Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Oncogene (2005) 24, 3554−3562. doi: 10.1038/sj.onc.1208426 Published online 7 March 2005

Published online 07 March 2005

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Laundette P Jones1, Minglin Li1, Ewa D Halama1, Yongxian Ma1, Ronald Lubet2, Clinton J Grubbs3, Chu-Xia Deng4, Eliot M Rosen1 and Priscilla A Furth1

1. 1Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
2. 2National Cancer Institute, Division of Chemoprevention, Bethesda, MD, USA
3. 3Chemoprevention Center, University of Alabama at Birmingham, Birmingham, AL, USA
4. 4National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA

Correspondence: PA Furth, Georgetown University, Research Building Room E520A, 3970 Reservoir Road, Washington, DC 20057, USA
Received 20 July 2004; Revised 01 November 2004; Accepted 01 December 2004; Published online 07 March 2005.

Abstract

Loss of full-length Brca1 in mammary epithelial cells of the mouse mammary tumor virus (MMTV)-Cre Brca1 conditional exon 11 deletion mouse model results in the development of mammary adenocarcinomas with similar genetic changes to those found in human BRCA1-mutation-related breast cancers. We used this experimental model to evaluate the chemopreventive effect of tamoxifen on the development of mammary preneoplasia and adenocarcinoma. No protective effects of tamoxifen administration on mammary cancer development were found. Instead, tamoxifen treatment significantly increased rates of mammary epithelial cell proliferation and the prevalence of mammary hyperplasia at 6 months of age. Tamoxifen-exposed mice developed adenocarcinomas at younger ages than control mice and a higher percentage of mice developed adenocarcinomas by 12 months of age. Both whole mouse and tissue culture cell models were used to test if loss of full-length Brca1 was associated with a relative increase in the agonist activity of tamoxifen. Tamoxifen induced increased ductal growth in MMTV-Cre Brca1 conditional mice compared to wild type. Estrogen receptor alpha (ERalpha) expression was downregulated in the tamoxifen-induced hyperplasias. Reducing BRCA1 levels in MCF-7 cells using siRNA resulted in a relative increase in the agonist activity of tamoxifen. Results suggest a model of mammary cancer progression in which loss of full-length Brca1 altered the agonist/antagonist activity of tamoxifen, resulting in tamoxifen-induced mammary epithelial cell proliferation with subsequent loss of ERalpha expression and development of ERalpha-negative hyperplasias and adenocarcinomas.

GeneticHealth website

http://www.genetichealth.com/index.shtml

2001 JAMA: Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2

http://jama.ama-assn.org/cgi/content/abstract/286/18/2251
Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2

National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial

Mary-Claire King, PhD; Sam Wieand, PhD; Kathryn Hale, BS; Ming Lee, PhD; Tom Walsh, PhD; Kelly Owens, PhD; Jonathan Tait, MD, PhD; Leslie Ford, MD; Barbara K. Dunn, MD, PhD; Joseph Costantino, DrPH; Lawrence Wickerham, MD; Norman Wolmark, MD; Bernard Fisher, MD

JAMA. 2001;286:2251-2256.

Context Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)–positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown.

Objective To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations.

Design, Setting, and Participants Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999).

Main Outcome Measure Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo.

Results Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive.

Conclusion Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.

Author Affiliations: Departments and Medicine and Genomic Sciences (Drs King, Lee, Walsh, and Owens and Ms Hale) and Laboratory Medicine (Dr Tait), University of Washington, Seattle; and National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh, Pittsburgh, Pa (Drs Wieand, Costantino, Wickerham, Wolmark, and Fisher); and National Cancer Institute, Bethesda, Md (Drs Ford and Dunn).

2001 study: Findings on Tamoxifen for BRCA-1 and 2 Mutation Carriers

http://www.bcaction.org/Pages/SearchablePages/2001Newsletters/Newsletter067B.html

2005 Brain metastases from epithelial ovarian cancer. The Hellenic Cooperative Oncology Group (HeCOG) experience and review of the literature.

Anticancer Res. 2005 Sep-Oct;25(5):3553-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16101179
Brain metastases from epithelial ovarian cancer. The Hellenic Cooperative Oncology Group (HeCOG) experience and review of the literature.

Pectasides D, Aravantinos G, Fountzilas G, Kalofonos C, Efstathiou E, Karina M, Pavlidis N, Farmakis D, Economopoulos T, Dimopoulos MA.
Second Department of Internal Medicine-Propaedeutic, Oncology Section, University General Hospital Attikon, Haidari, Athens, Greece.

BACKGROUND: Brain metastases from epithelial ovarian cancer (EOC) are rare. A retrospective study of all patients diagnosed with brain metastases from EOC over the last 20 years, according to the Hellenic Cooperative Oncology Group (HeCOG) tumor registry, was conducted.

PATIENTS AND METHODS: A total of 1450 patients with EOC were treated within various HeCOG protocols from 1983 to 2004. Seventeen (1.17%) of them developed brain metastases.

RESULTS: The median age at diagnosis of brain metastases was 58 years (range, 24 to 77). At initial diagnosis, 2 patients had stage II, 12 had stage III and 3 had stage IV disease. Serous papillary adenocarcinoma was the most common histological subtype [12 patients (71%)]. All patients had received initial cisplatin-based chemotherapy. The median time from initial diagnosis to central nervous system (CNS) relapse was 15.9 months (range, 1.4 to 70.8). The CNS was the only site of disease in 13 (76.5%) patients, whereas 4 (23.5%) patients had additional extracranial disease. Two (12%) patients with isolated single brain lesions underwent surgical excision of the metastases, followed by whole brain radiation therapy (WBRT) and chemotherapy. Four (24%) patients were treated with WBRT alone, 6 (35%) patients with WBRT plus chemotherapy and 2 (12%) had only supportive care, while 3 (18%) patients decided not to have any further treatment after the diagnosis of brain metastases. The median survival time from diagnosis of CNS relapse was 5.7 months (range, 0.2 to 22.6) and the median survival time from diagnosis of EOC was 27.4 months (range, 3.0 to 71.4). In patients with CNS recurrence as the only site of disease, the median survival time from diagnosis of CNS relapse was 5.3 months (range, 0.6 to 22.6) and in those with both CNS and extracranial disease, the median survival time was 3.9 months (range, 0.2 to 11.9) (p=0.5597). There was a statistically significant difference in survival for those treated with WBRT plus chemotherapy (10.0 months) versus those treated with WBRT alone (1.5 months) and those who had only supportive care (0.2 months) (p=0.0003).

CONCLUSION: The incidence of cerebral metastases in our patients with EOC was 1.17%, which is consistent with the mean value of all series reported in the literature. The prognosis of patients with brain metastases from EOC is poor. Patients who had WBRT and chemotherapy fared better than those who received WBRT alone.

2005 It Is Time to Get Serious About Diagnosing Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer

It Is Time to Get Serious About Diagnosing Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer With Defective DNA Mismatch Repair) in the General Population

http://www.gastrojournal.org/article/PIIS0016508505011959/fulltext

Doctors and Patients - Working Together to Make Medical Decisions

http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_081605/page4

Guest Commentary
Dr. Margaret Spitz

Doctors and Patients - Working Together to Make Medical Decisions

Several articles in the recent literature have suggested interesting patterns in health care decisions among groups of patients. One article describes how race and marital status were linked to the decisions a group of men diagnosed with localized prostate cancer made regarding the type of therapy to pursue - black and single men tended to choose radiation therapy, while white and married men tended to choose surgery. Another study shows that among women with locally advanced breast cancer, emotional, religious, and marital factors delayed their pursuit of treatment after diagnosis. It seems that many factors can influence patients' decisions about cancer treatment, not simply the advice of their physicians.

Doctors and Patients Working Together"We've generally assumed people will always make rational decisions when it comes to their health," explains Dr. Wendy Nelson of NCI's Basic and Biobehavioral Research Branch, "but as human beings, our decisions are often guided by intuition and emotion, rather than fact and reason."

Dr. Nelson leads a scientific initiative at NCI that promotes research on the cognitive and affective processes underlying decision making in cancer control - for example, reasons why some people delay treatment that they know is in their best interest. Much of the research that was discussed at the initiative's first meeting, held in February of 2004, is published in a supplement to this month's issue of Health Psychology. Additionally, two program announcements, "Decision Making in Health: Behavior Maintenance" and "Decision Making in Cancer: Single-Event Decisions" were released by NCI at the end of last year to encourage more research in this area.

"Patients aren't computers, nor do they have the resources and time to always make these very difficult decisions," explains Dr. Nelson. "Often people rely on heuristics - rules of thumb that serve as automatic, intuitive guides to decision making - instead. But whenever you're dealing with medical uncertainty, there's no right or wrong answer. Through this initiative, we're trying to understand how people make decisions so health care providers can help patients make a truly informed decision that is consistent with their own values and preferences."

When a patient is facing a serious medical issue, the choices are never easy. In these situations, older adults tend to defer to their doctors for advice, a relationship known as the paternalistic decision-making model, while younger people tend to take a more active role in the decision. But regardless of the process, it's clear that the way in which information is presented to the patient makes a difference.

For example, if a surgeon says to a patient, "You will have a 90 percent chance of survival with this procedure," instead of saying, "There is a 10 percent chance of mortality," that can make a difference.

Sometimes too much information, or information overload, can also interfere with optimal decision making. Numbers and statistics can also interfere with decision making. Many people have difficulty understanding and interpreting numbers and are not accustomed to thinking in terms of probabilities, but they are often asked to make decisions based on probabilities.

What happens when a physician provides a patient with all of the information that he or she deems necessary to make a decision, but then feels the patient has made a wrong choice? In this case, who is ultimately responsible for what happens? The answer isn't always clear.

An article in last year's Journal of the American Medical Association illustrates this point well: In it, a doctor describes his experience providing the standard of care to a 53-year-old patient during a physical exam, including an overview of the risks and benefits of prostate cancer screening. The patient declined the test, but when another doctor later ordered the PSA test without discussing these options with the patient - subsequently diagnosing the man with advanced prostate cancer - a jury found the first doctor's residency program liable and awarded the man's family $1 million.

How, then, can physicians work with their patients to make these potentially life-altering decisions? "We know that just providing information is not enough," says Dr. Nelson. "Unless we understand how people are using and processing that information, we can't be sure that they're making a truly informed treatment choice."

A Service of the National Cancer Institute
Department of Health and Human Services National Institutes of Health FirstGov.gov

eMedicine - Borderline Ovarian Cancer : Article by Andrew E Green, MD - Last Updated: July 7, 2005

http://www.emedicine.com/med/topic3233.htm

Last Updated: December 21, 2004 - Ovarian Cancer - Information on Ovarian Cancer Symptoms, Signs, Stages, and Treatment : Article by Agustin A Garcia, MD

http://www.emedicine.com/med/topic1698.htm

legal news - Armstrong vs Centenary

Armstrong v. Centenary Health Centre

Citation : 2002 CanLII 42546 (ON S.C.) Date: December 20, 2002
Ontario > Superior Court of Justice
http://www.canlii.org/on/cas/onsc/2002/2002onsc10605.html

Citation : 2005 CanLII 20712 (ON C.A.) Date: June 13, 2005
Ontario > Court of Appeal for Ontario
http://www.canlii.org/on/cas/onca/2005/2005onca10427.html

July 3rd - "Ellie and Lisi Show" July 3rd, 2005 9:30 pm - 11:00 pm CFRB 1010 radio/on line

'The Ellie & Lisi Show'
CFRB - Sunday, July 3rd 9:30 pm -11:00 pm
Invited guest: Sandi Pniauskas

Ellie Tesher's life history has focused on social justice causes and issues, both in Canada and Internationally. Most recently, Ellie was honoured by the Jewish Women International of Canada's award (Toronto) as 'Woman of the Year'.

Both Ellie Tesher and her daughter, Lisi, are 'relationship' columnists. Their endeavours include columns in the print media, which are syndicated in Canada and the U.S.. As a Mother/Daughter team, they have come together to bring to you CFRB's highly successful one and a half-hour call-in show.

Sandi Pniauskas, a cancer survivour and patient advocate, will be Ellie's guest on CFRB's July 3rd program to discuss the many topics surrounding all manner of cancer concerns, hopes, desires, fears and information needs. Sandi's question to you is this: "Do you want to talk about cancer?"

Calls are THE key to the show's success and names are never required to ensure confidentiality. Ellie invites everyone to participate and looks forward to chatting with you. It's going to be a lively, informative chat! CFRB brings you this opportunity to have your voice heard. Call with your concerns and issues relating to cancer which affect you, whether you have/had a cancer diagnosis, family, friends or someone in the medical community who cares for cancer patients and their families.

There are several ways to access the program:

1) radio by tuning into CFRB 1010 AM (Toronto)
2) listen online: http://www.cfrb.com (click on show and guest information) or direct link
3) direct link: (http://tinyurl.com/bw37f) or
http://www.http://cfrb.com/content/content_publish/program_details.asp?filename=program_id_755.html
4) email comments/questions before Saturday, July 2nd: needadvice@cfrb.com
5) CALLS: 416-872-1010; 1-800-561-CFRB (toll free - Ontario only); and *TALK (8255) on a cellular