Cancer genetics in oncology practice

Cancer is a genetic disease caused by the progressive accumulation of mutations in critical genes that control cell growth and differentiation. Completion of the Human Genome Project promises to revolutionize the practice of Medicine, especially Oncology care. The tremendous gains in the knowledge of the structure and function of human genes will surely impact the diagnosis, prognosis and treatment of cancer. Moreover, it will lead to more effective cancer control through the use of genetics to quantify individual cancer risks. This article reviews the current status of genetic testing and counseling for cancer risk assessment and will suggest a framework for integrating such counseling into oncology practic

Evidence-based management options for women at increased breast/ovarian cancer risk

Recent developments in our ability to predict breast cancer risk necessitates primary care physicians learn to evaluate breast cancer risk and its importance in shaping decisions concerning surveillance and risk reduction measures. This article reviews the current opinion on risk assessment and management of women with an increased risk of breast/ovarian cancer. Management options are given for women at slightly, moderately and highly elevated breast cancer risk, as well as for BRCA1/2 carriers, based on currently available evidenc

Key messages for communicating information about BRCA1 and BRCA2 to women with breast or ovarian cancer: Consensus across health professionals and service users

Copyright © 2017 John Wiley & Sons, Ltd. Background: Genetic testing of cancer predisposing genes will increasingly be needed in oncology clinics to target cancer treatment. This Delphi study aimed to identify areas of agreement and disagreement between genetics and oncology health professionals and service users about the key messages required by women with breast/ovarian cancer who undergo BRCA1/BRCA2 genetic testing and the optimal timing of communicating key messages. Methods: Participants were 16 expert health professionals specialising in oncology/genetics and 16 service users with breast/ovarian cancer and a pathogenic BRCA1/BRCA2 variant. Online questionnaires containing 53 inductively developed information messages were circulated to the groups separately. Participants rated each message as key/not key on a Likert scale and suggested additional messages. Questionnaires were modified according to the feedback and up to 3 rounds were circulated. Consensus was reached when there was ≥75% agreement. Results: Thirty key messages were agreed by both groups with 7 of the key messages agreed by ≥95% of participants: dominant inheritance, the availability of predictive testing, the importance of pretest discussion, increased risk of breast and ovarian cancer, and the option of risk-reducing mastectomy and bilateral salpingo-oophorectomy. Both groups agreed that key messages should be communicated before genetic testing and once a pathogenic variant has been identified. Conclusions: There was a high level of agreement within and between the groups about the information requirements of women with breast/ovarian cancer about BRCA1/BRCA2. These key messages will be helpful in developing new approaches to the delivery of information as genetic testing becomes further integrated into mainstream oncology services

Selection and immunomagnetic purging of peripheral blood CD34+ cells for autologous transplantation in B-cell non-Hodgkin's lymphomas

Background: Clonogenic tumor cells in the hematopoietic progenitor cell harvest may contribute to relapse after high dose therapy for B-cell malignancies. Purging of the HPC harvest requires large amounts of anti-B-cell antibodies, whereas CD34-selection enriches self renewing HPC's but malignant cells are still detectable in many CD34+ fractions. Patients and methods: We examined the feasability and safety of a CD34-selection followed by purging with anti-B-cell antibodies in 11 patients with B-cell non-Hodgkin's lymphomas undergoing high-dose therapy with cyclophospha-mide, BCNU and etoposide with retransfusion of autologous HPC's. Results: A mean number of 340 × 108 mononuclear cells was used for CD34-selection and immunomagnetic purging. CD34+ cells were enriched from a mean of 1.7% (range 0.2%-4.5%) to a mean of 68% (range 49%-87%) with a mean recovery of 27% (range 15%-43%). The mean number of retransfused CD34+ cells was 1.2× 106/kg (range 0.6-2.2 ×106/kg) body weight with a median of 11 days (range 10-13 days) to neutrophil recovery of 0.5×109/1 and 17 days (range 13-25 days) to platelet recovery of 50 × 109/1. Mean number of intravenous antibiotics and inpatient days were 8 (range 0-14) and 22 (range 19-26) respectively. Major toxicity consisted in four septicemias. Conclusions: CD34-selected and purged HPC's are safe and mediate rapid hematological recovery after high dose therapy for B-cell non-Hodgkin's lymphoma

Selection and immunomagnetic purging of peripheral blood CD34+ cells for autologous transplantation in B-cell non-Hodgkin's lymphomas

Background: Clonogenic tumor cells in the hematopoietic progenitor cell harvest may contribute to relapse after high dose therapy for B-cell malignancies. Purging of the HPC harvest requires large amounts of anti-B-cell antibodies, whereas CD34-selection enriches self renewing HPC's but malignant cells are still detectable in many CD34+ fractions. Patients and methods: We examined the feasability and safety of a CD34-selection followed by purging with anti-B-cell antibodies in 11 patients with B-cell non-Hodgkin's lymphomas undergoing high-dose therapy with cyclophospha-mide, BCNU and etoposide with retransfusion of autologous HPC's. Results: A mean number of 340 × 108 mononuclear cells was used for CD34-selection and immunomagnetic purging. CD34+ cells were enriched from a mean of 1.7% (range 0.2%-4.5%) to a mean of 68% (range 49%-87%) with a mean recovery of 27% (range 15%-43%). The mean number of retransfused CD34+ cells was 1.2× 106/kg (range 0.6-2.2 ×106/kg) body weight with a median of 11 days (range 10-13 days) to neutrophil recovery of 0.5×109/1 and 17 days (range 13-25 days) to platelet recovery of 50 × 109/1. Mean number of intravenous antibiotics and inpatient days were 8 (range 0-14) and 22 (range 19-26) respectively. Major toxicity consisted in four septicemias. Conclusions: CD34-selected and purged HPC's are safe and mediate rapid hematological recovery after high dose therapy for B-cell non-Hodgkin's lymphoma

Professional Development

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68715/2/10.1177_014572179301900204.pd

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB