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Aims: Negative sentinel node may predict tumour-free axillary nodes in breast cancer. We report the performance of sentinel node dissection at our Institution. Methods: We analysed data from 212 consecutive women with primary invasive breast tumours less than 3 cm in diameter and no axillary lymphadenopathy who underwent radioguided sentinel node dissection by means of 99mTc-colloidal albumin between 1999 and 2002. Completion axillary node dissection was performed if sentinel nodes contained metastases or if no sentinel nodes were identified. Results: Sentinel nodes were identified in 207/212 of the patients. Fifty-seven patients had tumour-positive sentinel nodes. Only tumour diameter showed significant association with sentinel node status (p

Objective:Thousands of women are treated each year for cancer; many of these are already in menopause, while other younger patients will go into early menopause due to surgery, or chemotherapy, or the need for radiotherapy to the pelvic region. In most cases the oncologist and the gynaecologist would advise these women against the use of HRT. The purpose of this paper is to review biological and clinical evidences in favour and against HRT use in the different tumours and to propose an algorithm that can help choosing the treatment for the single woman. Methods: We performed a systematic literature review through April 2002 concerning: (1) biological basis of hormonal modulation of tumour growth; (2) epidemiological data on the impact of HRT on different cancers risk in healthy women; (3) safety of HRT use in cancer survivors; (4) alternatives to HRT. Results: With the exception of meningioma, breast and endometrial cancer, there is no biological evidence that HRT may increase recurrence risk. In women with previous breast and endometrial cancer HRT is potentially hazardous on a biological basis, even if published data do not show any worsening of prognosis. Conclusions: Even if a cautious approach to hormonal-dependent neoplasias is fully comprehensible and the available alternative treatment should be taken into greater consideration, the reticence to prescribe HRT in women previously treated for other non hormone-related tumours has neither a biological nor a clinical basis. An algorithm based on present knowledge is proposed. © 2003 Elsevier Ireland Ltd. All rights reserved.

During the menopause, levels of SHBG, IGF-I and IGFBPs are significantly modified by the use of different HRT regimens. Objective: The aim of this study is to evaluate the influence of three different HRT regimens on serum levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in postmenopausal women. Methods: 41 postmenopausal women requesting HRT were enrolled in the study. Subjects were divided in three groups according to the therapy assigned; Group A: estradiol 2 mg/day+cyproterone acetate 1 mg/day in a cyclic sequential regimen; Group B: estradiol hemihydrate 2 mg/day plus norethisterone acetate (NETA) 1 mg/day in a continuous combined regimen; Group C: estradiol hemihydrate 1 mg/day plus NETA 0.5 mg/day in a continuous combined regimen. Blood samples were drawn before the start of hormonal treatment and after 6 months of HRT. Levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in the serum were measured by means of a specific immunoassay. Results: In group A, a significant increase of SHBG, no change of IGFBPs and a significant decrease of IGF-I were observed; in group B and in group C, no significant variations for any of the parameters were recorded. Conclusions: The association of cyproterone acetate to oral estradiol determines a significant reduction of IGF-I levels and an increase of SHBG; nevertheless, it does not seem to influence the serum levels of the IGF-I binding proteins. The treatment with oral continuous combined estrogens plus androgenic progestins, at low doses, produces minor, not significant, changes in the circulating levels of IGF-I, SHBG and IGFBPs.

Angiogenic factors produced by tumor cells are essential for tumor growth and metastasis. In our study, the expression of Angiopoietin-1 (ANG1) and Angiopoietin-2 (ANG2) mRNA in archival human breast cancer tumor samples and in 6 breast cancer cell lines was investigated. Total RNA from biopsies of 38 breast cancer patients was extracted and ANG1 and ANG2 mRNA expression was measured by means of quantitative real-time RT-PCR (Taqman). Matching data with available clinicopathologic and biochemical data revealed a significant association between ANG2 expression and axillary lymph node invasion. Univariate and multivariate survival analysis, by means of Kaplan-Meier method and Cox's proportional hazards model, showed significant and independent association between ANG2 mRNA level and both disease-free (p < 0.0001) and overall survival (p < 0.0003). An important fact is that, notwithstanding the small number of cases examined, this association was confirmed also in the group of lymph node-negative patients (DFS, p < 0.003; OS, p < 0.020). Immunohistochemical analysis demonstrated that Ang2 is expressed by both tumor cells and endothelial elements. Expression in tumor cells was confirmed by studying a panel of human breast carcinoma cell lines in culture by RT-PCR. In ZR75.1 and T47D cells, expression of ANG2 mRNA was increased up to 10-fold by treatment with estrogen within 24 hr. Although preliminary, these data suggest a possible role of ANG2 as a prognostic factor for primary breast cancer.

Background Hot flashes are frequent in postmenopausal breast cancer patients, especially when treated with tamoxifen. Estrogen replacement therapy is the most effective treatment for hot flashes, but its use is controversial in breast cancer survivors. Progestins may offer a good alternative for the control of hot flashes in this setting; in particular, oral megestrol acetate has been proven effective in a randomized, placebo-controlled clinical trial. With the aim of further improving these results, we have designed a randomized study comparing oral megestrol acetate with depot intramuscular (i.m.) medroxyprogesterone acetate (MPA) for the control of hot flashes in postmenopausal patients with a history of breast cancer. Patients and methods Seventy-one postmenopausal patients were randomized to receive an i.m. injection of depot MPA 500 mg on days 1, 14 and 28, or oral megestrol acetate 40 mg daily for 6 weeks. Patients recorded daily the number and severity of their hot flashes; response was defined as a ≥50% decrease in the number and severity of hot flashes. Results At week 6, hot flashes were reduced by 86% on average in the whole group of patients, without significant differences between the two progestins. Response was obtained by 75 and 67% of patients receiving MPA or megestrol, respectively (P = 0.5). Responders were followed to assess maintenance of response (without further treatment), which was significantly better with i.m. MPA: in this group, 89% of responders still showed a benefit at week 24, compared with 45% in the megestrol group (P = 0.03). Conclusions Our study shows that a short cycle of i.m. depot MPA injections provides significant and long-lasting relief from postmenopausal hot flashes in patients with a history of breast cancer, offering an alternative to estrogen replacement therapy or prolonged administration of oral megestrol.

Many kallikrein genes were found to be differentially expressed in various malignancies, and prostate specific antigen (encoded by the KLK3 gene) is the best tumour marker for prostate cancer. Prostate specific antigen has recently been shown to be an independent favourable prognostic marker for breast cancer. KLK15 is newly discovered kallikrein gene that is located adjacent to KLK3 on chromosome 19q13.4. KLK15 has 41% similarity to KLK3 and the encoded protein, hK15, can activate pro-prostate specific antigen. We studied the expression of KLK15 by real-time quantitative reverse transcriptase–polymerase chain reaction in 202 tissues from patients with breast carcinoma of various stages, grades and histological types. KLK15 expression was found to be a significant predictor of progression-free survival (hazard ratio of 0.41 and P=0.011) and overall survival (hazard ratio of 0.34 and P=0.009). When all other known confounders were controlled in the multivariate analysis, KLK15 retained its prognostic significance. Higher concentrations of KLK15 mRNA were found more frequently in node negative patients (P=0.042). No association was found between KLK15 expression and any other clinicopathological variable. Further, KLK15 is an independent prognostic factor of progression-free survival and overall survival in the subgroup of patients with lower grade and those with oestrogen receptor and progesterone receptor negative tumours in both univariate and multivariate analysis. KLK15 levels of expression were slightly higher (although not statistically significant) in the oestrogen receptor negative and progesterone receptor negative subgroups of patients. KLK15 is up-regulated by androgens in breast cancer cell lines. Time-course and blocking experiments suggest that this regulation is mediated through the androgen receptor. British Journal of Cancer (2002) 87, 1294–1300. doi:10.1038/sj.bjc.6600590 www.bjcancer.com © 2002 Cancer Research UK

DNA chips are small, solid supports such as microscope slides onto which thousands of cDNAs or oligonucleotides are arrayed, representing known genes or simply EST clones, or covering the entire sequence of a gene with all its possible mutations. Fluorescently labeled DNA or RNA extracted from tissues is hybridized to the array. Laser scanning of the chip permits quantitative evaluation of each individual complementary sequence present in the sample. DNA chip technology is currently being proposed for qualitative and quantitative applications, firstly for the detection of point mutations, small deletions and insertions in genes involved in human diseases or affected during cancer progression; secondly, to determine on a genome-wide basis the pattern of gene expression in tumors, as well as in a number of experimental situations. The extraordinary power of DNA chips will have a strong impact on medicine in the near future, both in the molecular characterization of tumors and genetic diseases and in drug discovery and evaluation. Quantitative applications will soon spread through all fields of biology.

Sex Hormone‐Binding Globulin (SHBG), the plasma carrier for androgens and estradiol, inhibits the estradiol‐induced proliferation of breast cancer cells through its membrane receptor, cAMP, and PKA. In addition, the SHBG membrane receptor is preferentially expressed in estrogen‐dependent (ER+/PR+) breast cancers which are also characterized by a lower proliferative rate than tumors negative for the SHBG receptor. A variant SHBG with a point mutation in exon 8, causing an aminoacid substitution (Asp 327 → Asn) and thus, the introduction of an additional N‐glycosylation site, has been reported. In this work, the distribution of the SHBG variant was studied in 255 breast cancer patients, 32 benign mammary disease patients, and 120 healthy women. The presence of the SHBG mutation was evaluated with PCR amplification of SHBG exon 8 and HinfI restriction fragment length polymorphism (RFLP) procedure. This technique allowed us to identify 54 SHBG variants (53 W/v and 1 v/v) in breast cancer patients (21.2%), 5 variants (4 W/v and 1 v/v) in benign mammary disease patients (15.6%), and 14 variants (W/v) in the control group (11.6%). The results of PCR and RFLP were confirmed both by nucleotide sequence of SHBG exon 8 and western blot of the plasma SHBG. No differences in the mean plasma level of the protein were observed in the three populations. The frequency of the SHBG variant was significantly higher in ER+/PR+ tumors and in tumors diagnosed in patients over 50 years of age than in the control group. This observation suggests the existence of a close link between the estrogen‐dependence of breast cancer and the additionally glycosylated SHBG, further supporting a critical role of the protein in the neoplasm.

The objective of this study was to determine the influence of transdermal estradiol administration on insulin-like growth factor I (IGF-I) serum level in a series larger than those published to date. Thirty-nine postmenopausal women with vasomotor symptoms were studied; blood samples (after overnight fast) were obtained just before and at the 6th month of treatment with transdermal estradiol 0.05 mg/day, and serum levels of IGF-I, growth hormone and sex hormone binding globulin (SHBG) were evaluated. Sixteen of the 39 women did not show variations of IGF-I values (group A), while 11 showed an increase (group B) and 12 showed a decrease (group C) by at least 20% with transdermal estradiol treatment. IGF-I basal levels were higher in group C as compared to group A (p < 0.05) and to group B (p < 0.01), intermediate in group A, and lower in group B. Group C showed a significant increase of SHBG values with transdermal estradiol treatment. Transdermal estradiol seems to induce a bimodal effect on IGF-I serum levels, depending on IGF-I basal values. This could be caused by a different responsivity to estrogen action on the liver (the major site of circulating IGF-I production) and also, possibly, by a different degree in insulin sensitivity changes caused by estrogen.

The most serious obstacle to the diffusion of hormone replacement therapy (HRT) in menopause is the concern that HRT, either estrogens alone or combined with progestins, may enhance morbidity and mortality due to the development of malignant neoplasia in reproductive organs, particular breast and endometrial cancer. We reviewed the literature on breast and gynecological cancer risk for HRT users, specifically addressing the issues of duration, dose, and type of hormonal compounds in influencing cancer risk.

During November 1993 to December 1994 researchers in Italy interviewed 300 women under 46 years of age with histologically proven breast cancer (registered at the Oncological Hospital M. Ascoli the Civic Hospital of Palermo and the gynecological oncology department of the University of Turin) and 300 women with acute diseases but no breast cancer living in the same geographic area as the cases. They aimed to examine the relationship between use of oral contraceptives (OCs) and breast cancer risk. Cases were more likely to have a family history of breast cancer than controls (age-adjusted odds ratio [OR] = 2.34; p = .02). Only 7% of all OC users used OCs longer than 5 years. 17% used OCs for no more than 1 year. Overall OC use was not associated with an increase in breast cancer risk. When the researchers restricted the analysis to each center OC use was still not associated with this risk. The variables examined included OC use length of OC use age at first OC use OC use before first full-term pregnancy and time from last OC use. These findings show that among all the variables analyzed only family history of breast cancer was a risk factor for breast cancer.

Unlike parenteral estrogens, oral estrogen administration in menopause causes, through its hepatocellular action, a significant decrease of circulating insulin-like growth factor I (IGF-I) levels; this effect is opposed by the addition of an androgenic progestogen. In vitro studies show that IGF-I is a potent mitogen for 'estrogen responsive' breast cancer cells. Moreover, some findings in breast cancer patients and in women treated with tamoxifen suggest that reduction of circulating IGF-I could be protective to the breast. However, by also considering (1) the potential action on breast cancer cells of IGF-II, (2) the possible consequences of the growth hormone (GH) increase caused by the IGF-I reduction and (3) the fact that in vitro results are not simply transferable to the in vivo condition, other 'scenarios' can be envisaged, besides the favorable one. In support of the latter, there are epidemiologic data which suggest that oral estrogen use could have some favorable peculiarities with regards to breast cancer risk. The associated decrease in circulating IGF-I level could well be one of these peculiarities.

Background Aromatase inhibitors (AI) are superior to TAM in the treatment of hormonal receptor positive metastatic breast cancer (MBC). Fulvestrant (F), an estrogen receptor antagonist demonstrated activity when used after failure of previous TAM or AI. Objective: To evaluate the position of F in the hormonal strategy sequence in hormonal responsive MBC related to the evolution of adjuvant hormonal therapy (HT). Material and methods MBC patients with disease progression after adjuvant HT or after treatment (CT or HT) for metastatic disease, candidate to receive F at the dose of 250 mg/ month (registered in AIFA database) from May 1st 2006 to July 31st 2008. The study registered the HT sequence in clinical practice. Overall 201 patients were collected from 13 Italian Centers. Main patients' characteristics are summarized in the table. Table: 340P Characteristics N 201 (%) Characteristics N 201 (%) T size Tis-T1-T2 T3-T4 T Unk 138(68,6) 40 (20) 23 (11,4) PgR Pos Neg Unk 142(70,6) 33 (16,4) 26 (13) Nodal Status N0 N+ Nx 54 (26,9) 120 (59,7) 27 (13,4) Adj CT Yes No Unk 105 (51,7) 94 (46,8) 3 (1,5) ER Pos Neg Unk 169 (84) 12 (6) 20 (10) Adj HT Yes No Unk 141 (70,1) 46 (22,9) 14 (7) Results ORR were: CR 2%; PR 7%; SD 43%; PD 41%; NE 7%. Eighty-six patients (43%) had visceral metastases. Median duration of F was 7 months (1-42); 8 patients are ongoing and for 1 patient the duration was unknown. 16, 39 and 56 patients received F as 1st, 2nd and 3rd line therapy respectively. For the remaining patients F was administered as more than the 4th line therapy. The possibility to obtain a benefit from F did not seem to correlate with the line of treatment. One of the 2 CR occurred in a patient with visceral disease (lung). Among the patients who progressed under treatment 42% had visceral disease, that was almost the same rate of the whole population. This data suggests that there is lack of correlation between the sites of disease and the probability of benefit. Toxicity was negligible. Conclusions More than 50% of the patients benefited from F notwithstanding 73% of them received the treatment as third or more line of HT. This study does not show any correlation between the sites of the metastases and the treatment results. Disclosure All authors have declared no conflicts of interest.

Oral oestrogen treatment in postmenopausal women causes a decrease of insulin-like growth factor I (IGF-I) serum level, probably through a hepatocellular effect. To explore the possibility that the androgenic progestogens oppose this effect, serum IGF-I and sex hormone binding globulin (SHBG) were evaluated in two groups of patients treated respectively with oral conjugated oestrogens (oCE) or transdermal oestradiol (tdE2), in a first phase with the addition of dydrogesterone (DYDR), a non-androgenic progestogen, and subsequently with the addition of norethisterone acetate (NETA). With respect to basal values, treatment with oCE+DYDR caused an increase of SHBG (P < 0.002) and a decrease of IGF-I serum levels (P < 0.05); the shift to NETA addition opposed both effects: SHBG levels decreased partially but significantly (P < 0.01 vs. oCE + DYDR) and IGF-I returned to basal values with a significant increase with respect to the oCE + DYDR phase (P < 0.02). No changes were observed in the tdE2 + DYDR treated women; in this group the shift to NETA addition caused a significant decrease of SHBG values (P < 0.001 vs. before treatment and vs. tdE2 + DYDR phase) and a slight increase of IGF-I values. These differential effects on IGF-I and SHBG serum levels might be relevant as far as breast cancer risk is concerned.

Long-term hormone replacement therapy (HRT) is being used not only for relief of immediate disturbances which arise during menopause, but also for the prevention of osteoporosis and cardiovascular disease. The most serious concern about the use of HRT in menopause has been centered on potential oncologic risk; in particular, endometrial and breast cancer have been etiologically linked to the action of steroid hormones.

Almost all of the epidemiological studies on the consequences of estrogen replacement treatment (ERT) refer to subjects treated with oral conjugated equine estrogens (CEE). These studies suggest that breast cancer (BC) risk is limited and can only be seen after long-term and/or high dosage use. Orally administered estrogens present a number of metabolic and endocrine peculiarities, some of which could be important in reducing the risk to the breast. Actually, these peculiarities are opposite to those observed in post-menopausal women with abdominal obesity (AO), a group which has recently been identified to be at high risk. AO (as other situations in which an increase in BC risk does exist) shows a sex-hormone-binding-globulin (SHBG) level reduction, which causes an increase of both estrogenic and androgenic activity. Further features of AO, possibly involved in BC risk, could be: i) increased free fatty acid (FFA) levels; ii) hyperinsulinemia; iii) increase of circulating insulin-like growth-factor-I (IGF-I) activity. On the contrary oral estrogens, through their hepatocellular effects, cause: i) a clearcut SHBG increase; ii) a trend to reduced circulating IGF-I activity. As a consequence, the possibility that oral estrogens are characterized by a favourable balance between estrogenic activity and biological modifications protective to the breast, is worth consideration. Even non-oral estradiol have a possible protective action through FFA level reduction; however, due to the absence of hepatocellular effect, it does not influence SHBG levels and IGF-I activity. It seems difficult to extend data on the relationship between BC and oral CEE to other types of types of ERT. For the latter, further study will be necessary.

Postoperative infectious complications are a frequent cause of morbidity and mortality in the surgical patient. The septic events usually involve the urinary or respiratory tracts or occur at the operative site. The incidence depends on the surgeon's experience, the surgical procedure applied and the clinical status of the patient. Radical hysterectomy with pelvic lymphadenectomy is associated with a high risk of postoperative infections. Factors that influence the risk are prolonged preoperative hospitalization, duration of operation, younger age, obesity, estimated blood loss and lack of antibiotic prophylaxis. Appropriate administration of prophylactic antibiotics requires awareness of the following considerations: the choice of antibiotic agent, the dosage and the timing of administration for maximum benefit without adverse effects. In this review we evaluate the results of studies that use different regimens of antibiotic prophylaxis for prevention of infectious morbidity after radical hysterectomy.

The frequencies of 13 different Ha-ras proto-oncogene alleles have been estimated in 92 breast cancer patients and 60 unaffected individuals. The Ha-ras alleles can be identified using a DNA restriction fragment length polymorphism (RFLP) closely linked to the 3' end of the gene, and are characterized by a different length due to a region of sequences repeated a variable number of times (variable tandem repeats, VTR). The statistical analysis of the data obtained shows that the frequency of alleles ranging between specific length limits is significantly higher in breast cancer patients than in controls. The same applies to specific genotypes bearing the aforementioned alleles. This suggests that the inheritance of these alleles may be associated with an increased risk of developing breast cancer.

Tamoxifen is actually considered the drug of choice for the hormonal treatment of early and metastatic breast cancer due to its efficacy and low toxicity. In addition, clinical trials of adjuvant therapy have demonstrated a 35% decrease in controlateral breast cancer in women receiving tamoxifen compared with controls, suggesting a potential role for this drug in chemoprevention of breast cancer in healthy women at increased risk of disease. Although tamoxifen is usually classified as an estrogen antagonist it also has partial estrogenic effects in some tissues such as liver, bone and uterus. The estrogenic action of tamoxifen on lipid metabolism and bone mineral density suggests additional benefits in protection against cardiovascular diseases and osteoporosis in postmenopausal women. Of particular interest could be the use of tamoxifen as an alternative to traditional estrogen replacement therapy in postmenopausal women previously treated for breast cancer or at increased risk of disease due to family history or histology on breast biopsy. The potential adverse effects of tamoxifen are partially similar to those of ERT and includes an increased risk of endometrial cancer, hepatic diseases, thromboembolic alterations and ocular toxicity. The mechanism of action of tamoxifen is briefly examined and the potential toxic effects and benefits of tamoxifen treatment are discussed.

KLK5 is a newly discovered human kallikrein gene. Many kallikrein genes have been found to be differentially expressed in various malignancies, and prostate-specific antigen (PSA; encoded by the KLK3 gene) is the best tumor marker for prostate cancer. Like the genes that encode PSA and other kallikreins, the KLK5 gene was found to be regulated by steroid hormones in the BT-474 breast cancer cell line.We studied KLK5 expression in 179 patients with different stages and grades of epithelial breast carcinoma by quantitative reverse transcription-PCR (RT-PCR), using LightCycler((R)) technology. An optimal cutoff point equal to the detection limit (65th percentile) was used. KLK5 values were then compared with other established prognostic factors in terms of disease-free (DFS) and overall survival (OS).High KLK5 expression was found more frequently in pre-/perimenopausal (P = 0.026), node-positive (P = 0.029), and estrogen receptor-negative (P = 0.038) patients. In univariate analysis, KLK5 overexpression was a significant predictor of reduced DFS (P0.001) and OS (P0.001). Cox multivariate analysis indicated that KLK5 was an independent prognostic factor for DFS and OS. KLK5 remained an independent prognostic variable in the subgroups of patients with large tumors (2 cm) and positive nodes. Hazard ratios derived from Cox analysis and related to DFS and OS were 2.48 (P = 0.005) and 2.37 (P = 0.009), respectively, for the node-positive group and 3.03 (P = 0.002) and 2.94 (P = 0.002), respectively, for patients with tumor sizes2 cm. KLK5 expression was also associated with statistically significantly shorter DFS (P = 0.006) and OS (P = 0.004) in the subgroup of patients with grade I and II tumors.KLK5 expression as assessed by quantitative RT-PCR is an independent and unfavorable prognostic marker for breast carcinoma.

LINC00472 is a novel long intergenic non-coding RNA. We evaluated LINC00472 expression in breast tumor samples using RT-qPCR, performed a meta-analysis of over 20 microarray datasets from the Gene Expression Omnibus (GEO) database, and investigated the effect of LINC00472 expression on cell proliferation and migration in breast cancer cells transfected with a LINC00472-expressing vector. Our qPCR results showed that high LINC00472 expression was associated with less aggressive breast tumors and more favorable disease outcomes. Patients with high expression of LINC00472 had significantly reduced risk of relapse and death compared to those with low expression. Patients with high LINC00472 expression also had better responses to adjuvant chemo- or hormonal therapy than did patients with low expression. Results of meta-analysis on multiple studies from the GEO database were in agreement with the findings of our study. High LINC00472 was also associated with favorable molecular subtypes, Luminal A or normal-like tumors. Cell culture experiments showed that up-regulation of LINC00472 expression could suppress breast cancer cell proliferation and migration. Collectively, our clinical and in vitro studies suggest that LINC00472 is a tumor suppressor in breast cancer. Evaluating this long non-coding RNA in breast tumors may have prognostic and predictive value in the clinical management of breast cancer.

Available epidemiologic data suggest the possibility that the use of oral conjugated equine estrogens (CEE) 0.625 mg/day as a first-choice dose could be associated with a very limited (if any) breast cancer risk increase. Some biological peculiarities of oral CEE back the possibility of a limited detrimental effect on breast tissue, due to either direct or indirect actions. Direct actions. Some experimental findings suggest that the 17 alpha-dihydroderivatives of equilenin and equilin (15% of the CEE components) have a non-estrogenic or even an anti-estrogenic effect on breast tissue. This could partially counterbalance the stimulatory action of the other CEE components. Indirect actions. Oral estrogens, through their metabolic and hepatocellular effects (emphasized by the first liver passage) cause a sharp increase in sex hormone binding globulin (SHBG) level which is followed by a lower quantity of both estrogen and androgen in the free, bioavailable, form. More importantly, they cause a decrease in circulating insulin-like growth factor I (IGF-I) activity, due to both a reduction in IGF-I synthesis by the liver and an increase in IGF-binding protein-1 level. A strong relationship between breast cancer risk and the concentration of circulating IGF-I in premenopausal women has been recently found. Actually, estrogens and IGF-I have a synergistic effect on cell proliferation, and IGF-I is necessary for maximum estrogen-receptor activation in breast cancer cell lines. The possibility does exist that the SHBG level increase and the IGF-I bioavailability decrease, caused by oral CEE, balance the increased estrogen stimulation on breast tissue.

To the Editor. —Investigations of the effect of progestin added to ERT in relation to breast cancer risk have produced inconsistent results. Dr Stanford and colleagues 1 point out that progestins usually prescribed in Northern Europe (levonorgestrel at a dose of 0.25 mg/d or norethisterone acetate at a dose of 5 to 10 mg/d) differ from those most commonly used in the United States (medroxyprogesterone acetate at a dose of 10 mg/d), and they suggest that the different androgenic action of these drugs could possibly account for the observed differences in study results. Oral conjugated estrogens, through hepatocellular action, cause biological modifications potentially protective against breast cancer such as an increase of sex hormone binding globulin (SHBG) 2 and a reduction of insulinlike growth factor I (IGF-I) serum levels. 3 SHBG is able to bind steroid hormones (estradiol and testosterone), thereby reducing their biological activity. 4 IGF-I is a potent