Pathological complete response in invasive breast cancer treated by skin sparing mastectomy and immediate reconstruction following neoadjuvant chemotherapy and radiation therapy: Comparison between immunohistochemical subtypes.

CONTEXT: Even if neoadjuvant chemotherapy (NACT) and oncoplastic techniques have increased the breast conserving surgery rate, mastectomy is still a standard for multifocal or extensive breast cancers (BC). In the prospect of increasing breast reconstruction, an alternative therapeutic protocol was developed combining NACT with neoadjuvant radiation therapy (NART), followed by mastectomy with immediate breast reconstruction (IBR). The oncological safety of this therapeutic plan still needs further exploration. We assessed pathological complete response (pCR) as a surrogate endpoint for disease free survival. METHODS: Between 2010 and 2016, 103 patients undergoing mastectomy after NACT and NART were recruited. After CT and RT were administrated, a completion mastectomy with IBR by latissimus dorsi flap was achieved 6 to 8 weeks later. pCR was defined by the absence of residual invasive disease in both nodes and breast. Histologic response was analyzed for each immunohistochemical subset. RESULTS: pCR was obtained for 53.4% of the patients. This pCR rate was higher in hormonal receptor negative (HER2 and triple negative) patients when compared to luminal tumours (69.7% vs 45.7%, p=0.023). DISCUSSION: The pCR rate found in this study is higher than those published in studies analyzing NACT (12.5%-27.1%). This can be explained by the combination of anthracycline and taxane, the use of trastuzumab when HER2 was overexpressed but also by RT associated to NACT. CONCLUSION: Inverting the sequence protocol for BC, requiring both CT and RT, allows more IBR without diminishing pCR and should therefore be considered as an acceptable therapeutic option.

Estradiol 17 beta-hydroxysteroid dehydrogenase, a marker of breast cancer hormone dependency.

Intratumoral activity of the progesterone-dependent enzyme 17 beta-hydroxysteroid dehydrogenase (E2DH) was measured in 114 patients with breast cancer (33 pre- and 81 postmenopausal) before and/or after 8 days of a progestin treatment (lynestrenol, 10 mg/day). In 12 postmenopausal patients, the ability of E2DH to be stimulated by lynestrenol was compared to estradiol receptor (ER) and progesterone receptor (PR) levels. In premenopausal patients, E2DH was higher when tumors were excised in the luteal phase than when excised in the follicular phase. In postmenopausal patients, E2DH was higher after progestin treatment. However, E2DH stimulation by lynestrenol depended on receptor levels. It was most often markedly stimulated in ER-positive, PR-positive tumors. It remained low in ER-negative, PR-negative tumors. Intratumoral measurement of the progesterone-dependent enzyme E2DH in breast cancer after progestin treatment could therefore provide a fine and reliable index of the presence and functional character of PR and hormone dependency of the tumor.

Inadequate corpus luteal function in women with benign breast diseases.

The corpus luteum function of 109 patients with benign breast disease was appreciated by way of plasma progesterone and estradiol determinations during the luteal phase. These patients had ovulatory cycles according to a biphasic basal body temperature curve; blood samples for plasma progesterone and estradiol estimation were collected between the first and the last day of the thermal plateau following the thermal nadir. Results obtained were compared to those observed in 50 normal ovulatory women. In the patients' group, the mean daily levels for progesterone ranged from 3.5 +/- 0.4 (SE) ng/ml to 8.1 +/- 3.8 (SE) ng/ml according to day of blood collection. These values are significantly different from the corresponding daily values observed in normal women. No significant difference was observed concerning plasma estradiol between patients and normal women. These findings indicate that women with benign breast disease have an inadequate corpus luteum function which may be secondary to an ovulation disorder. Pathophysiological implications resulting from this observation are discussed.

Benign breast disease I: hormonal investigation.

One hundred eighty-four patients with benign breast disease (BBD) were studied and compared with 50 normal women. All of the women had ovulatory cycles according to a biphasic basal body temperature and a plasma prolactin in the normal range. Their corpus luteum function was evaluated by way of plasma progesterone (P) and estradiol (E2) determinations at days 5, 7, and 9 of the hyperthermic phase. In the 184 patients, plasma P over plasma E2 ratio during the luteal phase was found significantly lower than in normal women. When the patients were grouped according to type of breast lesions, it appeared that plasma P was constantly lower in all groups than in the normal women, while plasma E2 was either normal or elevated in the groups of patients with adenosis tumors and increased nodularity of both breasts. From these results it may be postulated that an imbalance in the secretion of E2 and P by the corpus luteum is a constant finding in women with benign breast disease.

[Hormonal function of the ovarian corpus luteum during benign mammary diseases]. / La fonction hormonale du corps jaune ovarien au cours des affections mammaires bénignes

Plasma progesterone and oestradiol levels were estimated in 54 women who were suffering from breast pathology. (There were 18 cases of benign breast dysplasia, 28 cases of cystic disease of the breast and 8 cases of adenofibromata.) All these women had menstrual cycles that were apparently ovulatory, and the blood sampling was carried out on the 4th day after the rise in the temperature plateau. By way of controls, the same estimations were carried out on 20 normal women of the equivalent age at the same stage of the raised plateau. The levels of plasma oestradiol in patients who had breast pathology (136 +/- 75 pg/ml) were not significantly different from those of normal women (120 +/- 50 pg/ml). On the other hand patients with mastopathies had a far lower level of progesterone in the phase of the cycle that was considered to be luteal (5-7 +/- 3-1 ng/ml) in comparison with normal women (13-2 +/- 3-5 ng/ml). From these results the conclusion can be drawn that women who have benign breast disease while they are active from the ovulation point of view show a defect in secretion of progesterone by the corpus luteum. This defect is an isolated one. The physiopathological implications derived from this observation are discussed.

[Inadequate corpus luteum function in benign breast-diseases (author's transl)]. / Corps jaune inadéquat et mastopathies

The amount of progesterone and estradiol secreted by human corpus luteum depends upon an adequate release of FSH and LH by pituitary gland during follicular phase and ovulation. In this paper, plasma determination of progesterone and estradiol were carried out in 109 women with benign breast disease during the luteal phase of their menstrual cycle. Results obtained were compared with those observed in 25 normal women studied in the same conditions. In women with benign breast disease, the curve of daily progesterone concentrations during luteal phase was lower than that of normal women. The progesterone peak at 5th day of luteal phase was only 8,1 +/- 3.8 ng/ml instead of 17.2 +/- 3.5 ng/ml in normal women. No significative difference was observed concerning plasma estradiol between patients and normal women. These results indicate that women with benign breast disease have an inadequate corpus luteum function which may be the result of disorder of ovulation. Pathophysiological implications resulting from this observation are discussed.

[The treatment of benign pathological conditions of the breasts with progesterone and progestogens. The results according to the type of breast condition (260 case records) (author's transl)]. / Traitement des mastopathies bénignes par la progestérone et les progestatifs. Résultats en fonction du type de la mastopathie (à propos de 260 observations).

This work reports the clinical results which were obtained after treating 260 women who had pathological conditions of the breasts using a combination of a progestogen which was given by a generalised route (orally or by injection) and progesterone which was applied locally so that its effect would be percutaneous on the breasts. These results were evaluated according to the effectiveness of the treatment according to the different symptoms or groups of clinical symptoms and radiological findings which had been noted at the time of the first examination. A better therapeutic effect was found in cases of early lesions where oedema was the dominant factor (mastodynia) and glandular hyperplasia (diffuse polyadenomatosis). On the other hand, longstanding lesions (sclerocystic mastopathia) where sclerosis was marked showed a much more variable result of treatment with progestogens. Therefore its seems that benign conditions of the breasts should be treated early and particularly in the stage of mastodynia if development into irreversible sclerotic conditions is to be avoided. It also has to be carried on for a long time, especially if there are other risk factors for cancer which are associated with conditions in the breast. The prophylactic role of this treatment in regard to cancer of the breast is discussed.

Prolactin secretion in benign breast diseases.

In order to evaluate the importance of prolactin in the pathogenesis of benign breast diseases (BBD), serum prolactin (PRL) levels were determined before and during a TRH challenge test in 50 patients affected by various BBD studied during the luteal phase of their cycle. They were compared to 15 normal women also studied during the luteal phase. In all the subjects estradiol (E2) and progesterone (P) were also measured. The patients were studied as a total group and in different subgroups according to the type of their disease, before and after 3 months of treatment with a potent progestin, lynestrenol. No significant differences appeared between any group of patients and the control group either on the basal prolactin secretion or on its dynamic secretory pattern after TRH injection before and during treatment. The only significant difference observed between patients and controls was the progesterone values, respectively 6.86 +/- 0.9 ng/ml and 21.2 +/- 1.4 ng/ml. It can therefore be concluded that benign breast diseases are more likely to be related to an inadequate luteal phase than to any abnormality of prolactin secretion.

[Evaluation of 17-beta-hydroxysteroid dehydrogenase activity as a marker of the hormone dependence of breast cancers]. / Evaluation de l'activité enzymatique 17 beta-hydroxystéroïde deshydrogénase comme marqueur de l'hormonodépendance des cancers du sein.

Intratumoral activity of the enzyme 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) was measured in 55 patients with breast cancer (17 pre- and 38 post-menopausal) before and/or after 8 days of a progestin treatment (lynestrenol 10 mg/day). In 12 patients the 17 beta-HSD ability to be stimulated was compared to estradiol and progesterone receptor (ER and PR) levels. In premenopausal patients 17 beta-HSD was higher when tumorectomy was performed in the luteal phase than in the follicular phase. In post-menopausal patients, 17 beta-HSD is higher after progestin treatment. However 17 beta-HSD stimulation by lynestrenol depends on receptor levels. It is most after markedly stimulated in ER+ PR+ tumors. It remains low in ER- PR- tumors. In conclusion, intratumoral measurement of the progesterone dependent enzyme (17 beta-HSD) in breast cancer after progestin treatment provides a fine and reliable index of the presence and functional character of PR and hormone dependence of the tumor.