Disease Markers 15 (1999) 41–43 41 IOS Press

Short Communication

Familial Breast and Ovarian Cancer: Genetic Counseling and Clinical Management in Italy

Barbara Pasini and Marco A. Pierotti and an appropriate follow-up program. Labora- tories that already perform molecular screening Hereditary Tumors Unit, Istituto Nazionale for germline BRCA1 and BRCA2 are located in Tumori, Milan, Italy Milan, Pisa, Aviano, Modena, Padova, Rome and Turin. Although there are no unified eligibility criteria for BRCA1 and BRCA2 testing, most In Italy, where the health system is mainly laboratories and referral counseling services offer public (although the number of private clinics is a genetic test in the presence of a 10% cut-off increasing), genetic counseling on inherited prior probability in favor of a genetic defect, with predisposition to cancer and related genetic tests few differences among centers (see Table 1). are generally offered on the basis of research Approximately 730 eligible families have been projects, lacking specific national guide lines. selected to date, with a free decision in favor of Genetic counseling services on familial breast genetic testing ranging from 66% to 86%, and ovarian cancer have been established in depending on personal and familial disease Milan, Modena, Naples, Varese and Genoa, history. For example, refusal of testing was while their organization is in progress in Aviano, higher among women with early onset ovarian or Chieti, Florence, Padova, Pisa, Rome and Turin. breast cancer and negative family history (50% Counseling is usually offered as an outpatient and 23%, respectively) than in cases of familial service in the context of medical genetics breast cancer (10% refusal). The lowest rate of services departments of oncology, university refusal was observed when the index case had and/or local programs of mammography developed multiple tumors (bilateral breast screening with direct access for the general cancer cases: 7%, breast + ovarian cancer cases: population. Due to the different locations and 4.5%, all with positive family history). In purposes of these services, it is difficult to assess general, Italian women tend to agree with genetic how many Italian women have been evaluated testing, mainly because they want “to do” during the last three years. Roughly, we can something for their family. They believe in the estimate that approximately 1500 women have utility of early diagnosis and want to know more been consulted because of a relevant family about their disease. Many women have history of breast/ovarian cancer and/or early experienced in their own case, or in family onset of the same tumors. Most of the counseling members, that early diagnosis correlates with a services already established involve multiple better prognosis and this increases their health care professionals. Usually, oncologists, confidence in the utility of clinical surveillance medical geneticists, surgeons, gynecologists, programs. Among women refusing a genetic test psychologists and radiologists collaborate to offer there is a strong worry about the possibility of an evaluation of the cancer family history, an developing further malignancies (a second breast estimation of the prior probability of carrying a cancer or an ovarian cancer) and of transmitting major genetic defect, breast cancer risk the putative genetic defect. As expected, the assessment for relatives, psycho-social support feeling of danger for daughters is the main reason

0278-0240/99/$8.00 © 1999 – IOS Press. All rights reserved 42 B. Pasini and M.A. Pierotti / Genetic Counseling and Clinical Management in Italy

Table 1 Eligibility criteria for BRCA1 and BRCA2 testing in Italy Referral center Age at breast cancer (BC) Age at ovarian cancer (OC) Family history (FH) All centers < 35–36 yrs. independently of FH Most centers Bilateral BC any age independently of FH (Milan) (or< 43) All centers Male BC any age independently of FH Rome, Naples < 40 yrs. independently of FH Milan < 47 yrs. Most centers BC + OC any age independently of FH Milan BC + OC < 52 yrs. Milan Bilateral BC + OC < 56 yrs. Most centers OC any age Another OC any age Milan BC < 50 Another BC < 50 or bilateral BC any age or OC any age Rome, Naples BC < 40 Another BC any age Most centers BC any age 2 relatives (1 first degree) BC any age Modena BC < 40 2 relatives (1 first degree) BC any age (Amsterdam criteria “like”) Most centers BC any age 3 or more relatives BC or OC any age

for accepting or refusing a genetic test among “recurrent” mutations were usually present in 2 Italian women. In Italy, molecular analysis of or 3 apparently unrelated families. Therefore, BRCA genes is performed mainly by PTT complete screening of both BRCA1 and BRCA2 (protein truncation test) on BRCA1 exon 11 and genes is the testing procedure of choice in Italy. BRCA2 exons 10-11 and SSCP (single strand Approximately 280 carriers (211 affected and 69 confor-mational polymorphism) on the remaining healthy) have already been identified while 132 exons (Aviano, Milan, Padova, Pisa, Rome), at risk family members were non-carriers of direct sequencing (Modena) and Southern blot specific genetic defects. Although the option of analysis (Padova, Aviano). To date, among the prophylactic breast surgery is generally accepted laboratories contributing data, 166 Italian among the Italian medical community, as far as families carrying deleterious BRCA germline we know, no Italian woman followed by the mutations have been identified, 118 in BRCA1 referral centers underwent this treatment. Breast and 48 in BRCA2 genes. In different prophylactic surgery appears to most Italian laboratories, 4–27% of the identified mutations women a kind of “over treatment”, in relation to recurred among apparently unrelated families, the breast cancer risk and from personal family with slight differences depending on geographic experience. Even on diagnosis of a second breast region. In the experience of the National Cancer cancer, the most frequent choice is conservative Institute in Milan, which collected families from surgery, although an aesthetic reconstruction is all over Italy, just 11.7% of the identified always offered. The general surveillance mutations were recurrent in 2 to 13 protocol is based on breast clinical examination families. With the exception of BRCA1 every 6 months and annual breast imaging 5382insC and 1499insA identified in 13 and 4 (usually mammography in oblique projection different families, respectively, the other under 35 years of age, and in three projections B. Pasini and M.A. Pierotti / Genetic Counseling and Clinical Management in Italy 43 after 35 years). One Center suggests breast counseling, molecular testing and follow-up ultrasound every 6 months while at the National programs in familial breast and ovarian cancer. Cancer Institute in Milan young women carriers Research projects also include testing of of BRCA mutations will be followed by chemoprevention and/or dietary intervention, mammography alternating with MRI 12 months aimed at a modulation of genetic risk. apart. For those women who experienced in their family ovarian cancers, prophylactic oopho- rectomy seems a reasonable choice. Although Acknowledgments Italian women have the general feeling that mothers or sisters died from ovarian cancer We would like to thank the Italian colleagues because diagnosis was made too late, the pain providing data discussed in this report and caused by an ovarian cancer treatment (surgery, sharing their experience: chemotherapy, second-look and so on) seems to Dr. A. Viel, Dr. M. Boiocchi (Centro justify prophylactic surgery. Usually this Regionale di Oncologia, Aviano), Prof. M. decision is undertaken after 45 years of age and Federico, Dr. L. Mangone, Prof. V. Silingardi the surgery of choice is laparoscopic bilateral (Cattedra e Divisione di Oncologia Medica, oophorectomy together with a transvaginal Policlinico di Modena), Prof. Alma hysterectomy. In the experience of the National Contegiacomo (Napoli), Dr. E. D’Andrea, Dr. M. Cancer Institute of Milan, approximately 50% of Montagna, Prof. Chieco Bianchi (Dipartimento di carriers of deleterious germline mutations Scienze Oncologiche e Chirurgiche, Ospedale decided in favor of prophylactic oophorectomy, Busonera, Padova), Dr. M.A. Caligo, Dr. G. even when informed about the risk of an ovarian Cipollini, Prof. G. Bevilacqua (Divisione di cancer outside the ovaries. Pre-menopausal Anatomia Patologica, Università di Pisa), Dr. L. women usually decide to postpone prophylactic Ottini, Prof. R. Mariani Costantini (Istituto di surgery by a few years, undertaking a Patologia Generale, Dipartimento di Medicina surveillance program. There is a general Sperimentale e Patologia, Policlinico Umberto Iº, agreement in suggesting gynecological exam- Roma), Dr. P. Radice, Dr. V. Pensotti, Dr. P. ination, transvaginal ultrasound and CA125 every Fanales, Dr. S. Manoukian, Dr. V. De Benedetti 6 to 12 months, depending on family history or (Unità Tumori Ereditari, Istituto Nazionale per lo type of germline mutation. In conclusion, all Studio e la Cura dei Tumori, Milan). It is very over Italy, a number of referral centers have been likely that we have not covered all Italian established, or their organization is in progress. colleagues and referral centers professionally They are now involved in research projects to working on this field. We apologize for their evaluate the clinical relevance of genetic absence in this report.