Publications by authors named "Christian F Singer"

231 Publications

Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer.

NPJ Breast Cancer 2020 Sep 10;6(1):44. Epub 2020 Sep 10.

Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON, Canada.

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.
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http://dx.doi.org/10.1038/s41523-020-00185-6DOI Listing
September 2020

Weight Gain and the Risk of Ovarian Cancer in and Mutation Carriers.

Cancer Epidemiol Biomarkers Prev 2021 Aug 23. Epub 2021 Aug 23.

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.

Background: Weight gain and other anthropometric measures on the risk of ovarian cancer for women with mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among and mutation carriers.

Methods: In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer.

Results: This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; = 0.02). Current BMI of 26.5 kg/m or greater was associated with an increased risk of ovarian cancer in mutation carriers, compared with those with a BMI less than 20.8 kg/m (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer.

Conclusions: Adult weight gain is a risk factor for ovarian cancer in women with a or mutation.

Impact: These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0296DOI Listing
August 2021

The OncoMasTR test predicts distant recurrence in estrogen receptor-positive, HER2-negative early-stage breast cancer: A validation study in ABCSG Trial 8.

Clin Cancer Res 2021 Aug 11. Epub 2021 Aug 11.

Breast Centre, Hirslanden Klinik St. Anna.

Purpose: To validate the clinical performance of the OncoMasTR Risk Score in the biomarker cohort of ABCSG Trial 8.

Experimental Design: We evaluated the OncoMasTR test in 1200 formalin-fixed, paraffin-embedded surgical specimens from postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer with 0-3 involved lymph nodes in the prospective, randomized ABCSG Trial 8. Time to distant recurrence (DR) was analyzed by Cox models.

Results: The OncoMasTR Risk Score categorized 850 of 1087 (78.2%) evaluable patients as "low risk". At 10 years, the DR rate for patients in the low-risk group was 5.8% versus 21.1% for patients in the high-risk group (P<0.0001, absolute risk reduction 15.3%). The OncoMasTR Risk Score was highly prognostic for prediction of DR in years 0-10 in all patients (hazard ratio (HR) 1.91, 95% confidence interval (CI) 1.62 to 2.26, P<0.0001; C-index 0.73), in node-negative patients (HR 1.79, 95% CI 1.43 to 2.24, P<0.0001; C-index 0.72), and in patients with 1-3 involved lymph nodes (HR 1.93, 95% CI 1.44 to 2.58, P<0.0001; C-index 0.71). The OncoMasTR Risk Score provided significant additional prognostic information beyond clinical parameters, Ki67, Nottingham Prognostic Index, and Clinical Treatment Score.

Conclusions: OncoMasTR Risk Score is highly prognostic for DR in postmenopausal women with ER-positive, HER2-negative primary breast cancer with 0-3 involved lymph nodes. In combination with prior validation studies, this fully independent validation in ABCSG Trial 8 provides level 1B evidence for the prognostic capability of the OncoMasTR Risk Score.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1023DOI Listing
August 2021

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer.

N Engl J Med 2021 07;385(5):395-405

From the Comprehensive Cancer Center (M.G., C.F.S., C.D., F.F., K.W., S.K.-S.), the Department of General Surgery (F.F., K.W., S.K.-S.), the Department of Internal Medicine I, Division of Oncology (G.G.S., R.B.), and the Department of Obstetrics and Gynecology (C.F.S., C.D.), Medical University of Vienna, Austrian Breast and Colorectal Cancer Study Group (M.G., R.J., L.S., C.F.), Breast Care Center, Hanusch Hospital (U.W.), the Department of Gynecology, Hospital Hietzing, and Karl Landsteiner Institute for Gynecological Oncology and Senology (P.S.), Vienna, the Department of Internal Medicine III and Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, Paracelsus Medical University Salzburg, Salzburg (G.R., S.G.-R., S.P.G., R.G.), the Departments of Oncology (M.B., C.S.) and Gynecology (V.B.-R.), Medical University Graz, Graz, the Department of Surgery, Ordensklinikum Linz, Linz (D.H.), the Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels (J.T.), the Department of Gynecology, Medical University Innsbruck, Innsbruck (D.E., C.B.), Doctor's Office Manfreda, Klagenfurt (D.M.), the Department of Surgery, Hospital Wolfsberg, Wolfsberg (E.M.-Z.), the Department of Internal Medicine, Hospital Vöcklabruck, Vöcklabruck (F.H.), the Department of Surgery, General Hospital Baden, Baden (H.T.), and the Breast Center, Doctor's Office Wette, Sankt Veit an der Glan (V.W.) - all in Austria; and the Breast Unit, University Hospital Helios, University Witten Herdecke, Wuppertal, Germany (V.B.-R.).

Background: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear.

Methods: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture.

Results: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84).

Conclusions: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).
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http://dx.doi.org/10.1056/NEJMoa2104162DOI Listing
July 2021

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.
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http://dx.doi.org/10.1093/jnci/djab147DOI Listing
July 2021

Radiotherapy-Induced Fatigue in Breast Cancer Patients.

Breast Care (Basel) 2021 Jun 14;16(3):236-242. Epub 2020 Aug 14.

Department of Obstetrics and Gynecology, Division of Gynecology and Gynecologic Oncology, Medical University of Vienna, Vienna, Austria.

Background: A large proportion of breast cancer patients who undergo adjuvant radiotherapy suffer from radiotherapy-induced fatigue. The possible causative factors of this specific side effect are diverse.

Summary: Prevalence, duration, and severity of radiotherapy-induced fatigue are dependent on the type of radiotherapy, as well as on the irradiated volume, dose scheme, on the number of radiation fields, the combination with other treatments, diurnal rhythm, smoking, and time-to-hospitalization. Recommended treatments include non-pharmacologic interventions, such as physical and psychosocial interventions. Pharmacologic therapies include treatment with methylphenidate and modafinil. In addition to its early detection with standardized instruments, adequate education to breast cancer patients about risks and predisposing factors of radiotherapy-induced fatigue is essential. Multidimensional strategies help to maintain the patients' quality of life and therefore guarantee treatment adherence and efficacy.

Key Messages: Radiotherapy-induced fatigue is an underreported, underdiagnosed, and undertreated side effect. This review provides an overview of radiotherapy-induced fatigue in breast cancer patients receiving adjuvant radiotherapy.
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http://dx.doi.org/10.1159/000509410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248773PMC
June 2021

Genetic Testing in Breast Cancer: New Standards of Care.

Breast Care (Basel) 2021 Jun 2;16(3):193-195. Epub 2021 Jun 2.

Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1159/000516788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248776PMC
June 2021

Reliability of Tumor Testing Compared to Germline Testing for Detecting BRCA1 and BRCA2 Mutations in Patients with Epithelial Ovarian Cancer.

J Pers Med 2021 Jun 24;11(7). Epub 2021 Jun 24.

Comprehensive Cancer Center, Gynecologic Cancer Unit, Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, A-1090 Vienna, Austria.

Background: BRCA 1/2 mutation status has become one of the most important parameters for treatment decision in patients with epithelial ovarian cancer (EOC). The aim of this study was to compare tumor DNA with blood DNA sequencing to evaluate the reliability of BRCA tumor testing results.

Methods: Patients who were treated for EOC between 2003 and 2019 at the Medical University of Vienna and underwent both germline (gBRCA) and tumor (tBRCA) testing for BRCA mutations were identified. We calculated the concordance rate and further analyzed discordant cases.

Results: Out of 140 patients with EOC, gBRCA mutation was found in 47 (33.6%) and tBRCA mutation in 53 (37.9%) patients. Tumor testing identified an additional 9/140 (6.4%) patients with somatic BRCA mutation and negative germline testing. The comparison of germline testing with tumor testing revealed a concordance rate of 93.5% and a negative predictive value of tumor testing of 96.0%. After BRCA variants of uncertain significance were included in the analysis, concordance rate decreased to 90.9%.

Conclusion: Tumor testing identified the majority of pathogenic germline BRCA mutations but missed three (2.1%) patients. In contrast, nine (6.4%) patients harboring a somatic BRCA mutation would have been missed by gBRCA testing only.
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http://dx.doi.org/10.3390/jpm11070593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305542PMC
June 2021

Invasive lobular carcinoma: clinicopathological features and subtypes.

J Int Med Res 2021 Jun;49(6):3000605211017039

Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.

Objective: To analyze the characteristics of invasive lobular carcinoma (ILC) compared with invasive ductal carcinoma (IDC) and to investigate the impact of histology on axillary lymph node (ALN) involvement in luminal A subtype tumors.

Methods: We retrospectively analyzed patients diagnosed with ILC or IDC from 2012 to 2016 who underwent surgery. Patients constituted 493 primary early breast cancer cases (82 ILC; 411 IDC).

Results: Compared with IDC, ILC tumors were significantly more likely to be grade 2, estrogen receptor- (ER) positive (+), have a lower proliferation rate (Ki67 <14%), and a higher pathological T stage (pT2-4). The luminal A subtype was significantly more common in ILC compared with IDC. In a multivariate regression model, grade 2, ER+, progesterone receptor-positive, pT2, and pT3 were significantly associated with ILC. Additionally, with the luminal A subtype, ALN involvement (pathological node stage (pN)1-3) was significantly more frequent with ILC versus IDC.

Conclusions: Our data suggest that grade 2, positive hormone receptor status, and higher pathological T stage are associated with ILC. With the luminal A subtype, ALN involvement was more frequent with ILC versus IDC.
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http://dx.doi.org/10.1177/03000605211017039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258769PMC
June 2021

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
June 2021

Extraosseous osteoblastoma: A rare cause of breast mass in a prepubertal girl.

Clin Case Rep 2021 May 31;9(5):e04094. Epub 2021 Mar 31.

Department of Obstetrics and Gynecology Medical University of Vienna Vienna Austria.

Extraosseous osteoblastoma of the breast, a rare disease, was diagnosed in a prepubertal girl. After tumor excision, the patient recovered well and an optimal cosmetic result was achieved. Interdisciplinary discussions about the case are essential.
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http://dx.doi.org/10.1002/ccr3.4094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142408PMC
May 2021

Nonsurgical Prevention Strategies in and Mutation Carriers.

Breast Care (Basel) 2021 Apr 11;16(2):144-148. Epub 2020 May 11.

Department of Obstetrics and Gynecology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Female carriers of a or germline mutation face a high lifetime risk to develop breast and ovarian cancer. Risk-reducing surgery, such as prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy, are proven strategies to prevent breast and ovarian cancer. These procedures are, however, associated with considerable side effects, and the uptake of these highly effective interventions is therefore low in many countries. This highlights the need for alternative and noninvasive strategies for risk reduction in mutation carriers.

Summary: While endocrine treatments with tamoxifen and aromatase inhibitors (AI) have been shown to be effective in secondary prevention, their benefit in primary prevention has never been prospectively evaluated. Moreover, their side effect profile makes them inappropriate candidates for chemoprevention in healthy premenopausal women. Recently, denosumab, a well-tolerated osteoprotective drug, has been shown to have an antitumoral effect on RANK+, -deficient luminal progenitor cells in vitro, and has been demonstrated to abrogate tumors in -deficient mouse models.

Key Message: The prospectively randomized, double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy germline mutation carriers.
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http://dx.doi.org/10.1159/000507503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114042PMC
April 2021

Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34.

Br J Cancer 2021 May 24;124(11):1795-1802. Epub 2021 Mar 24.

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.

Background: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences.

Methods: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint.

Results: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation.

Conclusion: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.
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http://dx.doi.org/10.1038/s41416-021-01284-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144560PMC
May 2021

Decision theory for precision therapy of breast cancer.

Sci Rep 2021 Feb 19;11(1):4233. Epub 2021 Feb 19.

Section of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.

Correctly estimating the hormone receptor status for estrogen (ER) and progesterone (PGR) is crucial for precision therapy of breast cancer. It is known that conventional diagnostics (immunohistochemistry, IHC) yields a significant rate of wrongly diagnosed receptor status. Here we demonstrate how Dempster Shafer decision Theory (DST) enhances diagnostic precision by adding information from gene expression. We downloaded data of 3753 breast cancer patients from Gene Expression Omnibus. Information from IHC and gene expression was fused according to DST, and the clinical criterion for receptor positivity was re-modelled along DST. Receptor status predicted according to DST was compared with conventional assessment via IHC and gene-expression, and deviations were flagged as questionable. The survival of questionable cases turned out significantly worse (Kaplan Meier p < 1%) than for patients with receptor status confirmed by DST, indicating a substantial enhancement of diagnostic precision via DST. This study is not only relevant for precision medicine but also paves the way for introducing decision theory into OMICS data science.
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http://dx.doi.org/10.1038/s41598-021-82418-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895957PMC
February 2021

Tissue Sodium Concentration Quantification at 7.0-T MRI as an Early Marker for Chemotherapy Response in Breast Cancer: A Feasibility Study.

Radiology 2021 04 16;299(1):63-72. Epub 2021 Feb 16.

From the Institute for Clinical Molecular MRI in Musculoskeletal System, Karl Landsteiner Society, Vienna, Austria (O.Z., S.T.); Breast Health Center, Department of Obstetrics and Gynecology (A.F., E.A., C.F.S.), and High Field MR Center, Department of Biomedical Imaging and Image-guided Therapy (L.M., M.W., S.T.), Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany (S.L., A.M.N.); and Christian Doppler Laboratory for Clinical Molecular MRI, Christian Doppler Forschungsgesellschaft, Vienna, Austria (S.T.).

Background Tissue sodium concentration (TSC) is elevated in breast cancer and can determine chemotherapy response. Purpose To test the feasibility of using a sodium 23 (Na) MRI protocol at 7.0 T for TSC quantification to predict early treatment outcomes of neoadjuvant chemotherapy in breast cancer and to determine whether those quantitative values provide additional information about efficacy. Materials and Methods Women with primary breast cancer were included in this prospective study. From July 2017 to June 2018, participants underwent 7.0-T Na MRI. Multichannel data sets were acquired with a density-adapted, three-dimensional radial projection reconstruction pulse sequence. Two-dimensional tumor size and TSC were evaluated before and after the first and second chemotherapy cycle, and statistical tests were performed based on the presence or absence of a pathologic complete response (pCR). Results Fifteen women with breast cancer and six healthy women were enrolled. The mean baseline tumor size in women with a pCR was 7.0 cm ± 5.0 (standard deviation), and the mean baseline tumor size in women without a pCR was 19.0 cm ± 12.0. After the first chemotherapy cycle, women with a pCR showed a reduced tumor size of 32.9% (2.3 cm/7.0 cm), compared with 15.3% (2.9 cm/19.0 cm) in those without a pCR. The areas under the receiver operating characteristic curve for tumor size reduction after the first and second chemotherapy cycle were 0.73 (95% CI: 0.09, 0.50; = .12) and 0.93 (95% CI: 0.04, 0.60; < .001), respectively. Women with a pCR had a mean baseline TSC of 69.4 mmol/L ± 6.1, with a reduction of 12.0% (8.3 mmol/L), whereas those without a pCR had a mean baseline TSC of 71.7 mmol/L ± 5.7, with a reduction of 4.7% (3.4 mmol/L) after the first cycle. The areas under the receiver operating characteristic curve for TSC after the first and second cycles were 0.96 (95% CI: 0.86, 1.00; < .001) and 1.000 (95% CI: 1.00, < .001), respectively. Conclusion Using 7.0-T MRI for tissue sodium concentration quantification to predict early treatment outcomes of neoadjuvant chemotherapy in breast cancer is feasible, with reduced tissue sodium concentration indicative of cancer response. © RSNA, 2021
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http://dx.doi.org/10.1148/radiol.2021201600DOI Listing
April 2021

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study.

Am J Obstet Gynecol 2021 07 22;225(1):51.e1-51.e17. Epub 2021 Jan 22.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Background: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer.

Objective: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates.

Study Design: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use.

Results: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; P=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size.

Conclusion: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
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http://dx.doi.org/10.1016/j.ajog.2021.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278569PMC
July 2021

Receptor Discordance of Metastatic Breast Cancer Depending on the Molecular Subtype.

Breast Care (Basel) 2020 Dec 17;15(6):648-654. Epub 2020 Mar 17.

Breast Health Center, Division of Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.

Introduction: Almost 30% of all women with early-stage breast cancer develop metastases. Treatment of metastatic disease is often based on the immunohistochemical information of the primary tumor, despite possible discordance of the hormone and Her2 receptor status.

Objectives: The aim of this study was to compare the receptor status of the primary tumor with the metastasis, and to evaluate for receptor discordance with regard to the molecular subtype, receptor status, and the localization of the metastases.

Methods: We retrospectively analyzed the data of all consecutive women with metastatic breast cancer, who underwent treatment at the Medical University Vienna between 2009 and 2016. Associations were calculated using the χor Fisher's exact test; years from primary diagnosis to metastatic disease were calculated using the Kaplan-Meier method.

Results: We identified 213 metastatic breast cancer patients, of whom 67 (31.5%) showed a discordant receptor status. Out of 32 patients with luminal A subtype, 14 (43.8%) had a switch of at least one receptor; 27 of 53 patients (50.9%) with luminal B subtype and 21 of 32 patients (65.6%) with Her2+ subtype showed receptor discordance; for triple-negative disease, 5 of 19 patients (36.3%) had a switch of at least one receptor. In 63 samples of bone metastases, 13 (20.6%) had discordant estrogen receptor status ( = 0.04). In 55 samples of bone metastases, 35 (63.3%) had discordant Her2 status ( = 0.002).

Conclusions: Our data show high rates of receptor discordance in metastatic breast cancer. Apart from the primary tumor, the immunohistochemical receptor status of the metastasis needs to be verified. This can lead to a change in treatment and prognosis.
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http://dx.doi.org/10.1159/000506464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768158PMC
December 2020

Expression of COX-2, p16, and Ki67 in the range from normal breast tissue to breast cancer.

Neoplasma 2021 Mar 5;68(2):342-351. Epub 2020 Nov 5.

2nd Department of Gynecology and Obstetrics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.

The increasing number of diagnosed breast lesions lead to the critical need for new markers that would elucidate the process of tumorigenesis. The objective of the study was to examine COX-2, p16, and Ki67 expression in a broad spectrum of breast lesions in order to define the proteins' phenotype throughout the tumorigenesis. Expression was studied by immunohistochemistry in 308 human breast samples divided into 7 subgroups - flat epithelial atypia (FEA), atypical hyperplasia (ADH), intraductal carcinoma (DCIS), invasive cancer (IC), benign lesions (BLs), normal tissue adjacent to breast cancer (CANT), and fatty tissue (FT). Analysis among 4 subgroups - premalignant lesions (DIN), IC, BLs, and normal tissue was also performed. High prevalence of COX-2 overexpression was found in all breast lesions including BLs (70% FEA, 89% ADH, 86% DCIS, 81% IC, 44% CANT, 92% BLs, 29% FT). Significant dominance of p16 overexpression was found in premalignant lesions and BLs (50% FEA, 67% ADH, 50% DCIS, 37% IC, 8% CANT, 58% BLs, 21% FT). The location of staining within p16+ cells differed - BLs showed nuclear positivity, whereas in IC it was exclusively cytoplasmic. Premalignant lesions showed all types of p16 positivity. Significantly higher prevalence of COX-2+p16+Ki67+ phenotype was in premalignant tumors with the highest prevalence in ADH (40% of FEA, 67% ADH, 35% DCIS, 20% IC, 3% CANT, 20% BLs, 14% FT). Our observations showed a high prevalence of COX-2+p16+Ki67+ phenotype in premalignant lesions. Further studies are needed in order to elucidate if this phenotype reflects any specific pathway of future progression of premalignant breast lesions.
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http://dx.doi.org/10.4149/neo_2020_200731N798DOI Listing
March 2021

Breastfeeding and the risk of epithelial ovarian cancer among women with a BRCA1 or BRCA2 mutation.

Gynecol Oncol 2020 12 30;159(3):820-826. Epub 2020 Sep 30.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Electronic address:

Objective: BRCA mutation carriers face a high lifetime risk of developing ovarian cancer. The strong inverse association between breastfeeding and the risk of ovarian cancer is established in the general population but is less well studied among women with a germline BRCA1 or BRCA2 mutation.

Method: Thus, we conducted a matched case-control analysis to evaluate the association between breastfeeding history and the risk of developing ovarian cancer. After matching for year of birth, country of residence, BRCA gene and personal history of breast cancer, a total of 1650 cases and 2702 controls were included in the analysis. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) associated with various breastfeeding exposures.

Results: A history of ever-breastfeeding was associated with a 23% reduction in risk (OR = 0.77; 95%CI 0.66-0.90; P = 0.001). The protective effect increased with breastfeeding from one month to seven months after which the association was relatively stable. Compared to women who never breastfed, breastfeeding for seven or more months was associated with a 32% reduction in risk (OR = 0.68; 95%CI 0.57-0.81; P < 0.0001) and did not vary by BRCA gene or age at diagnosis. The combination of breastfeeding and oral contraceptive use was strongly protective (0.47; 95%CI 0.37-0.58; P < 0.0001).

Conclusions: These findings support a protective effect of breastfeeding for at least seven months among women with a BRCA1 or BRCA2 mutation, that is independent of oral contraceptive use.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.037DOI Listing
December 2020

Non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes.

Horm Mol Biol Clin Investig 2020 May 7;41(3). Epub 2020 May 7.

Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Wien, Austria.

Objectives To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Content Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Summary and outlook Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.
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http://dx.doi.org/10.1515/hmbci-2019-0057DOI Listing
May 2020

Association of germline variation with the survival of women with pathogenic variants and breast cancer.

NPJ Breast Cancer 2020 10;6:44. Epub 2020 Sep 10.

Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON Canada.

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in or genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30,  = 3.1 × 10). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.
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http://dx.doi.org/10.1038/s41523-020-00185-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483417PMC
September 2020

Microarray Normalization Revisited for Reproducible Breast Cancer Biomarkers.

Biomed Res Int 2020 6;2020:1363827. Epub 2020 Aug 6.

Section of Biosimulation and Bioinformatics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.

Precision medicine for breast cancer relies on biomarkers to select therapies. However, the reliability of biomarkers drawn from gene expression arrays has been questioned and calls for reassessment, in particular for large datasets. We revisit widely used data-normalization procedures and evaluate differences in outcome in order to pinpoint the most reliable reprocessing methods biomarkers can be based upon. We generated a database of 3753 breast cancer patients out of 38 studies by downloading and curating patient samples from NCBI-GEO. As gene-expression biomarkers, we select the assessment of receptor status and breast cancer subtype classification. Each normalization procedure is applied separately, and biomarkers are then evaluated for each patient. Differences between normalization pipelines are quantified as percentages of patients having outcomes different for each pipeline. Some normalization procedures lead to quite consistent biomarkers, differing only in 1-2% of patients. Other normalization procedures-some of them have been used in many clinical studies-end up with distrusting discrepancies (10% and more). A good deal of doubt regarding the reliability of microarrays may root in the haphazard application of inadequate preprocessing pipelines. Several modes of batch corrections are evaluated regarding a possible improvement of receptor prediction from gene expression versus the golden standard of immunohistochemistry. Finally, we nominate those normalization methods yielding consistent and trustable results. Adequate bioinformatics data preprocessing is key and crucial for any subsequent statistics to arrive at trustable results. We conclude with a suggestion for future bioinformatics development to further increase the reliability of cancer biomarkers.
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http://dx.doi.org/10.1155/2020/1363827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428878PMC
April 2021

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Genet Med 2020 10 15;22(10):1653-1666. Epub 2020 Jul 15.

Royal Devon & Exeter Hospital, Department of Clinical Genetics, Exeter, UK.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10) carriers. The associations in the prospective cohort were similar.

Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
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http://dx.doi.org/10.1038/s41436-020-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521995PMC
October 2020

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

JAMA Oncol 2020 08;6(8):1218-1230

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

Design, Setting, And Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

Main Outcomes And Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.

Conclusions And Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
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http://dx.doi.org/10.1001/jamaoncol.2020.2134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333177PMC
August 2020

Predictive Value of Molecular Subtypes in Premenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the ABCSG Trial 5.

Clin Cancer Res 2020 11 16;26(21):5682-5688. Epub 2020 Jun 16.

Institute of Cancer Research, Department of Medicine I, Breast Health Center and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy.

Experimental Design: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors.

Results: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: = 0.84 for RFS; = 0.69 for OS).

Conclusions: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0673DOI Listing
November 2020

The EndoPredict score predicts response to neoadjuvant chemotherapy and neoendocrine therapy in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients from the ABCSG-34 trial.

Eur J Cancer 2020 07 2;134:99-106. Epub 2020 Jun 2.

Institute of Cancer Research, Department of Medicine I, Breast Health Center and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Neoadjuvant chemotherapy (NaCT) and neoadjuvant endocrine therapy (NET) can reduce pre-operative tumour burden in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. This prospective translational study assessed the ability of a 12-gene molecular score (MS; EndoPredict®) to predict response to NaCT or NET within the ABCSG-34 trial.

Patients And Methods: Hormone receptor (HR)-positive, HER2-negative samples from patients in the ABCSG-34 randomized phase II trial were selected and EndoPredict testing was performed to generate a 12-gene MS. ABCSG-34 patients were assigned to receive either NaCT or NET based on menopausal status, HR expression, grade and Ki67. Response was measured by residual cancer burden (RCB).

Results: Patients selected for NaCT generally had high-risk disease by 12-gene MS (125/134), while slightly more patients treated with NET had low-risk disease (44/83). Low-risk NaCT-treated and high-risk NET-treated tumours responded poorly (NPV 100% [95% CI 66.4%-100%] and NPV 92.3% [95% CI 79.1%-98.4%], respectively]. The 12-gene MS significantly predicted treatment response for NaCT (AUC 0.736 [95% CI 0.63-0.84]) and NET (AUC 0.726 [95% CI 0.60-0.85]).

Conclusions: The 12-gene MS predicted RCB after treatment with neoadjuvant therapies for patients with HR-positive, HER2-negative early-stage breast cancer. Tumours with low MS were unlikely to benefit from NaCT, whereas a high MS predicted resistance to NET. This additional biologic information can aid personalized treatment selection in daily practice and builds a strong rationale to use EndoPredict in biomarker-driven studies in the neoadjuvant setting.
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http://dx.doi.org/10.1016/j.ejca.2020.04.020DOI Listing
July 2020

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

Factors influencing agreement of breast cancer luminal molecular subtype by Ki67 labeling index between core needle biopsy and surgical resection specimens.

Virchows Arch 2020 Oct 7;477(4):545-555. Epub 2020 May 7.

Department of Pathology and Comprehensive Cancer Center, Medical University of Vienna, 18-20 Waehringer Guertel, A-1090, Vienna, Austria.

Reliable determination of Ki67 labeling index (Ki67-LI) on core needle biopsy (CNB) is essential for determining breast cancer molecular subtype for therapy planning. However, studies on agreement between molecular subtype and Ki67-LI between CNB and surgical resection (SR) specimens are conflicting. The present study analyzed the influence of clinicopathological and sampling-associated factors on agreement. Molecular subtype was determined visually by Ki67-LI in 484 pairs of CNB and SR specimens of invasive estrogen receptor (ER)-positive, human epidermal growth factor (HER2)-negative breast cancer. Luminal B disease was defined by Ki67-LI > 20% in SR. Correlation of molecular subtype agreement with age, menopausal status, CNB method, Breast Imaging Reporting and Data System imaging category, time between biopsies, type of surgery, and pathological tumor parameters was analyzed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. CNB had a sensitivity of 77.95% and a specificity of 80.97% for identifying luminal B tumors in CNB, compared with the final molecular subtype determination after surgery. The correlation of Ki67-LI between CNB and SR was moderate (ROC-AUC 0.8333). Specificity and sensitivity for CNB to correctly define molecular subtype of tumors according to SR were significantly associated with tumor grade, immunohistochemical progesterone receptor (PR) and p53 expression (p < 0.05). Agreement of molecular subtype did not significantly impact RFS and OS (p = 0.22 for both). The identified factors likely mirror intratumoral heterogeneity that might compromise obtaining a representative CNB. Our results challenge the robustness of a single CNB-driven measurement of Ki67-LI to identify luminal B breast cancer of low (G1) or intermediate (G2) grade.
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http://dx.doi.org/10.1007/s00428-020-02818-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508960PMC
October 2020

Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomised, neoadjuvant phase II study (ABCSG 34).

Eur J Cancer 2020 06 20;132:43-52. Epub 2020 Apr 20.

Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients.

Patients And Methods: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life.

Findings: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone.

Interpretation: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.ejca.2020.03.018DOI Listing
June 2020

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987299PMC
July 2020
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