Greek Poetry (1797) and Philosophical Fragments (1798-1800) (Friedrich Schlegel); (6) Lectures on Dramatic Art (1811) (A. W. Schlegel); (7) Preface to Lyrical Ballads, with Pastoral and Other Poems (1802) (William Wordsworth); (8) Biographia Literaria (1817) (Samuel Taylor Coleridge); (9) Aesthetics: Lectures on Fine Art (1835) (G. W. F. Hegel); (10) The Function of Criticism at the Present Time (1864) (Matthew Arnold); (11) The Birth of Tragedy (1872) (Friedrich Nietzsche); (12) The Art of Fiction (1884) (Henry James); (13) Crisis of Verse (1897) (Stéphane Mallarmé); (14) Art as Technique (1917) (Viktor Shklovsky); (15) The Uncanny (1919) (Sigmund Freud); (16) Tradition and the Individual Talent (1919) and The Function of Criticism (1923) (T. S. Eliot); (17) A Room of One's Own (1929) (Virginia Woolf); (18) The Storyteller (1936): Reflections on the Works of Nikolai Leskov (Walter Benjamin); (19) Pierre Menard, Author of the "Quixote" (Jorge Luis Borges); (20) What is Literature? (1948) (Jean-Paul Sartre); (21) Literature and the Right to Death (1948) (Maurice Blanchot); (22) Language (1950) (Martin Heidegger); (23) Trying to Understand "Endgame" (1958) (Theodor W. Adorno); (24) The Meridian (1960) (Paul Celan); (25) What is an Author? (1969) (Michel Foucault); (26) Sorties: Out and Out: Attacks/Ways Out/Forays (1975) (Hélène Cixous); (27) What is a Minor Literature? (1975) (Gilles Deleuze and Félix Guattari); (28) Literature and Life (1993) (Gilles Deleuze); (29) The Literary Absolute (1978) (Philippe Lacoue-Labarthe and Jean-Luc Nancy); (30) Orientalism (1978) (Edward W. Said); (31) Autobiography as De-facement (1979) (Paul de Man); (32) Che cos'è la poesia? (1988) and Before the Law (1982) (Jacques Derrida); (33) Signs Taken for Wonders (1986): Questions of Ambivalence and Authority under a Tree Outside Delhi, May 1817 (Homi K. Bhabha); (34) What is the History of Literature? (1997) (Stephen Greenblatt); (35) A Critique of Postcolonial Reason (1999) (Gayatri Chakravorty Spivak); (36) Literature for the Planet (2001) (Wai Chee Dimock); (37) The Politics of Literature (2003) (Jacques Rancière); and (38) Close Reading in an Age of Global Writing (2013) (Rebecca L. Walkowitz).
Most local people in the agricultural areas of Hua-ruea sub-district, Ubon Ratchathani province (Thailand), generally consume shallow groundwater from farm wells. This study aimed to assess the ...health risk related to heavy metal contamination in that groundwater. Samples were randomly collected from 12 wells twice in each of the rainy and the dry seasons and were analyzed by inductive coupled plasma spectrometry-mass spectrometry (ICP-MS). The concentration of detected metals in each well and the overall mean were below the acceptable groundwater standard limits for As, Cd, Cr, Cu, Hg, Ni and Zn, but Pb levels were higher in four wells with an overall average Pb concentration of 16.66 ± 18.52 μg/l. Exposure questionnaires, completed by face-to-face interviews with 100 local people who drink groundwater from farm wells, were used to evaluate the hazard quotients (HQs) and hazard indices (HIs). The HQs for non-carcinogenic risk for As, Cu, Zn and Pb, with a range of 0.004–2.901, 0.053–54.818, 0.003–6.399 and 0.007–26.80, respectively, and the HI values (range from 0.10 to 88.21) exceeded acceptable limits in 58 % of the wells. The HI results were higher than one for groundwater wells located in intensively cultivated chili fields. The highest cancer risk found was 2.6 × 10⁻⁶ for As in well no. 11. This study suggested that people living in warmer climates are more susceptible to and at greater risk of groundwater contamination because of their increased daily drinking water intake. This may lead to an increased number of cases of non-carcinogenic and carcinogenic health defects among local people exposed to heavy metals by drinking the groundwater.
Pesticide use has experienced a dramatic increase worldwide, especially in China, where a wide variety of pesticides are used in large amounts by farmers to control crop pests. While Chinese farmers ...are often criticized for pesticide overuse, this study shows the coexistence of overuse and underuse of pesticide based on the survey data of pesticide use in rice, cotton, maize, and wheat production in three provinces in China. A novel index amount approach is proposed to convert the amount of multiple pesticides used to control the same pest into an index amount of a referenced pesticide. We compare the summed index amount with the recommended dosage range of the referenced pesticide to classify whether pesticides are overused or underused. Using this new approach, the following main results were obtained. Pesticide overuse and underuse coexist after examining a total of 107 pesticides used to control up to 54 crop pests in rice, cotton, maize, and wheat production. In particular, pesticide overuse in more than half of the total cases for 9 crop pest species is detected. In contrast, pesticide underuse accounts for more than 20% of the total cases for 11 pests. We further indicate that the lack of knowledge and information on pesticide use and pest control among Chinese farmers may cause the coexistence of pesticide overuse and underuse. Our analysis provides indirect evidence that the commercialized agricultural extension system in China probably contributes to the coexistence of overuse and underuse. To improve pesticide use, it is urgent to reestablish the monitoring and forecasting system regarding pest control in China.
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•Chinese farmers were surveyed for their patterns of pesticide use.•A novel index amount approach was introduced and implemented.•The status quo of pesticide use among the sample farmers was presented.•Pesticide overuse and underuse were found among Chinese farmers.•Policy recommendations were provided to improve farmers' pesticide use precision.
The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ...ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services.
Risk-reducing mastectomy is considered a safe and effective surgical procedure in high-risk individuals with
BRCA1/2
germline mutations. Multigene panels identify women with alterations in breast ...cancer susceptibility genes other than
BRCA1/2
. International guidelines classify these genes as high-, moderate-, and low-penetrance based on their associated relative risk for breast cancer. Classification of specific genes is not always concordant among guidelines, and the indications for risk-reducing mastectomy are not defined. In this opinion paper, we review some considerations to clarify these controversial points.
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline ...(g)
/
mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)
/
mutations or g/s mutations in homologous recombination (HR)-related genes other than
2.
Eligible patients had MBC with measurable disease and germline mutations in non-
/
HR-related genes (cohort 1) or somatic mutations in these genes or
/
(cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).
Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in
s
/
,
or
. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g
(ORR, 82%) and s
/
(ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable NA) for g
and 6.3 months (90% CI, 4.4 months to NA) for s
/
mutation carriers. No responses were observed with
or
mutations alone.
PARP inhibition is an effective treatment for patients with MBC and g
or s
/
mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g
/
mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
Ploidy abnormalities are a hallmark of cancer, but their impact on the evolution and outcomes of cancers is unknown. Here, we identified whole-genome doubling (WGD) in the tumors of nearly 30% of ...9,692 prospectively sequenced advanced cancer patients. WGD varied by tumor lineage and molecular subtype, and arose early in carcinogenesis after an antecedent transforming driver mutation. While associated with TP53 mutations, 46% of all WGD arose in TP53-wild-type tumors and in such cases was associated with an E2F-mediated G1 arrest defect, although neither aberration was obligate in WGD tumors. The variability of WGD across cancer types can be explained in part by cancer cell proliferation rates. WGD predicted for increased morbidity across cancer types, including KRAS-mutant colorectal cancers and estrogen receptor-positive breast cancers, independently of established clinical prognostic factors. We conclude that WGD is highly common in cancer and is a macro-evolutionary event associated with poor prognosis across cancer types.
Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well ...studied. We evaluated the ability of a variant-classification methodology based on American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole-exome sequencing in 404 individuals in 253 families and classified 1,640 variants. Potentially clinically actionable (likely pathogenic LP or pathogenic P) versus nonactionable (VUS, likely benign, or benign) calls were 95% concordant with locus-specific databases and Clinvar. LP or P mutations were identified in 12 of 25 breast cancer susceptibility genes in 26 families without identified BRCA1/2 mutations (11%). Evaluation of 84 additional genes associated with autosomal-dominant cancer susceptibility identified LP or P mutations in only two additional families (0.8%). However, individuals from 10 of 253 families (3.9%) had incidental LP or P mutations in 32 non-cancer-associated genes, and 9% of individuals were monoallelic carriers of a rare LP or P mutation in 39 genes associated with autosomal-recessive cancer susceptibility. Furthermore, 95% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant-classification guidelines. Additionally, evaluation of extended panels of cancer-associated genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results.
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