Women's Cancer Center
Winter 1997

In this issue:

• Practice Update:BRCA--What does this mean in your practice?
• New Center For Pelvic Reconstructive Surgery/Urogynecology
• Recent Peer Review Publications by WCC

Dear Collegues,

The challenge of providing care to the gynecologic oncology patient in the community setting has never been greater. As gynecologic oncology fellowships have become an integrated part of training programs in this country practice patterns in the community have changed to reflect this calling for an increase in the availability of specialists. Along similar lines patient awareness of specialists in this field has increased and as expected rising demand has followed. Yet the underlying incidence of gynecologic malignancies in the general population prevents a specialist from maintaining an adequate clinical volume at a single institution resulting in gynecologic oncologists "covering" multiple hospital staffs to the best of their abilities. Requirements of IPA's, HMO's hospital-based medical groups, and other "new" contractual aspects of medicine has only added to our challenge.

The Women's Cancer Center in Northern California developed conceptually and then in practice a means to address how to best provide care for the gynecologic oncology patient regionally so as to maximize the number of patients and physicians with access to sub-specialists while insuring that appropriate postoperative care and consultation will be provided on a daily basis. We have accomplished this by creating "true" Centers of Excellence as local/regional hubs where particularly complex patients are managed while caring for the more routine and vast majority of patients at the referring physician's hospital. The implementation of this concept has called for the development of teams of gynecologic oncologists -- this has been successful in Northern California and we are pleased to announce the opening of the following Centers.

In Southern California Centers have opened in:

• Tarzana
• Century City
• Pasadena
• Ventura

• John B. Schlaerth, M.D.
• Scott M. Eisenkop, M.D.
• Richard Friedman, M.D.
• Sergio Perticucci, M.D.
• Steven A. Vasilev, M.D.
• Paul S. Lin, M.D.

• Modesto
• San Pablo

• Peter C. Lim, M.D.
• A. Catherine Casey, M.D.
• Gerardo M. Perez, M.D.
• Albert Pisani, M.D.

Women's Cancer Center Begins BRCA Gene Screening

by Jerry Perez, M.D.

The theory that genetics may play a role in the development of certain cancers dates back to ancient Romans. Modern medical literature first elaborated on the genetic theory of cancer in 1866 when Paul Broca, a French surgeon reported ten cases of breast cancer spanning four generations of his wife's family. Recently, it has been shown that genetic predisposition accounts for five to ten percent of ovarian and breast cancers. Mary-Claire King and associates in 1990, localized the first major susceptibility gene for breast and ovarian cancer and have referred to it as BRCA 1 (BR = Breast and CA= Cancer). Since that time BRCA 2 which predisposes its carriers predominately to breast cancer has also been isolated. BRCA is thought to be a tumor suppressor gene that codes for a protein that regulates the transcription of genes involved in cellular proliferation. To date, over 100 mutations on BRCA 1 which are associated with trucation of the protein have been discovered. Missense mutations which are aberrations in the DNA which do not appear to confer any changes to the protein have also been described, but the clinical relevance of these changes is unclear. The "two hit" model for genetic predisposition assumes that a carrier is born with a mutation in one of the two BRCA genes. The normal BRCA gene imparts its protective effect until such time that the normal gene undergoes a mutation for whatever reason (e.g. environmental factor). At this point, the tumor suppressor protein is no longer encoded properly and a cancer develops.

Seven percent of breast cancers and 10% of ovarian cancers are related to susceptiblity genes, mainly BRCA 1 and BRCA 2. Obviously, not all susceptibility genes have yet been identified. It is suspected that as many as 1,000,000 (about 0.5% - 0.6%) in the United States are carriers of the altered BRCA 1 or BRCA 2 gene. Ashkenazi Jewish women are particularly high risk with up to two percent carrying the gene. Women that carry the mutation have an 82% risk of developing breast cancer and a 44% risk for ovarian cancer (BRCA 1) by age 70. Interestingly, when compared to cancers which are caused by sporadic mutations, these women are often afflicted at a younger age with 59% risk of breast cancer before the age of 50. Often these patients will be afflicted with cancer before the age of forty.

The American Society of Clinical oncology recommends that cancer predisposition testing be offered only when: 1) the person has a "strong family history" of cancer or early onset of the disease; 2) the test can be adequately interpreted; and 3) the results will influence medical management. However, "strong family history" was not defined. Early studies that test individuals who are first degree relatives of two people who developed breast or ovarian cancer before the age of 40 have a 53% chance of carrying the BRCA mutation. If one of the affected relatives was less than forty and the second relative was between the ages of 40 and 60 the mutation rate drops to 16%. The decision to test an individual should therefore be based not only on the number of relatives that were affected, but equally important is the age at which they were affected.

Management of patients that carry the aberration of the BRCA gene is still evolving. Medical modifications at a minimum, should include increased screening for breast and ovarian cancer, and discussion of prophylactic surgery. Lifestyle modifications should include refraining from alcohol, weight loss in the obese patient, possible use of oral contraceptives, and cessation of smoking, all of which have been shown to have deleterious effects on breast cancer. The use of antioxidants in this group of patients may also prove of benefit.

The Women's Cancer Center is now equipped to perform BRCA testing and counseling. We feel very strongly that genetic screening will play an integral part in the future of cancer prevention and treatment. The future begins today.

References

Announcing The Opening of the Center for Pelvic Reconstructive Surgery/Urogynecology

The Women's Cancer Center in Northern California is pleased to announce the opening of the New Center For Pelvic Reconstructive Surgery and Urogynecology. The Center offers a full range of diagnostic and therapeutic procedures as well as consultation services for women with urinary and fecal incontinence, special problems of pelvic support, and women who need reconstructive or reparative surgery. The Center accepts patients by referral only. The Center is directed by Dr. M. Thomas Margolis, who completed his fellowship in Pelvic Reconstructive Surgery at Emory University in 1992. The Center is devoted to providing the highest-quality Tertiary referral services in Northern and Central California.

Common Diagnoses

Common diagnoses that are evaluated and treated in the Center include but are not limited to:

• Recurrent urinary incontinence
• Urethral sphincter insufficiency
• Vesicovaginal and ureterovaginal fistulas
• Uretheral diverticulum
• Uretheral prolapse
• Vaginal vault prolapse
• Recurrent cystocele, rectocele and enterocele
• Vaginal agenesis and stenosis
• Detrusor instability (urgency incontinence)
• Overflow incontinence
• Fecal incontinence
• Rectovaginal fistulas
• Advanced endometriosis

Diagnostic & Treatment Options

Diagnostic services performed in the Center include:

• Simple urodynamics
• Complex urodynamics (cystometrogram, uroflow studies, urethral pressure studies and Valsalva leak-point pressure)
• Cystourethroscopy

These services are available at three different locations in the Bay Area. Some of the therapeutic procedures utilized include medical therapy, minimally invasive surgery, and open surgical procedures such as:

• Biofeedback for urinary and fecal incontinence
• Drug and behavioral modification therapies
• Periurethral collagen injection
• Goebell-Stoeckel fascia lata sling procedure
• Abdominal and laparoscopic retropubic urethropexy (MMK and Burch)
• Needle suspension procedures
• Vesicovaginal, ureterovaginal, and rectovaginal fistula repair
• Sphincterorrhapy and perineorrhaphy
• Laparoscopic and abdominal sacral colpopexy
• McIndoe vaginplasty
• Plastic reconstruction of the vulva and vagina
• Complicated hysterectomy

Using advanced laparascopic techniques, many of these procedures are now being performed via the laparocope. Indeed, within the last two years a number of laparascopic abdominal sacral colpopexies have been performed by members of the Center on patients with advanced pelvic prolapse.

Data from this series revealed a mean patient age of 68 years. Preoperative work-up included cystometrics and urethroscopy to evaluate bladder function prior to surgery. Burch procedures were not undertaken as a matter of routine. There was one failure requiring re-operation in patients undergoing vault suspension and no failures in patients undergoing Burch urethoropexy. The average hosptial stay was one day and no patient required transfusion. Bladder catherization remained in place for an average of three days. For the most part, our patients had at least one prior bladder repair, the majority of which were done by their primary gynecologist.

The following illustrations will hopefully help you better understand how incorporating a sound knowledge of pelvic anatomy gained during the performance of radical surgery, will lead to improved surgical results in patients such as these. For more information regarding pelvic reconstrucitive surgery and urogynecology, please contact the Center for Pelvic Surgery/ Urogynecology or any of the physicians at the Woman's Cancer Center.

The Center for Pelvic Surgery at the Women's Cancer Center

Fig. 1. The cul de sac is exposed and the uterosacral ligaments are grasped.

Fig. 2. The uterosacral ligaments are plicated.

Fig. 3. Progressive plication begins to obliterate the cul de sac.

Fig. 4. Complete obliteration of the cul de sac thus preventing an enterocele.

Fig. 5. Peritoneum over the vaginal cuff is mobilized and the distal graft is sutured to the apex.

Fig. 6. The proximal graft is sutured to the promontory of the sacrum.

Counseling for Genetic Testing

Counseling for genetic testing, as per the American Society of Clinical Oncology, should involve the following 11 points:

1. Information on the specific test being performed
2. Implications of positive and negative results
3. Options for estimation without genetic testing
4. Risk of passing a mutation to a child
5. Technical accuracy of the test
6. Possibility that the test will not be informative
7. Fees involved in testing
8. Risk of psychological distress
9. Risk of insurance or employer discrimination
10. Confidentiality issues
11. Options for medical surveillance and screening following testing

Practice Update

Flow Cytometric Analysis of Lymph Node and Peritoneal Metastases in Advanced Ovarian Cancer: Clinical and Biological Significance

R.E. Kimball, J.B. Schlaerth, T.E. Kute, A.C. Schlaerth, J.T. Santoso, S.C. Ballon, N.M. Spirtos

Objective

This study was undertaken to evaluate the DNA content and S-Phase fraction in advanced epithelial ovarian carcinomas to determine if lymph node metastases are biologically distinct from peritoneal sites of metastases.

Methods

Thirty-five patients with Stage III or IV epithelial ovarian cancer who had undergone complete pelvic and para-aortic lymphadenectomy had representative samples from the primary ovarian tumor, peritoneal metastases and lymph node metastases analyzed by flow cytometry (FC) for DNA nuclear content and S-phase fraction.

Results

The ploidy category frequency distribution of peritoneal metastases mirror that found in the primary tumor, and both are significantly different than the ploidy category frequency distribution found in metastatic lymph nodes. Heterogeneity among sites is common and is a positive predictor of lymph node metastases. Ploidy of the primary tumor is a predictor of survival. Heterogeneity and lymph node metastases are not related to survival in this group of patients.

Conclusions

A high proportion of tumor deposits found in metastatic lymph nodes can be expected to be resistant to chemotherapy and to radiation therapy based on flow cytometric characteristics. Selected patients may be best treated by therapeutic lymphadenectomy.

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