ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer

Recent reports suggest that two ATM gene mutations, 7271T>G and IVS10-6T>G, are associated with a high risk of breast cancer among multiple-case families. To assess the importance of these two mutations in another 'high-risk' group, young women (under age 51) with multiple primaries, we screened a large population-based series of young women with bilateral breast cancer and compared the frequency of these mutations among similar women diagnosed with unilateral breast cancer. The 1149 women included were enrolled in an ongoing population-based case-control study of the genetic factors that contribute to bilateral breast cancer; they were not selected on the basis of family history of cancer. Screening for 7271T>G and IVS10-6T>G ATM gene mutations was conducted using DHPLC followed by direct sequencing. The 7271T>G mutation was detected in one out of 638 (0.2%) women with unilateral breast cancer and in none of the bilateral cases, and the IVS10-6T>G mutation in one out of 511 (0.2%) bilateral and in eight out of 638 (1.3%) unilateral breast cancer cases. Carriers of either mutation were not limited to women with a family history. Given the likelihood that young women with bilateral breast cancer have a genetic predisposition, the observed mutation distribution is contrary to that expected if these two mutations were to play an important role in breast carcinogenesis among individuals at high risk

Correlations of EGFR mutations and increases in EGFR and HER2 copy number to gefitinib response in a retrospective analysis of lung cancer patients

<p>Abstract</p> <p>Background</p> <p>Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (<it>EGFR</it>), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, <it>EGFR </it>and <it>HER2</it>, in 39 patients treated with gefitinib at the BC Cancer Agency.</p> <p>Methods</p> <p>Archival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of <it>EGFR</it>, were amplified by PCR and sequenced. <it>EGFR </it>and <it>HER2 </it>copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test.</p> <p>Results</p> <p>Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with <it>EGFR </it>amplification, three with <it>HER2 </it>amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and <it>EGFR </it>mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in <it>EGFR </it>or <it>HER2 </it>copy number (p = 0.552 and 0.437, respectively).</p> <p>Conclusion</p> <p>Neither mutation of <it>EGFR </it>nor increased copy number of <it>EGFR </it>or <it>HER2 </it>was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond <it>EGFR </it>status may be necessary to accurately predict treatment outcome.</p

Cancer risk in close relatives of women with early-onset breast cancer – a population-based incidence study

Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs 24.5) and for ovarian cancer (20 vs 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast–ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers (standardized incidence ratio 2.5; 95% CI 0.5–7.4) and especially brothers (29; 7.7–74), although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer. © 1999 Cancer Research Campaig

Reasons for Lack of Referral to Medical Oncology for Systemic Therapy in Stage Iv Non-small-cell Lung Cancer: Comparison of 2003–2006 with 2010–2011

Introduction: Only approximately 25% of stage iv non-small-cell lung cancer (nsclc) patients receive systemic therapy. For such patients, we examined factors affecting referral to a cancer centre (cc) and to medical oncology (mo), and use of systemic therapy. Methods: Using the Glans–Look Lung Cancer database, we completed a chart review of stage iv nsclc patients diagnosed in Southern Alberta during 2003–2006 and 2010–2011, comparing median overall survival (mos), referral, and treatment in the two cohorts. Results: Of the 922 patients diagnosed in 2003–2006 and the 560 diagnosed in 2010–2011, 94% and 82% respectively were referred to a cc, with 22% and 23% receiving traditional chemotherapy (tctx). Referral to a cc or mo and use of tctx correlated with survival (p &lt; 0.0001): The mos duration was 11.2 months in those receiving tctx and 1.0 months in those not referred to a cc. The overall mos duration was similar in the two cohorts (4.1 months vs. 3.9 months, p = 0.47). Major reasons for lack of referral to mo included poor functional status, rapid decline, and patient wish, which were similar to the reasons for forgoing tctx. In the two cohorts, 87 (9.4%) and 42 (7.5%) patients received epidermal growth factor inhibitors, with a mos duration of 16.2 months. Multivariable analysis showed that male sex [hazard ratio (hr): 1.16; p = 0.008] and pulmonary embolus (hr: 1.2; p = 0.002) correlated with worse survival. In contrast, receipt of chemotherapy (hr: 0.5; p &lt; 0.001) and enrolment in a clinical trial (hr: 0.76; p = 0.049) correlated with better survival. Conclusions: Our experience confirms that, over time, uptake of systemic therapy, including tctx and targeted therapy, changed little despite their established efficacy. Most of the factors limiting systemic therapy uptake appear to be non-modifiable at the time of referral. Rapid diagnosis and the availability of well-tolerated drugs for all nsclc patients will likely be the most important factors in increasing systemic therapy uptake in this population