Category: Uncategorized

Hem/Onc News For April

Pemetrexed Maintenance Therapy Following Induction Therapy in Advanced NSCLC: Results of the Phase III PARAMOUNT Trial

According to a study in the February 16 online issue of The Lancet Oncology by Paz-Ares and associates, continuation of pemetrexed (Alimta, Eli Lilly) as maintenance therapy significantly reduced the risk of disease progression and was well tolerated in patients with advanced nonsquamous non–small cell lung cancer (NSCLC) who had not progressed after induction therapy with pemetrexed plus cisplatin. In the randomized, double-blind, multicenter phase III PARAMOUNT (Phase III Study of Maintenance Pemetrexed [pem] Plus Best Supportive Care [bsc] Versus Placebo Plus bsc Immediately Following Induction Treatment With Pem Plus Cisplatin for Advanced Nonsquamous Non-Small Cell Lung Cancer [NSCLC]) trial, patients with advanced nonsquamous NSCLC received standard induction therapy with 4 cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on a 21-day cycle. Of the 939 patients who received induction therapy, 539 patients who did not progress and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were subsequently randomized to maintenance therapy with either pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (359 patients) or placebo plus best supportive care (180 patients) until disease progression. Progression-free survival (PFS) was the primary endpoint. Patients who received pemetrexed maintenance therapy had a significant reduction in the risk of disease progression compared to patients who received a placebo (hazard ratio [HR] 0.62; 95% confidence interval [CI], 0.49–0.79; P<.0001). Median PFS was 4.1 months for the pemetrexed arm versus 2.8 months for the placebo arm. Grade 3/4 adverse events that occurred more commonly in the pemetrexed group versus the placebo group were anemia (4% vs <1%), neutropenia (4% vs 0%), and fatigue (4% vs <1%). Patients in the pemetrexed group experienced more grade 3/4 adverse events (9%) than patients in the placebo group (1%). There were 19 patients (5%) in the pemetrexed treatment group and 6 patients (3%) in the placebo group who discontinued treatment due to drug-related adverse events.

 

Origin of Acute Myeloid Leukemia Linked to Founding Clones and Subclones that Cause Myelodysplastic Syndromes 

In order to identify the somatic mutation specific to secondary acute myeloid leukemia (AML), Walter and colleagues performed whole-genome sequencing of 7 paired samples of skin and bone marrow in 7 patients with secondary AML. To establish whether the specific somatic mutations were present at that stage, the investigators then genotyped marrow samples obtained during the antecedent myelodysplastic syndrome (MDS) stage from each patient. The entire clonal structure of each pair of samples from the MDS to the AML stage was analyzed in order to identify recurrent mutations. Regardless of the myeloblast count, there was an approximate 85% clonality between MDS and AML cells from paired bone marrow samples. An antecedent founding clone was observed in each case, containing 182–660 somatic mutations. A new subclone with hundreds of new mutations was also observed to be emerging from the founding clone. At least 1 mutation in a coding gene was present in all founding clones and subclones. Published in the March issue of The New England Journal of Medicine, the study results suggest that AML evolves from the cells that cause MDS after these cells have undergone multiple cycles of mutations and clonal selection.

 

Helicobacter Pylori Eradication Therapy in Early-Stage Gastric Diffuse Large B-Cell Lymphoma

Kuo and coworkers evaluated the efficacy of Helicobacter pylori eradication (HPE) therapy in early-stage gastric diffuse large B-cell lymphoma (DLBCL) without features of mucosa-associated lymphoid tissue (MALT), known as pure (de novo) DLBCL, compared with its efficacy in high-grade transformed tumors (DLBCL with features of MALT; DLBCL[MALT]). The study included 50 patients with stage IE/IIE1, H. pylori–positive gastric DLBCL with frontline HPE. Of the 16 de novo DLBCL patients, 100% experienced successful eradication of H. pylori infection, compared with 32 of the 34 DLBCL(MALT) patients (94.1%). Complete pathologic remission (pCR) following HPE occurred in 68.8% (11/16) of patients with de novo DLBCL and in 56.3% (18/32) of patients with DLBCL(MALT). The median time-to-pCR was 2.1 months for de novo DLBCL patients versus 5 months for DLBCL(MALT) patients (P=.024). With the exception of 1 patient with de novo DLBCL who died of lung cancer, all patients with pCR after HPE were alive and free of lymphoma at a median follow-up of 7.7 years. Results from this explorative study, which were published in the March 7 online issue of Blood, showed that a significant portion of early-stage, H. pylori–positive gastric de novo DLBCL is H. pylori–dependent and responds to antibiotic treatment. Future prospective studies should be considered in order to validate these findings.

 

By Stacey Small


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Gastro/Hep News For April

Colonoscopic Polypectomy Reduces Mortality Due to Colorectal Cancer

The premise underlying surveillance colonoscopy is that early detection and removal of cancerous polyps reduces both the incidence of colorectal cancer and subsequent death. The impact of colonoscopy on colorectal cancer rates has been examined previously, and a study published in The New England Journal of Medicine has now reported the effect of colonoscopy on mortality rates. Using data from patients who underwent colonoscopy between 1980 and 1990 as part of the National Polyp Study, Zauber and coauthors identified 2,602 patients who had adenomas removed during this 10-year period. After a median follow-up period of 15.8 years, a total of 1,246 of these patients had died from any cause, but only 12 of these deaths were due to colorectal cancer. In comparison, the Surveillance Epidemiology and End Results program estimated that there would be 25.4 expected deaths due to colorectal cancer in the general population. Thus, the standardized incidence-based mortality ratio with colonoscopic polypectomy was 0.47 (95% confidence interval [CI], 0.26–0.80), indicating that this procedure reduced mortality by 53%.

In addition to identifying patients from the National Polyp Study who had adenomas removed, the study by Zauber and colleagues also identified 773 patients with nonadenomatous polyps. Mortality in both groups was similar during the first 10 years after polypectomy (relative risk, 1.2; 95% CI, 0.1–10.6). After this period, however—when surveillance for the adenoma group was no longer organized—mortality in the adenoma group rose compared to the nonadenoma group, a finding that reinforces the importance of routine surveillance colonoscopies in patients with advanced adenomas.

 

Vitamin D Intake Is Associated with Reduced Risk of Crohn’s Disease

Using data from the Nurses’ Health Study, Ananthakrishnan and colleagues evaluated vitamin D status and prospectively followed a large cohort of women to determine subsequent diagnoses of Crohn’s disease or ulcerative colitis. The 72,719 women evaluated in this study had completed an assessment of diet and lifestyle in 1986; 25-hydroxy vitamin D prediction scores were then developed using these data, and these scores were validated against measured plasma levels of 25-hydroxy vitamin D. Over the course of almost 1.5 million person-years of follow-up, 122 women were diagnosed with Crohn’s disease, and 123 women were diagnosed with ulcerative colitis.

When the study cohort was organized into quartiles based on vitamin D status, women in the top quartile were found to have a 25-hydroxy vitamin D level of 32.2 ng/mL, while women in the lowest quartile had a level of 22.3 ng/mL. Comparing these 2 groups, the researchers found that women in the highest quartile had a 45% lower risk of developing Crohn’s disease compared to women in the lowest quartile (multivariate-adjusted hazard ratio=0.54; 95% CI, 0.30–0.99). For ulcerative colitis, the multivariate-adjusted hazard ratio was 0.65 (95% CI, 0.34–1.25), but this trend was not statistically significant.

Unlike retrospective studies, which can be limited by reverse causation and/or recall and selection biases, this prospective study used vitamin D levels measured 10–12 years prior to diagnosis, and all cases of Crohn’s disease and ulcerative colitis were confirmed through medical record review. While further studies are needed to determine how vitamin D impacts the pathogenesis of inflammatory bowel disease, this study suggests that measurement of vitamin D levels and/or vitamin D supplementation might be beneficial in patients diagnosed with or at risk for Crohn’s disease or ulcerative colitis. Results of this study were published in the March issue of Gastroenterology.

 

Long-Term Mortality Rate of Live Liver Donors Is Similar to Mortality in the General Population

Given the shortage of organs for liver donation, transplantation of part of the liver from a live donor is increasingly being considered. However, this procedure carries risks for donors, and some donors have died. To examine mortality rates among live liver donors, Muzaale and coauthors followed 4,111 live liver donors over a mean follow-up period of 7.6 years.

Results of this study, which was published in the February issue of Gastroenterology, showed that 7 donors died within 90 days after donation, yielding a rate of 1.7 early deaths per 1,000 (95% CI, 0.7–3.5). Looking at all catastrophic events (early deaths or acute liver failure), this rate was 2.9 per 1,000 (95% CI, 1.5–5.1). Neither the risk of death nor the risk of catastrophic events varied with the age of the recipient (adult vs pediatric) or the portion of the liver donated (left lateral segment, left lobe, or right lobe). In terms of long-term mortality, rates were similar among live liver donors, live kidney donors, and matched healthy participants from the Third National Health and Nutrition Examination Survey (1.2%, 1.2%, and 1.4% at 11 years, respectively; P=.9).

 

By Kay Downer

Clinical Updates Week of March 17, 2012

Link roundup for the week of March 17, 2012

 

Oncology News

MBCC: Emerging Therapies for Triple-Negative Breast Cancer

http://www.cancernetwork.com/conference-reports/mbcc2012/content/article/10165/2045206 

H. pylori Eradication Therapy Is Effective in the Treatment of Early-Stage H. pylori-Positive Gastric Diffuse Large B-Cell Lymphomas

http://oncologystat.com/journals/journal_scans/H._Pylori_Eradication_Therapy_Is_Effective_in_the_Treatment_of_Early-Stage_H._Pylori-Positive_Gastric_Diffuse_Large_B-Cell_Lymphomas.html

Leukemia Arises from ‘Founding Clones’ in MDS

http://www.medpagetoday.com/HematologyOncology/Leukemia/31681

Clonal Architecture of Secondary Acute Myeloid Leukemia

http://www.nejm.org/doi/full/10.1056/NEJMoa1106968

 

Gastro News

Vitamin D Intake Associated With Reduced Risk for Crohn’s Disease

http://www.medscape.org/viewarticle/759732

Abdominal CT Radiation Risk

http://agajournals.wordpress.com/2012/03/05/abdominal-ct-radiation-risk/

Clinical Updates Week of March 3, 2012

Oncology link roundup for the week of March 3, 2012:

A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis 

http://www.nejm.org/doi/full/10.1056/NEJMoa1110557

http://www.newswise.com/articles/drug-improves-survival-and-quality-of-life-for-people-with-myelofibrosis

Breast conserving therapy versus mastectomy for stage I—II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70042-6/abstract

Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy†

http://onlinelibrary.wiley.com/doi/10.1002/cncr.26568/full

FDA Acts to Curb Doxorubicin, Methotrexate Shortages

http://www.oncologystat.com/news/FDA_Acts_to_Curb_Doxorubicin__Methotrexate_Shortages_US.html

Highlights From the 2011 San Antonio Breast Cancer Symposium

December 6–10, 2011 • San Antonio, Texas

Complete abstracts are available at http://www.sabcs.org
Download the pdf of this article at clinicaladvances.com

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P5-19-03    Albumin-Bound Paclitaxel (ab-pac) Versus Docetaxel for First-Line Treatment of Metastatic Breast Cancer (MBC): Overall Survival and Safety Analysis of a Randomized Phase II Trial

WJ Gradishar, D Krasnojon, S Cheporov, AN Makhson, GM Manikhas, A Clawson, P Bhar

Gradishar and colleagues provided updated results of an open-label, multicenter, phase II study that evaluated the safety and efficacy of different dosing regimens of albumin- bound paclitaxel (nab-paclitaxel; Abraxane, Celgene) and docetaxel in the first-line metastatic breast cancer (MBC) treatment setting. Patients were randomized to 1 of the following: nab-paclitaxel 300 mg/m2 every 3 weeks (q3w [arm A; n=76]), nab-paclitaxel 100 mg/m2 the first 3 of 4 weeks (qw 3/4 [arm B; n=76]), nab-paclitaxel 150 mg/m2 qw 3/4 (arm C; n=74), and docetaxel 100 mg/m2 q3w (arm D; n=74). The longest median overall survival (OS) was 33.8 months in arm C (27.7 months, 22.2 months, and 26.6 months for arms A, B, and D, respectively). Progression-free survival (PFS) was 14.6 months in arm C, compared with 10.9 months, 7.5 months, and 7.8 months for arms A, B, and D, respectively. The safety profile of nab-paclitaxel was consistent with previous reports, with grade 3 neuropathy occurring most frequently in arm C (21%, 9%, 22%, and 12% for arms A, B, C, and D, respectively; P=.083). Among patients who received nab-paclitaxel 150 mg/m2 (arm C), the best response occurred at cycle 2, whereas dose reductions due to toxicities occurred at later treatment cycles. Dose reductions occurred in 18%, 17%, 47%, and 28% of patients in arms A, B, C, and D, respectively. The researchers concluded that a 150-mg/m2 weekly dose of nab-paclitaxel may help patients achieve a clinical response before the onset of dose-limiting adverse events.

S3-7    Everolimus for Postmenopausal Women With Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial

GN Hortobagyi, M Piccart, H Rugo, H Burris, M Campone, S Noguchi, M Gnant, KI Pritchard, L Vittori, P Mukhopadhyay, T Sahmoud, D Lebwohl, J Baselga 

The pivotal phase III BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial enrolled 724 postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who recurred or progressed while on or following previous treatment with letrozole or anastrozole. Patients received oral exemestane (Aromasin, Pfizer) 25 mg daily with either everolimus (Afinitor, Novartis) 10 mg daily (n=485) or placebo (n=239). The updated analysis by Hortobagyi and associates was based on a median follow-up of 12.5 months. Investigator-assessed PFS revealed a hazard ratio (HR) of 0.44 (95% confidence interval [CI], 0.36–0.53) and a median duration of 7.4 months (everolimus + exemestane) versus 3.2 months (exemestane alone). Twelve-month estimates of patients without disease progression were 31% and 10% in the everolimus plus exemestane and exemestane-alone arms, respectively. An additional analysis based on an independent central radiology review showed that everolimus extended PFS to 11 months compared to 4.1 months, and 12-month estimates of patients without disease progression were 48% and 18%, respectively. Response rates and clinical benefit rates were higher for patients who received everolimus plus exemestane versus exemestane alone (12% vs 1.3% and 50.5% vs 25.5%, respectively). Side effects were consistent with those previously reported with everolimus. Everolimus increased exemestane steady-state Cmin and Cmax levels by 45% and 64%, respectively, with no difference in estradiol levels. Serum markers of bone resorption and bone formation increased in the exemestane-alone arm, and typically decreased in the everolimus plus exemestane arm.

S5-5    A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial To Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA)

J Baselga, SB Kim, SA Im, R Hegg, YH Im, L Roman, JL Pedrini, J Cortés, A Knott, E Clark, GA Ross, SM Swain

In the randomized, double-blind, placebo-controlled phase III CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study, Baselga and coworkers evaluated the efficacy and safety of pertuzumab combined with trastuzumab (Herceptin, Genentech) and chemotherapy compared to trastuzumab and chemotherapy alone in 808 patients with centrally confirmed, HER2-positive, metastatic or locally recurrent, unresectable breast cancer. Patients received placebo plus trastuzumab and docetaxel (control group) or pertuzumab plus trastuzumab and docetaxel (pertuzumab group) until disease progression or unmanageable toxicities occurred. The median PFS was 12.4 months in the control group versus 18.5 months in the pertuzumab group (P<.001). The interim analysis of OS was performed after 165 events had occurred, and survival data were incomplete at the time of presentation. The overall response rate (ORR) was 80.2% in the pertuzumab group versus 69.3% in the control group (P=.0011). Grade 1/2 diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were more common in the pertuzumab group, and typically occurred during concomitant docetaxel administration. Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group. Study results were simultaneously published in the December 9 online edition of the New England Journal of Medicine.

S1-1    A Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First-Line Therapy for Postmenopausal Women With Metastatic Breast Cancer: SWOG S0226

RS Mehta, WE Barlow, KS Albain, T Vandenberg, SR Dakhil, NR Tirumali, DL Lew, DF Hayes, JR Gralow, RB Livingston, GN Hortobagyi 

In a randomized phase III trial by Mehta and associates, 707 postmenopausal MBC patients received anastrozole (Arimidex, AstraZeneca), either alone or in combination with fulvestrant (Faslodex, AstraZeneca). The median PFS was 13.5 months in the anastrozole-alone arm versus 15 months in the anastrozole plus fulvestrant arm (HR, 0.80; 95% CI, 0.68–0.94). Patients treated with anastrozole plus fulvestrant had a median OS of 47.7 months, compared with 41.3 months for patients treated with anastrozole alone (HR, 0.81; 95% CI, 0.65–1.00). Patients with no prior tamoxifen treatment (60%, n=414) had a median PFS of 12.6 months in the anastrozole-alone arm compared with 17 months in the anastrozole plus fulvestrant arm. Patients who received prior tamoxifen treatment had a median PFS of 14.1 months and 13.5 months for the anastrozole-alone arm and the anastrozole plus fulvestrant arm, respectively. Grade 3 toxicities were reported in 11.4% of patients in the anastrozole-alone arm and in 13.3% of patients in the anastrozole plus fulvestrant arm. Three deaths, 1 grade 4 pulmonary embolism, and 1 grade 4 neutropenia and lymphopenia also occurred in the anastrozole plus fulvestrant arm. Grade 4 toxicities occurred in 4 patients in the anastrozole-alone arm. Only 4 patients in the anastrozole monotherapy arm and 11 patients in the combination arm discontinued treatment due to toxicity.

P5-19-13    A Randomized Phase II Trial of First-Line Metastatic Breast Cancer (MBC) Patients: Sub-Set Analysis of Albumin-Bound Paclitaxel (ab-pac) Given Weekly at 150 mg/m2

WJ Gradishar, D Krasnojon, S Cheporov, AN Makhson, GM Manikhas, A Clawson, P Bhar

An open-label, multicenter, randomized phase II trial evaluated the efficacy and safety of 3 different dosing regimens of nab-paclitaxel versus docetaxel for the first-line treatment of 300 MBC patients. Gradishar and colleagues reported updated results for the 74 patients who were treated with nab-paclitaxel at 150 mg/m2 qw 3/4. Of that subset, 35 patients (47%) required a dose reduction due to toxicity. Investigator-assessed ORR and PFS were numerically higher in patients who had dose reductions (ORR, 80%; median PFS, 14.8 months) versus patients whose dosing remained the same (ORR, 69%; median PFS, 12.8 months). The median OS was 33.8 months for all patients in the subset, 35.2 months for patients who had dose reductions, and 31.8 months for patients without dose reductions. Patients in whom the dose was reduced received a median of 10 cycles of treatment compared with 8 cycles in patients without dose reductions.

S5-7    A Phase 2, Randomized, Open-Label, Study of Neratinib (HKI-272) vs Lapatinib Plus Capecitabine for 2nd/3rd-Line Treatment of HER2+ Locally Advanced or Metastatic Breast Cancer

M Martin, J Bonneterre, CE Geyer, Jr., Y Ito, J Ro, I Lang, S-B Kim, C Germa, J Vermette, ML Vo Van, K Wang, A Awada

Martin and colleagues presented results from a phase II, randomized, open-label study of neratinib (Puma Biotechnology, Inc.) versus lapatinib (Tykerb, Glaxo-SmithKline) in combination with capecitabine (Xeloda, Genentech) in patients with HER2-positive, metastatic or locally advanced breast cancer. Patients had disease progression following prior treatment with trastuzumab and taxane chemotherapy. Patients received either neratinib 240 mg daily (n=117) or lapatinib 1,250 mg daily plus capecitabine 1,000 mg/m2 twice daily on days 1–14 of each 21-day cycle (n=116). For patients in the neratinib arm versus the lapatinib plus capecitabine arm, respectively, 2% and 4% experienced a complete response, 27% and 36% experienced a partial response, and 15% and 23% had stable disease for more than 6 months. The ORR for the neratinib arm was 29%, compared with 40% for the lapatinib plus capecitabine arm. There was a clinical benefit rate of 44% and 63%, respectively. Median PFS was 4.5 months in the neratinib arm and 6.8 months in the lapatinib plus capecitabine arm (P=.231). No unexpected toxicities were reported.

Survival Benefits of Platinum-Based Doublet Chemotherapy in Elderly Patients With NSCLC

In a multicenter, open-label, randomized phase III trial, Quoix and colleagues compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced non–small-cell lung cancer (NSCLC). A total of 451 patients between ages 70 and 89 years with locally advanced or metastatic NSCLC and World Health Organization performance status scores of 0–2 were enrolled. There were 226 patients who received 5 cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Doublet chemotherapy, consisting of 4 cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) was administered in 225 patients. The median overall survival was 10.3 months among patients treated with combination chemotherapy and 6.2 months among patients treated with monotherapy (hazard ratio [HR] 0.64; 95% confidence interval [CI], 0.52–0.78; P<.0001). The 1-year survival was 44.5% (95% CI, 37.9–50.9%) in the doublet chemotherapy arm and 25.4% (95% CI, 19.9–31.3%) in the monotherapy arm. Toxicities occurred more frequently in the doublet chemotherapy arm versus the monotherapy arm, including decreased neutrophil count (48.4% vs 12.4%, respectively) and asthenia (10.3% vs 5.8%, respectively). The study was published in the September issue of The Lancet. Despite the increased toxicities of platinum-based doublet chemotherapy, the results suggest that elderly patients with advanced NSCLC can be considered for the same aggressive therapy as younger patients; additional research is warranted.

CHEK2 Mutations and Family History in Predicting Risk of Breast Cancer

In order to investigate the relationships among CHEK2 mutations, family history of breast cancer, and the risk of breast cancer, Cybulksi and associates conducted a prospective study that included 7,494 BRCA1 mutation–negative patients with breast cancer and 4,346 control women. Family history of breast cancer in first-degree and second-degree relatives was considered. Study participants were genotyped for 4 founder mutations in CHEK2. A total of 227 patients with breast cancer (3%) and 37 controls (0.8%) had a truncating CHEK2 mutation (odds ratio [OR], 3.6; 95% CI, 2.6–5.1). Women who had a first- or second-degree relative with breast cancer had a higher OR (OR, 5.0; 95% CI, 3.3–7.6) than those with no family history of the disease (OR, 3.3; 95% CI, 2.3–4.7). The OR was 7.3 (95% CI, 3.2–16.8) if both a first- and second-degree relative had breast cancer. Assuming a 6% baseline risk of breast cancer (the general population risk in Poland), the lifetime risk of breast cancer for a woman with a CHEK2 mutation was estimated to be 20% if there was no family history of breast cancer, 28% if a second-degree relative had breast cancer, 34% if a first-degree relative had breast cancer, and 44% if both a first- and second-degree relative had breast cancer. The study was published in the August 29 online issue of the Journal of Clinical Oncology. Although gene mutations and baseline risks of breast cancer differ across countries, these results suggest that CHEK2 gene mutations do contribute to some cases of breast cancer, and that risk may be particularly high for women who have both a CHEK2 gene mutation and a family history of the disease.