P. Bougnoux

N‐3 and N‐6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case‐control study in Tours, France

Experimental studies have indicated that n‐3 fatty acids, including alpha‐linolenic acid (18:3 n‐3) and long‐chain n‐3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n‐3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n‐3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case‐control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer‐risk and n‐3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha‐linolenic acid (18:3 n‐3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19–0.78) compared to women in the lowest tertile (trend p = 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n‐3) had an odds ratio of 0.31 (95% CI = 0.13‐0.75) compared to women in the lowest tertile (trend p = 0.016). Women in the highest tertile of the long‐chain n‐3/total n‐6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17–0.66) compared to women in the lowest tertile (trend p = 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n‐3 fatty acids on breast cancer risk and support the hypothesis that the balance between n‐3 and n‐6 fatty acids plays a role in breast cancer.

Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MBA‐MB‐231: Relationship to lipid peroxidation

Exogenous polyunsaturated fatty acids modulate the cytotoxic activity of anti‐cancer drugs. In this study, we examined whether lipid peroxidation is a potential mechanism through which fatty acids enhance drug cytotoxicity. We measured cell viability in the human breast cancer cell line MDA‐MB‐231 exposed to doxorubicin in the presence of non‐cytotoxic concentrations of various polyunsaturated fatty acids for 6 days. To determine the role of lipid peroxidation, the hydroperoxide level was measured in cell extracts. Among all polyunsaturated fatty acids tested, docosahexaenoic acid (DHA, 22:6n‐3) was the most potent in increasing doxorubicin cytotoxicity: cell viability decreased from 54% in the presence of 10−7 M doxorubicin alone to 21% when cells were incubated with doxorubicin and DHA. After addition of an oxidant system (sodium ascorbate/2‐methyl‐1,4‐naphthoquinone) to cells incubated with doxorubicin and DHA, cell viability further decreased to 12%. Cell hydroperoxides increased commensurately. The effect of DHA on doxorubicin activity and lipid hydroperoxide formation was abolished by a lipid peroxidation inhibitor (dl‐α‐tocopherol) or when oleic acid (a non‐peroxidizable fatty acid) was used in place of DHA. No effect was observed with mitoxantrone, a drug with a low peroxidation‐generating potential. Thus, DHA may increase the efficacy of oxyradical‐producing drugs through a mechanism involving a generation of lipoperoxides. This may lead in vivo to a modulation of tumor cell chemosensitivity by DHA and oxidant agents. Int. J. Cancer 75:578–583, 1998.

Low alpha-linolenic acid content of adipose breast tissue is associated with an increased risk of breast cancer

Data derived from experimental studies suggest that alpha-linolenic acid may have a protective effect in breast cancer. Observations obtained from epidemiological studies have not allowed conclusions to be drawn about a potential protective effect of dietary alpha-linolenic acid on breast cancer, possibly because of methodological issues. This case-control study conducted in an homogeneous population from a central area in France was designed to explore the hypothesis that alpha-linolenic acid inhibits breast cancer, using fatty acid levels in adipose breast tissue as a biomarker of past qualitative dietary intake of fatty acids. Biopsies of adipose breast tissue at the time of diagnosis were obtained from 123 women with invasive non-metastatic breast carcinoma. 59 women with benign breast disease served as controls. Individual fatty acids were analysed by capillary gas chromatography. An unconditional logistic regression model was used to obtain odds ratio estimates whilst adjusting for age, menopausal status and body mass index (BMI). No association was found between fatty acids (saturates, monounsaturates, long-chain polyunsaturates n-6 or n-3) and the disease, except for alpha-linolenic acid which showed an inverse association with the risk of breast cancer. The relative risk of breast cancer for women in the highest quartile of adipose breast tissue alpha-linolenic acid level was 0.36 (95% confidence interval=0.12-1.02) compared with those in the lowest quartile (P trend=0.026), suggesting a protective effect of alpha-linolenic acid in the risk of breast cancer. The effects of dietary alpha-linolenic on the risk of breast cancer warrant further study.

Cytotoxic drugs efficacy correlates with adipose tissue docosahexaenoic acid level in locally advanced breast carcinoma

SummaryExperimental studies indicated that long-chain polyunsaturated fatty acids may increase sensitivity of mammary tumours to several cytotoxic drugs. To evaluate this hypothesis in breast cancer, we have prospectively studied the association between levels of fatty acids stored in breast adipose tissue and the response of the tumour to chemotherapy in 56 patients with an initially localized breast carcinoma. Adipose breast tissue was obtained at the time of biopsy, and individual fatty acids were measured as a percentage of total fatty acids using capillary gas chromatography. Patients then received primary chemotherapy, combining mitoxantrone, vindesine, cyclophosphamide and 5-fluorouracil every 4 weeks. Tumour size was reassessed after three cycles of chemotherapy. Tumour response was evaluated according to World Health Organization criteria. Complete or partial response to chemotherapy was achieved in 26 patients (47%). Level of n-3 polyunsaturated fatty acids in adipose tissue was higher in the group of patients with complete or partial response to chemotherapy than in patients with no response or with tumour progression (P < 0.004). Among n-3 polyunsaturated, only docosahexaenoic acid (22:6n-3) was significantly associated with tumour response (P < 0.005). In a logistic regression analysis taking into account age, body mass index and tumour size, 22:6 n-3 level proved to be an independent predictor for chemosensitivity (P = 0.03). These results suggest that, in breast cancer, 22:6 n-3 may increase the response of the tumour to the cytotoxic agents used.

alpha-Linolenic acid content of adipose breast tissue: a host determinant of the risk of early metastasis in breast cancer.

The association between the levels of various fatty acids in adipose breast tissue and the emergence of visceral metastases was prospectively studied in a cohort of 121 patients with an initially localised breast cancer. Adipose breast tissue was obtained at the time of initial surgery, and its fatty acid content analysed by capillary gas chromatography. A low level of alpha-linolenic acid (18:3n-3) in adipose breast tissue was associated with positive axillary lymph node status and with the presence of vascular invasion, but not with tumour size or mitotic index. After an average 31 months of follow-up, 21 patients developed metastases. Large tumour size, high mitotic index, presence of vascular invasion and low level of 18:3n-3 were single factors significantly associated with an increased risk of metastasis. A Cox proportional hazard regression model was used to identify prognostic factors. Low 18:3n-3 level and large tumour size were the two factors predictive of metastases. These results suggest that host alpha-linolenic acid has a specific role in the metastatic process in vivo. Further understanding of the biology of this essential fatty acid of the n-3 series is needed in breast carcinoma.

N-6 polyunsaturated fatty acids in human breast carcinoma phosphatidylethanolamine and early relapse

N-6 polyunsaturated fatty acids in human breast carcinoma phosphatidylethanolamine and early relapse

Lymphadenectomy in the management of endometrial carcinoma stage I and II. Retrospective study of 155 cases

In our institution endometrial carcinomas Stage I and II were treated with initial uterovaginal brachytherapy 60 Gy followed by modified radical hysterectomy with pelvic lymphadenectomy. We have studied the results in order to assess the value of lymphadenectomy in the treatment strategy. Between 1976 and 1986, 155 patients were treated (107 Stage I, 48 Stage II mean age 60.2 years). Twenty-six patients also received postoperative pelvic external beam irradiation on account of lymph node involvement and/or deep tumour invasion into the myometrium. Fourteen patients (9%) had lymph node involvement. External iliac lymph nodes were involved in 78.5% of these cases. Lymph node involvement rate was higher for stage II, grade 3 tumours and when there was deep tumour invasion of the myometrium. The rate of local (pelvic) treatment failure was 12% for node-negative patients and 36% for node-positive patients and the 5-year actuarial survival rates for the two groups were 83% and 41% respectively. As a consequence of our interpretation of the findings and influenced by the high complication rate which we attribute to lymphadenectomy and the information given by other prognostic indicators, we have changed to a policy of carrying out pelvic external radiotherapy for all Stage II, grade 2 or 3 cases and those with deep myometrial invasion. Lymphadenectomy is not performed in these cases. For patients with Stage I grade 1 tumours without deep tumour invasion only external iliac node sampling is performed. If this shows tumour, external irradiation is given in addition to vaginal vault brachytherapy.

Is lymphadenectomy useful in the treatment of endometrial carcinoma

Newdspletheekddeiacaabiaatiaawitb~(ACR)witb highreapoerateill gynedogieaI adeaecmillomas Chen J-T; Hirai Y; Shimizu Y; Hasumi K, Masubuchi K Department of Gynecology, CMcer Institute Hospital, Tokyo, JPN GYNECOL ONCOL 1990,38/l (l-5) Fourteen patients with recurrent gynecological adenocarcinemas (nine with endometrial cancer and six with ovarian cancer) were treated with cisplatin given by 14-day continuous infusion at a daily dose of 10 mg/m2 in combination with aclarubicin (ACR) at a dose of 20 mg/body on alternate days during each M-day course. The daily dose of cisplatin was given with 1 liter of fluids; no diuretics were administered. The overall response rate was 71.4% (50% in endometrial cancer and 100% in ovarian cancer). It was especially interesting that a 100% response rate was obtained in five patients previously treated with cisplatin; i.e., the present cisplatin dosing schedule was highly effective as second-line therapy in these patients. No renal or gastrointestinal toxicity was observed. These results were pharmacokineticahy explained by the plasma concentration of tilterable platinum. A low-level, plateau-like curve with a great area under fdterable [Pt]-time curve (AUC) seemed to ensure exposure of cancer cells to filterable platinum for sufficiently long periods and freedom from gastrointestinal and renal side effects.