Response to neoadjuvant chemotherapy in lobular and ductal breast carcinomas: a retrospective study on 860 patients from one institution.

BACKGROUND: We compared the impact of neoadjuvant chemotherapy on pathologic response and outcome in operable invasive lobular breast carcinoma (ILC) and invasive ductal breast carcinoma (IDC). PATIENTS AND METHODS: We extracted from our database all patients with pure invasive lobular (n=118, 14%) or pure invasive ductal carcinomas (n=742, 86%). Their treatment included neoadjuvant chemotherapy, adapted surgery, radiotherapy and adjuvant hormonal treatment. RESULTS: Compared with IDC, ILC presented with larger tumors (T3: 38.1% versus 21.4%, P=0.0007), more N0 nodes status (55.9% versus 43.3%, P=0.01), less inflammatory tumors (5.9% versus 11.8%, P=0.01), more hormone receptor positivity (65.5% versus 38.8%), lower histological grade (P<0.0001). Final surgery was a mastectomy in 70% of patients with ILC (34% were reoperated after initial partial mastectomy) and in 52% of IDC after 8% of reoperation (P=0.006). A pathological complete response (pCR) was achieved in 1% of ILC and 9% of IDC (P=0.002). The outcome at 60 months was significantly better for ILC, but histologic type was not an independent factor for survival in multivariate analysis. CONCLUSIONS: ILC appeared less responsive to chemotherapy but presented a better outcome than IDC. While new information on biological features of ILC is needed, we consider that neoadjuvant endocrine therapy in hormone receptor-positive ILC may be a more adapted approach than neoadjuvant chemotherapy.

Nonlinear discriminant analysis and prognostic factor classification in node-negative primary breast cancer using probabilistic neural networks.

BACKGROUND: We used non-linear kernel discriminant analysis (KDA) to predict the outcome of 134 axillary node-negative primary breast cancer patients not treated with adjuvant therapy in a non censored database. MATERIAL: Posterior probabilities of relapse at 5 years were estimated using probabilistic neural networks (PNN) and a cross-validation (leave-one-out) technique to avoid overfitting the data. A stepwise method was used to construct the models to define the best combination of risk factors among eleven prognostic factors: age, menopausal status, Scarff-Bloom-Richardson grade, clinical tumor size, pathological tumor size, estrogen and progesterone receptor status, urokinase-type plasminogen activator, p53 protein level, c-erbB-2 protein and epidermal growth factor receptor. The different variables were tested individually and in combination to determine their prognostic power using a ROC indicator, which measures the separation between the probability distributions of the output neuron activations under the null hypothesis (no recurrence at 5 years) and under the alternative hypothesis (recurrence at 5 years). RESULTS: The best predictive one-dimensional model was obtained with uPA (ROC indicator = 0.75). A two-factor model including uPA and clinical tumor size (T) gave the best discrimination between recurrence and non recurrence at 5 years (ROC indicator = 0.84). Additional variables did not improve the accuracy of the prediction. The uPA-T model generated a map useful in predicting the posterior probability of cancer recurrence in a given patient. This representation allows the entire database to be easily visualized and each patient can be compared with the entire database. CONCLUSION: This is a powerful approach to analyze the impact of prognostic factors and it could find clinical applications in breast cancer.

[Survivorship of breast implants used in breast reconstruction. 949 implants]. / Durée de vie des implants mammaires en reconstruction mammaire. A propos de 949 implants.

The authors present from a series of 949 implants their method to calculate the life span of a mammary implant in the framework of breast reconstruction after cancer. In this statistical study, they have calculated the median life span of breast implants (loss of half of staff) by distinguishing it according to each type of implant (content, brand, indication...). The global median life span of a breast implant is 127 months. The median life span of a silicone gel-filled implant is superior than a saline implant because the frequency of deflation of saline implants is more important than the first one, despite that the real rupture percentage of silicone gel-filled implants is under-evaluated by the number of asymptomatic rupture. For saline implants, the median life span is clearly decreased by the initial under-inflation (108 months against 127 months) doubling the secondary deflation risk. In this series, the authors have been able to compare the evolution of implants according to their initial indication (reconstruction or aesthetic) and sometimes at a same patient, they have not observed significant difference of the median life span over a period of five years for an implant used in breast reconstruction after cancer or for an implant used in symmetricalization. In this series, the life span of saline implants is significant different in function of the brand of the implant demonstrating the comparative study usefulness by brands.

[Initial medical treatment for breast cancer]. / Traitement médical d'induction et cancer du sein.

Rationale for primary medical treatment of breast cancer relies on experimental data showing that the incidence of metastatic disease is dependent on the primary tumour mass and tumoral angiogenesis. Although this concept may be applied to both chemotherapy and hormonotherapy, only the first was extensively explored for patients with locally advanced breast cancer, and more recently in smaller tumours. Despite high clinical +/- radiological response rates, only pathologic information, carefully assessed in both the primary and axillae lymph nodes, stands out as the major source of prognostic information on patients' outcome. Recent developments in chemotherapy (dose-intensity, new drugs) do not seem to influence these results, indicating the possible limitations of conventional chemotherapy. Of 6 published randomized trials comparing neo versus adjuvant strategy, none showed any significant impact of primary chemotherapy on survival, with in some a trend towards delayed and/or distant recurrences if neoadjuvant treatment given. That some recent reports suggest that local relapse rate might be increased after conservative treatment following induction chemotherapy in subgroups analyses should cause oncologists to revise the role for post neoadjuvant treatment conservative surgery without calling into question the global strategy. Through sequential samplings, neoadjuvant medical treatment provides indeed the opportunity (a) to identify molecular mechanisms associated with pathologic response and (b) to study the possibility to guide the choices for induction treatment and patients' populations submitted to primary medical treatment.

[Treatment of breast cancer after 70 years of age. Report of 1143 cases]. / Le traitement du cancer du sein après 70 ans. A propos de 1143 cas.

STUDY AIM: Breast cancer is the most frequent type of cancer in women, increasing in frequency with the elderly. In Europe, a third of new breast cancers occur in women over 70 years of age. The aim of this retrospective study was to analyse the tumoural lesions and therapeutic results in a female population over 70, treated in the same medical centre over a 15-year period. PATIENTS AND METHODS: From 1978 to 1992, 1,143 female patients aged 70 or over were treated for a unilateral breast cancer without metastases and followed-up during a mean 6-year period. The initial treatment was surgical in 1,012 patients: radical mastectomy in 95% of the cases with axillary node dissection in 97.6%. Adjuvant radiotherapy was performed in 289 patients and adjuvant treatment with Tamoxifen in 411 patients. The results were compared with those obtained in 2,947 patients aged 50 to 69, treated during the same period in the same medical centre. RESULTS: The 5-year survival rate in women 70 and over was 80% vs 85.5% in women aged 50 to 69 (P < 0.000001). The same rate of loco-regional recurrences and metastases occurred in both populations. In the patients who initially underwent surgery, after multivariate analysis according to the Cox model, the prognosis factors (similar to those observed in the group of younger women) were: the number of involved nodes (P = 0.000001), the clinical size of the tumour (P = 0.00001), the histological grade (P = 0.01), and the estrogen receptors (P = 0.02). CONCLUSIONS: In this series, the treatment was focused on surgery complemented with adjuvant radiotherapy according to node invasion and adjuvant hormonotherapy according mostly to hormonal receptors. However, the complete treatment could not be applied to all cases: only 50% of patients with node involvement were irradiated. The 5-year survival rate lower than that of younger patients may be attributed to incomplete adjuvant treatment. Specific controlled trials taking into account quality of life had to be undertaken in elderly patients in order to adjust the treatment in relation with the patients' age and physiological condition.

[Mitomycin-vinorelbine combination as second-line chemotherapy in metastatic cancer of the breast]. / Association mitomycine-vinorelbine en deuxième ligne chimiothérapique dans le cancer du sein métastatique.

Fourty-six patients (41 evaluable) were treated in second line chemotherapy of metastatic breast cancer (MBC) by an association of mitomycin (M), vinorelbine (V) (M 8 mg/m2 D1, V 25 mg/m2 D1 and DI 8 every 4 weeks). Median age was 58 years (36-78), median performance status 1 (0-3). Thirty-seven per cent of the tumors were estrogen receptors positive and 17% progesterone receptors positive. Seventeen patients received an adjuvant chemotherapy and 39 a first line chemotherapy with anthracycline (A). The median number of metastatic sites was 2 (1-4) and 27 patients (67%) had visceral metastases. Twelve patients were refractory to anthracyclines and 5 resistant. No toxic death nor hemolytic uremic syndrome were observed. Seven (3.7%) febrile neutropenias happened responsible for 4 hospitalizations. A grade 3 or 4 neutropenia was noted in 34% of the cycles but no other clinic toxicity nor grade 3 or 4 thrombopenia. The rate of objective response (OR) was 37.5% with 2 complete responses (CR) and 13 partial responses (PR). Seven patients had stable disease and 18 progressed. The rate of hepatic OR was 31%. Five (40%) A-refractory patients responded but no resistant patient. Median OR time was 10 weeks (8-12) and median OR duration was 5 months (3-6). Median survival was 11.5 months. MV association is well tolerated and effective in second line chemotherapy for MBC even with hepatic metastasis and in patients refractory to anthracyclines.

Mitomycin-vinorelbine as second line chemotherapy in metastatic breast cancer

Fourty-six patients (41 evaluable) were treated in second line chemotherapy of metastatic breast cancer (MBC) by an association of mitomycin (M), vinorelbine (V) (M 8 mg/m2 D1, V 25 mg/m2 D1 and DI 8 every 4 weeks). Median age was 58 years (36-78), median performance status 1 (0-3). Thirty-seven per cent of the tumors were estrogen receptors positive and 17% progesterone receptors positive.eventeen patients received an adjuvant chemotherapy and 39 a first line chemotherapy with anthracyclin (A). The median number of metastatic sites was 2 (1-4) and 27 patients (67%) had visceral metastases. Twelve patients were refractory to anthracyclins and 5 resistant. No toxic death nor hemolytic uremic syndrom were observed.even (3,7%) febrile neutropenias happened responsible for 4 hospitalizations. A grade 3 or 4 neutropenia was noted in 34% of the cycles but no other clinic toxicity nor grade 3 or 4 thrombopenia. The rate of objective response (OR) was 37,5% with 2 complete responses (CR) and 13 partial responses (PR).even patients had stable disease and 18 progressed. The rate of hepatic OR was 31%. Five (40%) A-refractory patients responded but no resistant patient. Median OR time was 10 weeks (8-12) and median OR duration was 5 months (3-6). Median survival was 11,5 months. MV association is well tolerated and effective in second line chemotherapy for MBC even with hepatic metastasis and in patients refractory to anthracyclins.

[Adjuvant chemotherapy of breast cancer]. / Chimiothérapie adjuvante des cancers du sein.

Numerous randomized trials have been conducted in an attempt to demonstrate the role of adjuvant chemotherapy in localized operable breast cancer. A major meta-analysis has demonstrated its effectiveness in certain indications. These trials show that only long-term combination chemotherapy has an undeniable efficacy. The reference protocol is the classical CMF combining cyclophosphamid, methotrexate and 5 fluoro-uracil. Efficacy is clear for patients under 50 years of age. After this age, tamoxifen is effective. There does not appear to be any benefit from prolonging chemotherapy over 6 months. The meta-analysis has not however answered all the questions raised by adjuvant chemotherapy. Should chemotherapy be used in N-forms? What is the effect of treatment in patients over 65? What is the optimal treatment duration? Is there a dose-efficacy relationship? What is the relative effect of chemotherapy versus radiotherapy? Does perioperative chemotherapy add any benefit? What should be the relative roles of hormone therapy and chemotherapy? Is castration as effective as chemotherapy before menopause and tamoxifen after menopause? Currently, only partial answers to these questions have been obtained and many remaining problems will only be solved by the results of controlled trials currently under way.

[Genetic alterations in localized cancers of the prostate: identification of a common region of deletion on the chromosome 18q]. / Altérations génétiques dans les cancers localisés de la prostate: identification d'une région commune de délétion sur le chromosome 18q.

Prostate cancer is one of the most common malignancies in men. Few authors have attempted to identify consistent genetic alterations at the molecular level in adenocarcinoma of the prostate, but those most frequently reported are loss of heterozygosity (LOH) involving chromosome arms 8p, 10q, 16q, and 18q and inactivation of the TP53 tumor suppressor gene. In order to determine if alterations frequently found in other adenocarcinomas (breast, ovarian, colorectal), including losses of genetic material from chromosome arms 1p, 3p, 7q, 8p, 11p, 17p, 17q, and 18q, are also involved in prostate cancer, we examined 20 localized early-stage prostate tumors. We detected no mutations of the TP53 gene. Allelic losses were found from 7q (33%), 8p (50%), 10q (20%), and 18q (33%). Furthermore, as the first step toward isolating tumor suppressor genes on 18q, we used six polymorphic markers and identified a small common deleted region between the chromosome 18 centromere and the D18S19 locus.

[Clinical prognostic factors in breast cancer. Retrospective study of 5609 cases]. / Les facteurs cliniques de pronostic dans le cancer du sein. Etude rétrospective de 5609 cas.

We studied the clinical factors of metastatic risk of breast cancer in 5609 consecutive cases of unilateral invasive breast cancer, wholly treated and followed at René-Huguenin Center from 1962 to 1988, and without any other cancer (even a controlateral breast cancer). All these patients were protocolary treated; these protocols, especially medical treatments (chimio and hormonotherapy), being modified along with years. At 20 years, the global metastasis free survival was 56%. Clinical size, existence of inflammatory signs, UICC clinical stage, clinical nodal status were highly significant in the Cox multivariate analysis (P < 0.000001). Age (P < 0.0008) and adherence to skin or underlying parietal (P < 0.007) were also but less significant. On the other hand, location of the tumor, time between first signs and diagnosis were not predictive. The women under 35 years had more metastatic locations during their evolution (P < 0.05) and maybe more visceral metastasis (NS).

Genetic alterations in localized prostate cancer: identification of a common region of deletion on chromosome arm 18q.

Accumulation of mutations in oncogenes and tumor suppressor genes transforms a normal cell into a malignant cell by allowing it to escape from normal control of growth. In prostate tumorigenesis, the current model envisages specific mutations of the TP53 tumor suppressor gene and loss of loci, detected by loss of heterozygosity (LOH), on chromosome arms 8p, 10q, 16q, and 18q. In order to determine if alterations frequently found in other adenocarcinomas (breast, ovarian, gastric, colorectal), including losses of genetic material from chromosome arms 1p, 3p, 7q, 8p, 11p, 17p, 17q, and 18q, are also involved in prostate cancer, we examined 20 localized early-stage prostate tumors. We detected no mutations of the TP53 gene. Allelic losses were found from 7q (33%), 8p (50%), 10q (20%), and 18q (33%). Furthermore, as the first step toward isolating tumor suppressor genes on 18q, we used six polymorphic markers and identified a small common deleted region between the chromosome 18 centromere and the D18S19 locus.

Phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer.

PURPOSE: The study investigated the therapeutic effects of a combination of Navelbine (vinorelbine or 5'noranhydrovinblastine; Pierre Fabre Médicament, Boulogne, France) and doxorubicin in women who had received no prior chemotherapy for locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Ninety-seven patients with progressive and assessable advanced or metastatic breast cancer who had received no prior chemotherapy except in an adjuvant setting were entered onto the study. Eighty-nine patients were assessable for toxicity and response by World Health Organization (WHO) criteria; the other eight patients were excluded because they did not meet entry criteria or because of protocol violations. Navelbine was administered at 25 mg/m2 by 30-minute intravenous (IV) infusion on days 1 and 8, and doxorubicin at 50 mg/m2 by slow IV infusion on day 1, with each course repeated at 3-week intervals. Patients were treated for a maximum of 11 cycles or until progression or major toxicity. RESULTS: Objective responses were observed in 66 of 89 assessable patients (74%; 95% confidence interval, 63% to 85%). There were nineteen (21%) complete responses (CRs) and 47 (53%) partial responses (PRs). In addition, 20 patients (22.5%) had stable disease and three (3.5%) progressed while on treatment. Responses were observed at all sites of metastatic disease. Forty-one of 58 patients with visceral disease responded (71%) and 25 of 31 with soft tissue and bone disease experienced an objective response (81%). The median duration of response was 12 months (range, 2.4 to 40.5), and the median overall survival was 27.5 months (range, 4 to 46). Neutropenia was dose-limiting, with 36 patients (41%) experiencing grade 3 or 4 toxicity. Of 727 cycles administered, there were 20 admissions (3%) for treatment of febrile neutropenia, involving 14 of 89 patients (16%). Treatment-related cardiotoxicity at grade 2 to 4 was experienced by 10% of patients and necessitated the interruption of treatment in 1.5% of cycles. Other side effects were uncommon or manageable by conventional means. CONCLUSION: The encouraging response rates and duration achieved with this combination of Navelbine/doxorubicin under the conditions of this study deserve further randomized comparative trials with standard regimens.

Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

PURPOSE: To evaluate the benefit of adjuvant chemotherapy in adult patients with soft tissue sarcomas. The principal end points were freedom from local recurrence and/or metastases and overall survival. PATIENTS AND METHODS: Between January 1977 and June 1988, 468 patients entered this randomized study and 317 were considered eligible. Following complete surgical resection with or without radiotherapy, outcome in 145 eligible patients receiving cyclophosphamide 500 mg/m2 intravenously (IV) bolus on day 1, vincristine 1.4 mg/m2 IV bolus on day 1, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) 50 mg/m2 IV bolus on day 1, and dacarbazine (DTIC) 400 mg/m2 by 1-hour infusion on days 1 to 3 (CYVADIC) cycles repeated every 28 days for eight courses was compared with that in 172 control patients. RESULTS: With a median follow-up duration of 80 months (range, 39 to 165), actuarial percentage survival figures at 7 years were compared. Relapse-free survival rates were higher for CYVADIC, 56% versus 43% (P = .007), and local recurrence was significantly reduced in the CYVADIC arm at 17% versus 31% (P = .004). In contrast, distant metastases occurred with similar frequency in both arms, 32% for CYVADIC versus 36% for control patients (P = .42), and overall survival rates were not significantly different at 63% versus 56% (P = .64). A reduction in local recurrence was only apparent in the group of head, neck, and trunk sarcomas (P = .002), but not in limb tumors (P = .31). CONCLUSION: Adjuvant chemotherapy with CYVADIC cannot be recommended outside the context of a clinical trial. Experience from this study has been used to plan a trial of neoadjuvant chemotherapy with doxorubicin/ifosfamide, which is currently in progress.

[Difficulties encountered in the evaluation of prognostic criteria of breast cancer: apropos of the experience of the René Huguenin center]. / Difficultés rencontrées dans l'évaluation des critères de pronostic du cancer du sein: à propos de l'expérience du centre René Huguenin.

The use of prognostic factors to help select breast cancer patients for adjuvant therapy is of considerable concern to the oncology community. This need for selection of prognostically less favorable cases is stimulating investigators to identify new and more powerful prognostic factors. Unfortunately however, this identification process is becoming more confusing because of a lack of guidelines for investigators to use to study new factors and for reviewers and readers to use to evaluate papers on this topic. In this paper, we will describe across our experience the main problems encountered in the study of biological prognostic studies. Considering evaluation criteria to be developed in the future, it appears that only multicentric and multidisciplinary structures are able to define decisional trees based on technically and clinically validated parameters in particular patients subgroups. Such a structure exists at the european level ("Receptor Study Group" of the EORTC) and a similar structure has now been created in France to answer these questions.

[Hormone therapy in breast cancer]. / Hormonothérapie au cours des cancers du sein.

Hormonotherapy, the oldest known effective medical treatment for breast cancer, is still widely used today. The effectiveness of numerous hormone (anti-oestrogen) treatments for breast cancer, with tumour regression reaching about 30% of the advanced forms or more in hormono-dependent forms identified by tumour hormone receptor assays has been demonstrated. Castration by surgery, radiotherapy or anti-LHRH agents is still proposed as one of the possible suppressive treatments. The other type of hormone management currently used is the anti-oestrogen agent tamoxifen which is general well tolerated. High doses of synthetic progesterones or anti-aromatase agents such as aminoglutethimide are also prescribed. These treatments require a less well tolerated association with hydrocortisone or corticosteroid treatments. Indications for hormonotherapy have become quite precise. As an adjuvant, castration before menopause and tamoxifen after menopause have been shown to be important methods in a meta-analysis published in 1992. The role of each of these treatments as part of an overall chemotherapy management is yet to be determined. In cases with metastases, hormonotherapy, whatever the modality used, is still particularly useful in elderly women with positive hormone receptor assays.

[Role of conservative treatment of ductal carcinoma in situ of the breast]. / Place du traitement conservateur dans les carcinomes canalaires in situ du sein.

In 1994, the treatment of ductal carcinoma in situ of the breast remains a controversial subject. There are two reasons for this: first, there are many possible treatments and secondly, there is still much discussion on choice criteria. Possible options are: Total mastectomy which or without axillary dissection. Tumorectomy followed by locoregional radiation therapy. Simple tumorectomy. Tamoxifen can be added to each of these options. The choice criteria are based on our knowledge of the complex natural history of these cancers. In this area some of the current concepts must be seriously revised. All of the former concepts were based on lesions observed at the time of their elaboration. These were voluminous tumours, diagnosed late with no prior conservative treatment. However, today, the lesions observed are quite different. We see "young" lesions which are naturally much smaller. It would appear that the natural history of small sized in situ ductal carcinoma of the breast is quite different from that of large sized tumours. The lesions seen today are less multifocal and less multicentric in nature than is generally thought. The progression of a small tumour is essentially segmentary. Likewise, the risk of occult micro-invasion is certainly less than previously thought. Even if the risk of micro-invasion still does exist, the risk of axillary lymph node invasion (resulting from an unknown infiltrating zone of tumoural tissue) is much lower. Finally the dogma of radioresistance, which was not based on any carefully conducted radiobiological study, has lost its substance since recent results on radiosurgery combinations have been published.(ABSTRACT TRUNCATED AT 250 WORDS)