G. Petrella

ADJUVANT THERAPY WITH TAMOXIFEN IN OPERABLE BREAST CANCER: 10 year results of the Naples (GUN) study

Treatment with tamoxifen (TM), alone or in combination with cyclophosphamide, methotrexate, and fluorouracil (CMF), was used as an adjuvant to surgery in 433 patients with stage I, II, or III(T3a) breast cancer. Oestrogen receptors (ER) and progesterone (PgR) receptors were assayed in most cases. 308 premenopausal node-negative and postmenopausal node-negative or node-positive patients were randomised to receive TM, 30 mg daily for 2 years, or no further therapy. 125 premenopausal node-positive patients were randomised to receive either CMF for nine courses plus TM or CMF alone. After a median follow-up of 63 months TM significantly reduced the incidence of relapses and deaths compared with no therapy. A significant interaction between treatment effect and ER/PgR status was seen. Disease-free and overall survival were similar after treatment with CMF+ TM or CMF.

CMF vs alternating CMF/EV in the adjuvant treatment of operable breast cancer. A single centre randomised clinical trial (Naples GUN-3 study).

The aim of this study was to test the hypothesis of Goldie and Coldman that the use of non-cross-resistant regimens of chemotherapy could lead to maximal anti-tumour effect. We compared standard CMF (cyclophosphamide, methotrexate, fluorouracil) with alternating CMF/EV (epirubicin, vincristine) in the adjuvant therapy of early breast cancer. Stage II premenopausal node-positive or post-menopausal node-positive oestrogen receptor-negative and stage III breast cancer patients were eligible for the study. From January 1985 to December 1990, 220 patients were randomised (115 to CMF and 105 to CMF/EV). Toxicity was mild; neurotoxicity, vomiting and hair loss were more frequent in the CMF/EV group, while permanent amenorrhoea, diarrhoea, stomach ache and minor infections occurred more often in the CMF arm. At a follow-up of 48 months, 113 patients (51.4%) had had recurrence (62 on CMF and 51 on CMF/EV) and 54 (24.5%) had died (30 on CMF and 24 on CMF/EV). There was no significant difference in disease-free and overall survival between the two arms. After adjusting for menopausal status and stage, the relative risk (RR) of recurrence for CMF/EV patients was 0.93 (95% CL 0.64-1.35), while the RR of death was 0.85 (95% CL 0.49-1.47). In conclusion, the Goldie-Coldman model of alternating therapy is not confirmed in this trial of adjuvant therapy of early breast cancer, although in view of its design a difference of less than 20% in 3 year disease-free survival could not be excluded.

A predictive index of axillary nodal involvement in operable breast cancer

We investigated the association between pathological characteristics of primary breast cancer and degree of axillary nodal involvement and obtained a predictive index of the latter from the former. In 2076 cases, 17 histological features, including primary tumour and local invasion variables, were recorded. The whole sample was randomly split in a training (75% of cases) and a test sample. Simple and multiple correspondence analysis were used to select the variables to enter in a multinomial logit model to build an index predictive of the degree of nodal involvement. The response variable was axillary nodal status coded in four classes (N0, N1-3, N4-9, N > or = 10). The predictive index was then evaluated by testing goodness-of-fit and classification accuracy. Covariates significantly associated with nodal status were tumour size (P < 0.0001), tumour type (P < 0.0001), type of border (P = 0.048), multicentricity (P = 0.003), invasion of lymphatic and blood vessels (P < 0.0001) and nipple invasion (P = 0.006). Goodness-of-fit was validated by high concordance between observed and expected number of cases in each decile of predicted probability in both training and test samples. Classification accuracy analysis showed that true node-positive cases were well recognised (84.5%), but there was no clear distinction among the classes of node-positive cases. However, 10 year survival analysis showed a superimposible prognostic behaviour between predicted and observed nodal classes. Moreover, misclassified node-negative patients (i.e. those who are predicted positive) showed an outcome closer to patients with 1-3 metastatic nodes than to node-negative ones. In conclusion, the index cannot completely substitute for axillary node information, but it is a predictor of prognosis as accurate as nodal involvement and identifies a subgroup of node-negative patients with unfavourable prognosis.

Prolactin receptor does not correlate with oestrogen and progesterone receptors in primary breast cancer and lacks prognostic significance. Ten year results of the Naples adjuvant (GUN) study

The correlation between prolactin (PRLR) and oestrogen (ER) or progesterone receptors (PgR) in breast cancer and a possible prognostic significance of PRLR at 10 year follow-up have been investigated in the Naples (GUN) adjuvant trial. A total of 308 pre- and post-menopausal patients with early breast cancer, who entered the trial from 1 February 1978 to 31 December 1983, received randomly Tamoxifen (TM), 30 mg per die for 2 years, or no therapy. PRLR status was known in 229 (74.3%) patients. Values of specific binding less than 1% were considered negative. PRLR was positive in 75/229 (32.8%). ER was assayed in 210/229 (91.7%) patients and PgR in 188/229 (82.1%). No significant correlation, by the Spearman test, was found between PRLR and ER or PgR, while ER status was highly interrelated with PgR status. By the Cox model no evidence of an independent prognostic role of PRLR on disease-free survival (DFS) was observed, nor an interaction between PRLR and adjuvant treatment with TM was found.

A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node-positive breast cancer.

The sequential doxorubicin → CMF (CMF=cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF × 6 cycles (CMF); (b) doxorubicin × 4 cycles followed by CMF × 6 cycles (A → CMF); (c) CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (CMF → GT); and (d) doxorubicin × 4 cycles followed by CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (A → CMF → GT). The study used a 2 × 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A → CMF or arms a+c vs b+d) and (2) the effect of adding GT after chemotherapy (arms a+b vs c+d). At a median follow-up of 72 months, A → CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR)=0.740 (95% confidence interval (CI): 0.556–0.986; P=0.040) and produced a nonsignificant improvement of overall survival (OS) (HR=0.764; 95% CI: 0.489–1.193). The addition of GT after chemotherapy significantly improved DFS (HR=0.74; 95% CI: 0.555–0.987; P=0.040), with a nonsignificant improvement of OS (HR=0.84; 95% CI: 0.54–1.32). A → CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients.

The first breast cancer screening program in southern Italy: preliminary results from three municipalities of the Naples province

Aims and Background It has been demonstrated that breast cancer screening induces a 30% reduction of specific mortality. In May 1990, we started a pilot screening program to assess the feasibility of carrying out such a program in Campania (southern Italy). Herein we report the results of the first round of the program from three municipalities (Giugliano, Mugnano and Qualiano) that lie within the local health district no. 23, close to the city of Naples. Methods Women between the ages of 50 and 69 years were sent a personalized letter inviting them to attend the screening test; those not responding were sent a second invitation. The screening test consisted of clinical examination followed by two-view mammography. Second–level diagnostic tools were sonography, fine needle aspiration (manual, echo-guided and stereotaxic) and surgical biopsy. Results Out of 5,732 women invited for the first round, 1,813 (31.6%) attended the screening. Attendance rate was higher among younger women. Ninety-one women were positive at the screening test and underwent further examination (recall rate, 5.0%). Among them, 19 had surgical biopsy (biopsy rate, 1.0%) that led to breast cancer diagnosis in 11 cases. The benign/malignant biopsy rate was 0.73. Detection rate was 6.07 × 1,000 screened women and varied among age categories, increasing within the 60–69 subgroup; detection rate/expected incidence ratio in the overall group was 4.5 and also increased within the older age category. Seven out of 11 cancers were at UICC stage 0-I. Among 327 self-referring women, 38 were positive (recall rate, 11.6%), and 14 underwent biopsy (biopsy rate, 4.3%), which showed cancer in 7 cases (benign/malignant biopsy rate, 1.0). In addition, 2 inflammatory cancers were diagnosed without surgical biopsy. Thus 9 cancer cases were detected in this group. Self-referring women differed from responding women in that they had a higher frequency of symptoms or familiar history of cancer, and a higher educational level and awareness of preventive medicine. Clinical examination added no diagnostic advantage in the responding group but did not significantly worsen the recall rate. In the self-referring group, one case of inflammatory cancer was missed by mammography and diagnosed by clinical examination. Conclusion The early results (recall rate = 5%, detection rate/expected incidence ratio = 4.5, benign/malignant biopsy rate = 0.73, advanced cancers = 36.4%) are encouraging and indicate the validity of the program. Strategies to improve attendance rate are planned.

Selecting High-risk Early Breast Cancer Patients: What to Add to the Number of Metastatic Nodes?

High-risk early breast cancer patients are usually identified by the number of metastatic axillary nodes. To study whether other easily and inexpensively detectable morphological factors are able to detect high-risk patients, we performed a retrospective analysis of tumor size, and skin/fascia and nipple invasion. The data consisted of 941 node-positive cases registered between 1978 and 1991. Tumour size, and skin/fascia and nipple invasion were closely associated with the number of metastatic nodes (chi 2 test). The number of metastatic nodes, tumour size, skin/fascia and nipple invasion significantly affected disease free survival (DFS) and overall survival (OS) at univariate analysis. These results were confirmed by multivariate analysis with a model containing the number of metastatic nodes, tumour diameter categories, skin/fascia invasion, nipple invasion and adjuvant therapy as covariates: all variables significantly and independently affected risk of relapse and of death. All the variables studied were prognostic, within individual nodal categories, for both DFS and OS. In conclusion, the number of metastatic nodes is not the only prognostic tool with which to select high-risk patients for new intensive adjuvant programmes. Tumour size, and skin/fascia invasion or nipple invasion, taken singly or combined, are valuable prognostic factors that can identify patients with few metastatic nodes and poor outcome. On the basis of our data, we believe that a reconsideration of the pT4 category within the pTNM classification is in order, that is, chest wall invasion should be substituted by fascia invasion, and combined skin/fascia invasion could be a subcategory of each class defined by tumour size.

Steroid hormone receptor levels and adjuvant tamoxifen in early breast cancer - Ten year results of the Naples (GUN) study

SummaryTen year disease-free survival (DFS) results of the Naples randomized trial of adjuvant tamoxifen (TM), 30 mg per day for 2 years versus no therapy according to receptor levels, are reported. From Feb. 1, 1978, through Dec. 31, 1983, 308 pre- and postmenopausal patients with early breast cancer entered the trial. Estrogen receptor (ER) data were available on 239 (77.6%) patients, progesterone receptor (PgR) data on 194 (63.0%), and both receptor data on 181 (58.8%).ER and PgR were assayed by dextran-coated charcoal technique in a single laboratory. The effect of adjuvant TM was significantly related to ER and PgR concentration of the primary tumor. The greatest TM benefit on DFS was evident in patients with the highest levels of receptors. The interaction between the treatment effect and receptor concentration was found whether ER and PgR were considered separately or together.

Failure to Demonstrate Plasma Hormone Abnormalities in Women with Operable Breast Cancer

The endocrine profile of patients with breast cancer has been the object of extensive studies during the past several years. Abnormal secretion of a variety of hormones has been described on different occasions in patients with breast cancer (Gambrell, 1982; Henderson et al., 1982; Kirschner et al., 1982; Kwa and Wang, 1977; Ohgo et al., 1976), and has been considered a possible risk factor. However, conclusive evidence has not yet been presented to show that the cancer patients are significantly different in endogenous hormone profiles from their healthy counterparts. The main purpose of the present study was to critically reevaluate this controversial issue and possibly identify hormonal changes in a large population of patients with operable breast cancer not present in a comparable population of normal healthy women.