Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers.

Background: Platinum-based therapy is an effective treatment for a subset of triple-negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. Patients and methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared with resistant triple-negative breast cancers in two independent neoadjuvant cisplatin-treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. Results: We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum-sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin but has no effect on paclitaxel sensitivity. Conclusions: A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple-negative breast cancer and ovarian cancer.

Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.

Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.

Pollen-food allergy syndrome is a common allergic comorbidity in adults with eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is associated with atopic diseases including asthma, allergic rhinitis, and atopic dermatitis; however, limited data exist on the correlation between pollen-food allergy syndrome (PFAS) and EoE. We analyzed 346 adults with EoE treated at a single center between 2002 and 2016. Demographic and EoE-specific data including clinical features and measures of EoE disease severity and treatments were collected. The presence of other atopic diseases, family history, prevalence of peripheral eosinophilia and elevated IgE, and details of PFAS triggers were collected. Twenty six percent of the 346 subjects in our cohort had both EoE and PFAS (EoE-PFAS). Compared to subjects with EoE alone, subjects with EoE-PFAS had an increased frequency of allergic rhinitis (86.7% vs. 64.2%, P < 0.001) and family history of allergies (71.1% vs. 53.3%, P = 0.003), and comprised a higher proportion of EoE diagnoses made in the spring (Χ2 < 0.001). 43.3% of subjects with concurrent EoE and PFAS opted for treatment with elimination diet, and these measures failed to induce remission in 46.2% of cases. In most cases, elimination diet failed despite strict avoidance of PFAS trigger foods in addition to common EoE triggers including dairy, wheat, and eggs. EoE-PFAS was also associated with higher serum IgE at the time of EoE diagnosis (460.6 vs. 289.9, P < 0.019). Allergic rhinitis and a family history of food allergy were independently associated with having EoE-PFAS. The most common triggers of PFAS in adults with EoE are apples (21.1%), carrots (15.5%), and peaches (15.5%). Along with asthma, allergic rhinitis and atopic dermatitis, PFAS is a common allergic comorbidity that is highly associated with EoE. Further studies aimed at understanding mechanistic similarities and differences of PFAS and EoE may shed light on the pathogenesis of these closely related food allergy syndromes.

Prevention of Depression in At-Risk Adolescents: Moderators of Long-term Response.

In a randomized controlled trial, we found that a cognitive behavioral program (CBP) was significantly more effective than usual care (UC) in preventing the onset of depressive episodes, although not everyone benefitted from the CBP intervention. The present paper explored this heterogeneity of response. Participants were 316 adolescents (M age = 14.8, SD = 1.4) at risk for depression due to having had a prior depressive episode or having current subsyndromal depressive symptoms and having a parent with a history of depression. Using a recursive partitioning approach to baseline characteristics, we (Weersing et al. 2016) previously had identified distinct risk clusters within conditions that predicted depressive episodes through the end of the continuation phase (month 9). The present study used the same risk clusters that had been derived in the CBP group through month 9 to reclassify the UC group and then to examine group differences in depression through month 33. We found that in this overall very high-risk sample, the CBP program was superior to UC among youth in the low-risk cluster (n = 33), characterized by higher functioning, lower anxiety, and parents not depressed at baseline, but not in the middle (n = 95) and high-risk (n = 25) clusters. Across conditions, significantly more depression-free days were found for youth in the low-risk cluster (M = 951.9, SD = 138.8) as compared to youth in the high-risk cluster (M = 800.5, SD = 226.7). Identification of moderators, based on purely prognostic indices, allows for more efficient use of resources and suggests possible prevention targets so as to increase the power of the intervention.

De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017.

The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.

Mycobacterium fortuitum lipoid pneumonia in a dog.

A 1-year old female spayed German Shepherd dog was evaluated for acute onset of dyspnea. Pyogranulomatous inflammation and green globoid structures were present on aspirates of the affected lung. Impression smears and histopathology confirmed pyogranulomatous pneumonia, with large amounts of lipid corresponding to the green structures noted cytologically, and identified poorly staining bacterial rods within lipid vacuoles. Special stains confirmed the presence of acid-fast bacterial rods, and polymerase chain reaction and DNA sequencing identified the organism as Mycobacterium fortuitum. M. fortuitum pneumonia is well described in humans and has previously been reported in 4 dogs and 1 cat. Lipid was a prominent cytologic and histologic feature, as is often described in humans and in the single feline case report. Additionally, this case highlights the variable cytologic appearance of lipid, as well as Mycobacterium spp, which are classically nonstaining with Wright-Giemsa.

Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors.

BACKGROUND: To establish the maximum tolerated dose, determine safety/tolerability and evaluate the pharmacokinetics and preliminary efficacy of olaparib in combination with cisplatin in patients with advanced solid tumors. PATIENTS AND METHODS: Patients aged ≥ 18 years with advanced solid tumors, who had progressed on standard treatment, were assigned to a treatment cohort and received oral olaparib [50-200 mg twice daily (bid); 21-day cycle] continuously or intermittently (days 1-5 or 1-10) in combination with cisplatin (60-75 mg/m(2) intravenously) on day 1 of each cycle. RESULTS: Dose-limiting toxicities (DLTs) of grade 3 neutropenia (cisplatin 75 mg/m(2) with continuous olaparib 100 mg bid or 200 mg bid; n = 1 each) and grade 3 lipase elevation (cisplatin 75 mg/m(2) with olaparib 100 mg bid days 1-10 or 50 mg bid days 1-5; n = 1 each) were reported. Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1-5 and 60 mg/m(2), respectively; no DLTs were reported for patients receiving this regimen. The most frequent grade ≥ 3 adverse events were neutropenia (16.7%), anemia (9.3%) and leucopenia (9.3%). Thirty patients (55.6%) received colony-stimulating factors for hematologic support. The overall objective response rate was 41% for patients with measurable disease, and 43% and 71% among patients with a BRCA1/2 mutation who had ovarian and breast cancer, respectively. CONCLUSIONS: Olaparib in combination with cisplatin 75 mg/m(2) was not considered tolerable; intermittent olaparib (50 mg bid, days 1-5) with cisplatin 60 mg/m(2) improved tolerability. Promising antitumor activity in patients with germline BRCA1/2 mutations was observed and warrants further investigation.

Doppler broadening thermometry of acetylene and accurate measurement of the Boltzmann constant.

In this paper, we present accurate measurements of the fundamental Boltzmann constant based on a line-shape analysis of acetylene spectra in the ν1 + ν3 band recorded using a tunable diode laser. Experimental spectra recorded at low pressures (0.25 - 9 Torr), have been analyzed using a Speed Dependent Voigt model that takes into account the molecular speed dependence effects. This line-shape model reproduces the experimental data with good accuracy and allows us to determine precise line-shape parameters for the P(25) transition of the ν1 + ν3 band. From the recorded spectra we obtained the Doppler-width and then determined the Boltzmann constant, k(B).

Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.

We analysed 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene, using single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. A total of eight putative disease-causing alterations were identified: four of these are frameshifts and two are nonsense mutations. In addition, we found two missense mutations, one of which changes the final cysteine of the BRCA1 zinc finger motif to glycine. These data are consistent with a tumour suppressor model, and support the notion that this candidate gene is in fact BRCA1. The heterogeneity of mutations, coupled with the large size of the gene, indicates that clinical application of BRCA1 mutation testing will be technically challenging.

BRCA2 germline mutations in male breast cancer cases and breast cancer families.

The breast cancer susceptibility gene, BRCA2 on chromosome 13q12-13, was recently isolated. Mutations in BRCA2 are thought to account for as much as 35% of all inherited breast cancer as wall as a proportion of inherited ovarian cancer. Many BRCA2-linked families also contain cases of male breast cancer. We have analysed germline DNA from 50 males with breast cancer (unselected for family history) and 26 individuals from site-specific female breast and breast-ovarian cancer families for mutations in BRCA2. All 17 breast-ovarian cancer families have been screened for BRCA1 coding region mutations and none were detected. Conformation-sensitive gel electrophoresis (CSGE) analysis of PCR-amplified DNA followed by direct sequencing was used to detect sequence variants. Three of eleven individuals carry the same mutation, all are of Ashkenazi Jewish descent, supporting the observation by Neuhausen et al. in this issue that there is a common mutation in this population. Eleven truncating mutations and nine polymorphisms were identified -- all were coding region variants. No loss-of-transcript mutations were identified in the sixteen samples for which this analysis was possible. Seven of the nine disease-associated mutations were detected in the 50 men with breast cancers; for thus in our series, BRCA2 mutations account for 14% of male breast cancer, all but one of which had a family history of male and/or female breast cancer.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM, CHEK2, BARD1 and RAD51D.

Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20-50%), and specific locus. Germline PVs in BRCA1 and BRCA2 play important roles in the development of breast and ovarian cancer in particular, as well as in other cancers such as pancreatic and prostate cancers and melanoma. Recent studies suggest that other cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C and RAD51D confer differential risks of breast and other specific cancers. In the era of multigene panel testing, advances in next-generation sequencing technologies have notably reduced costs in the United States (US) and enabled sequencing of BRCA1/2 concomitantly with additional genes. The use of multigene-panel testing is beginning to expand in Europe as well. Further research into the clinical implications of variants in moderate penetrance genes, particularly in unaffected carriers, is needed for appropriate counselling and risk management with data-driven plans for surveillance and/or risk reduction. For individuals at high risk without any pathogenic or likely pathogenic variant in cancer susceptibility genes or some carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2, polygenic risk scores offer promise to help stratify breast cancer risk and guide appropriate risk management options. Cancer patients whose tumours are driven by the loss of function of both copies of a predisposition gene may benefit from therapies targeting the biological alterations induced by the dysfunctional gene e.g. poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in cancers with DNA repair deficiencies. A better understanding of mechanisms by which germline variants drive various malignancies may lead to improvements in both therapeutic and preventive management options.

Does neoadjuvant bevacizumab increase surgical complications in breast surgery?

BACKGROUND: Neoadjuvant chemotherapy is being increasingly used in operable breast cancer. There are limited data on the safety of bevacizumab (bev) in the neoadjuvant setting. We sought to explore the safety of neoadjuvant cisplatin/bev in a protocol for triple negative breast cancer (TNBC). MATERIALS AND METHODS: A total of 51 patients with confirmed TNBC were enrolled in a single-arm trial of neoadjuvant cisplatin plus bev. Of the 51 patients, 28 with confirmed TNBC were enrolled in our trial of single-agent neoadjuvant cisplatin. Two-sided Fisher exact test were used for comparing the 2 trials. RESULTS: The 51 patients received neoadjuvant protocol therapy with cisplatin/bev and underwent definitive local therapy. Breast conserving therapy (BCT) was performed in 29 (57%) and mastectomy with or without reconstruction in 22 (43%). Postoperative complications were reported in 22 patients (43%); 4 (8%) required explanation of expanders. Also, 28 patients completed neoadjuvant cisplatin therapy. BCT was performed in 13 (46%) and mastectomy with or without reconstruction in 15 (54%). Postoperative complications were reported in 11 patients (39%). None of the 5 reconstructions were lost. We compared all toxicities between the two trials (P = .81 NS), and wound healing related complications between the two trials (P = .10 NS). CONCLUSIONS: Cisplatin/bevacizumab and cisplatin alone neoadjuvant therapy resulted in a significant number of postoperative complications. Specifically, use of expanders/implants may be problematic for patients treated with bev. However, this was a single-arm trial; randomized controlled studies will be needed to determine the optimal use of bevacizumab in the timing of breast cancer surgery.

Genetic testing in young women with breast cancer: results from a Web-based survey.

BACKGROUND: Young women with breast cancer have an increased risk for harboring a BRCA1 or BRCA2 mutation. Frequency of genetic testing and factors associated with testing have not been well described in this population. PATIENTS AND METHODS: We evaluated the rate of genetic testing among young breast cancer survivors identified through the Young Survival Coalition (YSC), an advocacy group for young women with breast cancer. Items regarding family history and genetic testing were included in a Web-based cross-sectional survey. RESULTS: A total of 701 women were eligible based on a history of breast cancer diagnosed < or =40 years. Mean age at diagnosis was 32.9 years and mean age at survey 35.7 years. About 41% reported a first- or second-degree relative with breast or ovarian cancer. About 24% had undergone genetic testing, and 26% of those tested reported that a mutation was found. By multivariate logistic regression, likelihood of having undergone testing was higher in women who were younger at diagnosis, were more educated, had a first- or second-degree relative with breast or ovarian cancer, had a mastectomy rather than breast conservation, and considered themselves at high risk for a cancer-predisposing mutation. CONCLUSION: Most women diagnosed with breast cancer < or =40 years do not undergo genetic testing.

Survival of patients with multiple primary malignancies: a study of 783 patients with gastrointestinal stromal tumor.

BACKGROUND: We sought to investigate the characteristics and survival rate of patients with gastrointestinal stromal tumor (GIST) associated with other primary malignancies. PATIENTS AND METHODS: A total of 783 patients with GIST were identified from 1995 to 2007. Additional primaries included tumors not considered metastasis, invasion, or recurrence of GIST, nor non-melanoma skin cancer. Data on gender, age at diagnosis, follow-up time after diagnosis, and death were collected. RESULTS: Of the 783 patients with GIST, 153(20%) were identified with at least one additional primary. Patients with additional primaries were more often men (M : F 1.5 versus 1.3) and older (66 versus 53 years). More patients had another cancer diagnosed before (134) than after (52) GIST. Primaries observed before GIST were cancers of the prostate (25), breast (12), esophagus (9), and kidney (7) and melanoma (6). Lung (5) and kidney (5) primaries were the most frequent after GIST. The 5-year survival was 68% for patients with primaries before GIST, 61% for patients with primaries after GIST, 58% for patients with GIST only, and 49% for patients with two or more primaries in addition to GIST (P = 0.002). CONCLUSIONS: Approximately 20% of patients with GIST develop other cancers. Inferior median 5-year survival was observed in patients with GIST with two or more other cancers. The etiology and clinical implications of other malignancies in patients with GIST should be investigated.

Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.

The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.