The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: first results of the endometrial sub-protocol following 2 years of treatment.

BACKGROUND: Tamoxifen treatment results in a doubling of the risk of endometrial cancer after 1-2 years of treatment and a quadrupling after 5 years. Anastrozole, a third-generation aromatase inhibitor, with superior efficacy to tamoxifen, may also offer tolerability benefits in terms of effects on the endometrium. METHODS AND RESULTS: A sub-protocol of the ATAC trial compared the incidence/type of intrauterine changes following treatment with these agents in a subgroup of patients (n = 285) from the main trial. After 2 years anastrozole treatment, endometrial thickness remained

The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: baseline endometrial sub-protocol data on the effectiveness of transvaginal ultrasonography and diagnostic hysteroscopy.

BACKGROUND: The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind trial comparing anastrozole ('Arimidex'), alone or in combination with tamoxifen, relative to tamoxifen alone as 5 year adjuvant treatment for post-menopausal women with early breast cancer. Since tamoxifen is associated with endometrial pathology, the ATAC endometrial sub-protocol was initiated to establish the background prevalence of intrauterine pathology, and to assess prospectively the incidence and nature of intrauterine changes following endocrine therapy. Another aim was to provide data from which advice could be generated on the best endometrium screening method for patients receiving tamoxifen. METHODS: Patients underwent endometrial assessments at entry to the sub-protocol. The baseline investigations comprised transvaginal ultrasound scanning (TVUS), a hysteroscopy and an endometrial biopsy. RESULTS: A total of 285 gynaecologically asymptomatic women from 31 centres in 10 countries entered the endometrial sub-protocol. The mean uterine volume was 47.7 cm3. The median endometrial thickness overall was 3 mm. Twenty-four histologically confirmed, pathological changes were observed. Twenty-three pathologies were confirmed by TVUS, and 21 were identified by hysteroscopy and confirmed by histopathology. Women with or without intrauterine pathology had median endometrial thickness of 5 and 3 mm respectively. CONCLUSIONS: The presence of pathology was associated with increased endometrial thickness. The relative sensitivity and specificity of hysteroscopy and endometrial thickness for the diagnosis of endometrial pathology was comparable to other studies. If screening of the endometrium prior to treatment is appropriate, this study supports the use of an endometrial thickness of 3 mm, as assessed by TVUS, as a threshold for needing further investigation. This study demonstrates that if the endometrial thickness is >3 mm, hysteroscopy and biopsy is the optimal method of detecting intrauterine pathology in women with breast cancer who are about to commence endocrine treatment.

The ATAC adjuvant breast cancer trial in postmenopausal women: baseline endometrial subprotocol data.

OBJECTIVE: The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial is a randomised, double-blind trial comparing 'Arimidex' (anastrozole), alone or in combination with tamoxifen, relative to tamoxifen alone as a five year adjuvant treatment for postmenopausal women with early breast cancer. Because tamoxifen is associated with endometrial pathology, the ATAC endometrial subprotocol was initiated to establish the background prevalence of pathology, and to assess prospectively the incidence and nature of intrauterine changes before and following endocrine therapy. SETTING: International. POPULATION AND STUDY DESIGN: Two hundred and eighty-five women entered the subprotocol: the mean age was 60 years (range 44-80 years); 113 women (40%) had taken hormone replacement therapy prior to randomisation, and 238 women were parous (84%). The age at onset of the menopause was 32-58 years, with the majority becoming menopausal between 46 and 55 years of age. Two hundred and seventy-two women had a hysteroscopy before they commenced trial medication. Hysteroscopy was performed successfully in 265 women. In six women, failure of hysteroscopy at baseline led to withdrawal from the study. Three of the women who withdrew had a pipelle biopsy taken. Therefore, the total number of endometrial biopsies at baseline was 268. MAIN OUTCOME MEASURES: To assess the demographic characteristics of women entering the endometrial subprotocol and their hysteroscopic and histological findings before commencing trial medication. RESULTS: At hysteroscopy, there was a diagnosis of endometrial polyps in 34 women (13%), fibroids in 16 women (6%) and one case of suspicious endometrium, which was confirmed as a polyp on histology. Only 21 of the 34 polyps seen hysteroscopically were proven histologically (62% accuracy of hysteroscopy). Final histology found the prevalence of endometrial diagnostic categories as follows: 123 inactive endometrium (46%), 20 benign polyps (7%), 17 secretory endometrium (6%), 7 proliferative endometrium (3%), 3 atypical hyperplasia (2 in a polyp), 1 simple hyperplasia (in a polyp) and 1 fibroid. The remaining women had pipelle samples with insufficient tissue obtained, indicating a normal endometrial cavity. CONCLUSION: This is the first study of such size in gynaecologically asymptomatic breast cancer patients. This paper describes the findings in individual patients before any trial treatment was given. In this baseline group, 82% (219/268) of women had a normal endometrial cavity; 18% (49/268) had endometrial activity (proliferative or secretory endometrium in 9%) or an intracavity abnormality (hyperplasia, polyps and a fibroid in 9%). In total, 36% of biopsies had insufficient tissue for diagnosis, which in combination with a normal hysteroscopy was classed as normal. The appearance of a polyp hysteroscopically in this group was not proven histologically in approximately 40% of cases. The development of uterine pathology over time in the ATAC study will subsequently be assessed against the findings of this baseline paper.

Endometrial disorders in 406 breast cancer patients on tamoxifen: the case for less intensive monitoring.

OBJECTIVES: To describe the endometrial appearance in postmenopausal breast cancer patients on tamoxifen and to assess a routine surveillance scheme for endometrial lesions. STUDY DESIGN: Three hundred and seventeen postmenopausal breast cancer women already on tamoxifen at the start of the study (group I) and 89 breast cancer women assessed before any tamoxifen intake (group II) underwent an initial and then yearly scans with transvaginal ultrasonography, followed by an hysteroscopy and biopsy for women with an endometrium thickened above 8mm. Endometrial thickness was also measured in 823 women with no breast cancer nor tamoxifen intake (group III). RESULTS: Initial mean endometrial thickness was 8.2mm in group I, 4.4mm in group II and 3.4mm in group III (P<0.001). Eighteen percent endometrial lesions were found in group I and 3.3% in group II. We observed a significant association between endometrial pathology and both cumulated dose and total duration. Polyps were the most frequent and first to appear pathology. Five cancers were detected in group I, and all of them had taken tamoxifen for more than 3 years. CONCLUSION: Our surveillance scheme could be lightened; an acceptable screening scheme might include a baseline assessment before the start of tamoxifen and, if normal, yearly screening after 3 years of tamoxifen therapy, yearly surveillance for women with an abnormal baseline assessment and immediate investigation for symptomatic women.

Cytology alone versus cytology and cervicography for cervical and cervicography for cervical cancer screening: a randomized study. European Society for Oncological Research.

OBJECTIVE: To compare the ability of combined cytology and cervicography with cytology alone to decrease the number of premalignant cervical lesions found in subsequent screening. METHODS: Five thousand five hundred fifty women 18-91 years old were randomized to cytology plus cervicography or cytology alone. One year later, women were rescreened using both cytology and cervicography. All women with positive lesions were referred for colposcopically directed biopsies and treatment as indicated. We expected to decrease by half the number of cervical intraepithelial neoplasia (CIN) lesions at 1-year screening by adding cervicography to cytology at initial screening. RESULTS: Compared with cytology screening alone, screening with cytology plus cervicography showed a 30% reduction in CIN I-II-III cervical lesions at 1-year screening round (relative risk [RR] 0.70; 95% confidence interval [CI] 0.32, 1.55, P = .35) and a 43% reduction in CIN II-III cervical lesions (RR 0.57; Cl 0.14, 2.16, P = .36). Most lesions detected by one test were not detected by the other. In a retrospective search, nine biopsies (one normal and eight revealing CIN I or more on histopathology) were found to be positive for the human papillomavirus; five of the nine biopsies were found by cytology, three by cervicography, and one by both tests. CONCLUSION: The addition of cervicography to cytology in initial screening did not significantly decrease the number of premalignant cervical lesions detected 1 year later, probably because of the transient nature of most of these lesions. Because cytology and cervicography seemed to detect different premalignant lesions, it is possible that cervicography could detect lesions that do not express the cellular abnormalities necessary for detection by cytology.

A multicentre study comparing cervicography and cytology in the detection of cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate in a multicentre setting the performance of cervicography compared with cytology for the detection of cervical intraepithelial neoplasia. DESIGN: Prospective comparative multicentre study. SETTING: Three hospitals with outpatient gynaecology clinics and three cancer screening clinics. PARTICIPANTS AND METHODS: Cervical cytology and cervicography were performed on 5724 women. If one or both tests showed an abnormality suggestive of at least a low grade squamous intraepithelial lesion, a colposcopy with directed biopsy was carried out. Cervicograms were evaluated by four experienced 'senior' assessors and by ten new 'junior' assessors. RESULTS: Results were fully analysed for 5192 women (91%). A cervical biopsy was carried out on 228 women and this confirmed a true positive lesion in 116 cases (incidence rate: 2.2%). Of these, 72 cases (62.1%) were detected by cervicography and 64 (55.2%) by cytology. This difference was not statistically significant (McNemar: P=0.475). Only 20 cases of CIN (17%) were concordantly detected by both tests. Senior assessors performed significantly better with a detection capacity of 80.6% compared to a detection capacity of 56.6% for the junior assessors (chi2 test: P=0.034). CONCLUSIONS: Cervicography must be considered as a complementary test to cytology. Overall detection of CIN is improved, but this is mainly due to the detection of more low grade lesions. The lower sensitivity and specificity in high grade lesions compared with cervical cytology is the main limitation of cervicography in screening for CIN. An important finding was that the performance of cervicography was highly dependent on the assessors' experience.

Transformation zone location and intraepithelial neoplasia of the cervix uteri.

We examined the relationship between the frequency of premalignant lesions of the cervix and location of the transformation zone on the cervix among 8758 women as assessed using cervicography. An endo- and exocervical smear test was performed at the same time. Women with smear test classified CIN I or more were recalled and any abnormal area was biopsied under colposcopy. The transformation zone was located on the exocervix in 94% of women younger than 25 years old; as age increased, the proportion of women with a transformation zone located on the exocervix steadily decreased to reach less than 2% after 64 years old. As compared with women having a transformation zone in the endocervical canal, the age-adjusted likelihood of discovering a histologically proven dysplastic lesion was 1.8 times more frequent among women with a transformation zone located on the exocervix (95% confidence interval 1.1-2.9). This higher frequency seemed not attributable to a lower sensitivity of the smear test when the transformation zone was hidden. The results also showed that deliveries tended significantly to maintain the transformation zone on the exocervix. Parity is a known risk factor for cervix cancer, but the mechanism by which it favours malignant lesions remain unknown. Our results suggest that with increasing numbers of livebirths, the transformation zone is directly exposed for longer periods to external agents involved in dysplastic lesions.

[Surgical approach to subclinical breast lesions]. / Approche chirurgicale des lésions infracliniques du sein.

The treatment of non palpable lesions is one of the most important aspect of breast surgery. Mortality due to breast cancer significantly decreases by about 40% if the tumor is treated before becoming palpable. However, specific modalities have to be strictly respected by a multidisciplinary and experienced medical team. Due to the lack of mass screening organised by public health authorities, physicians in charge of the first line have to generously prescribe mammograms to their patients aged 50-70. Expertise is required for the second line. An expert radiologist is a radiologist who is able to detect subclinical breast lesions and to precisely locate them within the breast. An expert surgeon is an experienced one who can read a mammogram, locate a non palpable lesion and completely remove it according to radiologist information. The pathologist refusing a frozen section and having a look on the mammogram to understand the medical story is the good one, allowing an appropriate therapy based on a precise and complete histologic diagnosis.

Is there a role for cervicography in the detection of premalignant lesions of the cervix uteri?

The characteristics of cervicography and the Papanicolaou smear test have been compared for the detection of cervix lesions classified as CIN I or more. A total of 4,015 women were entered into the study. The sensitivity of cervicography is significantly higher (McNemar test, P < 0.0001), but its specificity remains significantly lower (McNemar test, P < 0.0001), and its higher sensitivity does not apply to lesions classified as CIN II or more (high-grade lesions). Hence, if patients with a positive screen result are to be referred for colposcopy-biopsy, cervicography is not a suitable alternative to the smear test for the screening of cervical cancer. However, cervicography can be envisaged as a complementary tool to the smear test because of (a) its higher capability to detect high-grade lesions among women less than 35 years old and (b) its potential superiority in following low-grade lesions. It may also serve as a tool for quality assurance audit of the smear test.

Antisteroid immune complexes and vascular thrombosis during steroid hormone therapy.

To test an immunological hypothesis proposed to explain the pathogenesis of cerebrovascular thrombosis in steroid users, circulating immune complexes were assayed in the sera from 6 control subjects, 14 ever users of oral contraceptive having developed a neurological ischaemic accident, and 7 patients with the same clinical history during use of other sex steroid not containing ethinylestradiol. Beaumont's ammonium sulfate and polyethylene glycol precipitation methods, together with a specific method of isolation of circulating immune complexes using affinity chromatography on Protein A, were used. Radioactivity from labeled ethinylestradiol added to the sera before precipitation was monitored in the precipitates to detect anti-ethinylestradiol antibodies. There were no significant differences for these parameters in the three groups. However, protein content and 3H-EE activity in the precipitates were equally and dramatically reduced after affinity chromatography in the three groups. These latter results do not support the presence of antibodies against ethinylestradiol in steroid users with cerebrovascular thrombosis. Moreover, our data suggest a lack of specificity of Beaumont's method for the isolation of immune complexes containing anti-ethinylestradiol antibodies.

[Breast-preserving treatment of breast cancer and peroperative curietherapy]. / Traitement conservateur du cancer du sein et curiethérapie peropératoire.

From May 1988 to December 1990, 35 patients benefitted from a breast-conserving treatment (tumor resection with at least 1 cm of free margin, axillary dissection and peroperative brachytherapy). The iridium sources were introduced 24 h later, delivering between 15 to 17.5 Gy. Three weeks later an additional course of external radiation delivered a dose of 50 Gy in 5 weeks to the whole breast. In this series, only very early breast lesions were included and no patient received additional chemotherapy. Due to the short period of observation, we only report on the acute side effects even if until now we have not seen any case of tumor relapse. We did not observe any major complications after this combined approach: only three patients developed a local infection requiring antibiotics. Esthetic evaluation is quite encouraging with all women showing good and excellent results from the physician's and patient's points of view. This approach seems to be quite interesting cosmetically as it allows to correct the breast shape while preserving an adequate position of the implant and so preserving a good oncological approach.

Comparison of fine needle aspirates of breast cancers to imprint smears by means of digital cell image analysis.

Morphonuclear assessments were performed using the SAMBA 2005 cell image processor on cell nuclei in fine needle aspirates and corresponding imprint smears from 17 not-otherwise-specified (NOS) breast carcinomas to study the influence of cell sampling on the morphonuclear measurements. Fourteen parameters related to densitometric (nuclear DNA content), morphometric (nuclear area) and textural (chromatin organization and distribution) characteristics were computed for each nucleus. The results demonstrated that such morphonuclear features evolved significantly and positively with respect to conventional histopathologic grading. The method of cell sampling significantly influenced the results, but without altering the general conclusions regarding evolution of the morphonuclear features.

Reasons for non-entry of patients with DCIS of the breast into a randomised trial (EORTC 10853).

In EORTC trial 10853, patients with histologically confirmed surgical clearance of ductal carcinoma in situ (DCIS) are being randomised to observation alone or to receive external radiation to the breast (50 Gy). So far, 190 patients have been entered from 27 centres. An analysis has been conducted of patients with DCIS presenting to 6 of the participating hospitals. Within these centres there was a total of 216 patients with biopsy confirmed DCIS, without invasion, between 1985 and 1989. However only 77 (36%) were entered into the trial. The major reason for non-entry was that DCIS was too extensive (76/139, 55%), so that in situ disease extended to the margins of excision. Other reasons for exclusion included prior breast cancer (18%), delay in histological diagnosis (6%) and a lump measuring more than 3 cm in diameter (4%). Only 6 patients (4%) refused to take part in the trial. Thus the eventual results of the trial may be applicable only to a minority of patients with DCIS.

[Morbidity of surgical treatment for advanced cancer of the breast after irradiation]. / Morbidité du traitement chirurgical du cancer due sein avancé après irradiation.

The authors reviewed the medical files of 100 patients with locally advanced breast cancer (stage III), treated in the department of surgery of the Institut Jules-Bordet between 1974 and 1988. All patients received preoperative radiotherapy (average total dose of 45 Grays). This preoperative irradiation was associated with chemotherapy in 74% of patients. All patients subsequently underwent surgery and a modified radical mastectomy was performed in 92% of cases. Our data analysis reveals an incidence of 25% of local wound infections, 34% of delayed wound healing, 63% of seroma formation and 22% of lymphoedema of the upper limb. The local postoperative morbidity appears to be increased in patients preoperatively irradiated. This indicates that preoperative chemotherapy may be preferable in these patients to minimise the local postoperative morbidity and its impact on the quality of life.

[The value of screening using cervicography in dysplasia and neoplasms of the uterine cervix]. / Intérêt du dépistage par cervicographie dans la pathologie dysplasique et néoplasique du col utérin.

In cervical dysplasia and neoplasia, recent studies have reported the unreliability of the pap smear. We have used a new screening technique, cervicography and have compared it to cervix cytology. We have performed biopsies under colposcopy as reference and quality control. On a series of 65 selected patients with pap smear screening program which were sent to the colposcopic triage, the cervicography is more sensitive (83%) than the pap smear (sensitivity: 42%). However, those two tests are from a specificity point of view, comparable (cervicography: 95% versus pap smear: 98%). The association of these two techniques has detected all the lesions: they seem to be complementary. In the Bordet Institute we decided to systematically perform both pap smear and cervicography for cervix screening.

Local postoperative morbidity following pre-operative irradiation in locally advanced breast cancer.

The authors have reviewed the medical files of 100 patients with locally advanced breast cancer (Stage III), who were treated in the Department of Surgery at the Institut Jules Bordet between 1974 and 1988. All patients received pre-operative radiotherapy (average total dose 45 Gy), which was associated with chemotherapy in 74% of patients. All patients were subsequently subjected to surgery, using a modified mastectomy in 92% of cases. Our data reveal an incidence of 25% local wound infection, 34% delayed wound healing, 63% seroma formation and 22% lymphoedema of the upper limb. It seems that local postoperative morbidity is increased in patients pre-operatively irradiated. This indicates that pre-operative chemotherapy may be preferable in these patients to minimize the local postoperative morbidity and its impact on the quality of life.

Detection of human papillomaviruses 16-18 in cervical cells by molecular hybridization: relationship with morphonuclear cell image analyses.

Forty-one Feulgen-stained cervical imprint smears were analyzed by means of the SAMBA 200 cell image processor in order to quantitatively score human papillomavirus (HPV) 16-18-induced morphonuclear modifications as assessed by morphometric, densitometric, and textural parameters. Molecular hybridization technology using 16 and 18 type specific genetic probes made it possible to divide our series into three groups: Group 1, containing noninfected smears; Group 2, containing "suspicious", i.e., borderline positive, smears; and Group 3, those related to infected patients. Our results show that nuclei from infected smears are much more hyperchromatic and bigger than those arising from noninfected smears. This quantitative description of HPV 16-18-induced chromatin modifications enabled us to create preliminary data banks which could lead to an objective and reproducible grading of unknown cases. This approach is now being prospectively assessed on a large series of cases because the value of the current study is limited until the data bank is tested against unknown specimens with a broader spectrum of HPV infection.