Failure Of Endocrine Therapy Research Articles

Oncogene amplification and prognosis in breast cancer: Relationship with systemic treatment

In the present study, we aimed to clarify the potential of oncogene amplifications as markers for the prediction of ( i) (relapse-free) survival, ( ii) response to first-line endocrine therapy and ( iii) subsequent chemotherapy in patients with recurrent breast cancer. To attain this goal, amplification of different oncogenes (HER-2/ neu, c- MYC and INT-2) was studied in primary tumors of a series of 259 patients with breast cancer (median follow-up of 72 mo). Of these tumors, 49.8% did not contain an amplification of any of the oncogenes studied, whereas in the amplified subgroup, INT-2 was amplified in 13%, HER-2/ neu in 24% and c- MYC in 20% of the tumors. In univariate analysis, INT-2 amplification was associated with an increased risk of relapse ( p <0.03), especially in the subgroups of 85 node-negative ( p = 0.05) and 156 ER/PgR-positive patients ( p = 0.01). Cox multivariate regression analysis showed that c- MYC was the only oncogene whose amplification was significantly related with the rate of relapse. With respect to amplification in patients developing metastatic disease, who received first-line hormonal therapy ( n = 114), HER-2/ neu amplification was associated with a less favorable response to endocrine therapy (objective response rate only 17% and a progression-free survival (PFS) of only 4% at 12 mo). Interestingly, distinct INT-2 amplification might predict a better response to endocrine therapy (objective response rate of 56%, and a PFS after relapse of 42% at 12 mo). After failure of hormonal therapy, ensuing chemotherapy caused a prolonged PFS of 287 days vs. 90 days for those patients whose tumors showed HER-2/ neu amplification vs. those without HER-2/ neu amplification. We conclude that oncogene amplification is related to relapse-free survival (RFS), response to systemic therapy, and to overall survival with different outcomes for the respective oncogenes. Simultaneous determination of these oncogenes may be of importance with respect to both selection of patients at high risk for recurrence and for selection of a particular type of therapy.

Sensitivity and insensitivity of breast cancer to tamoxifen

Tamoxifen is the endocrine treatment of choice for breast cancer. In several laboratory models in vivo tamoxifen is a tumoristatic agent. When MCF-7 breast cancer cells are inoculated into athymic mice, palpable tumors do not grow unless the animals are treated with estrogen, and tamoxifen inhibits estrogen-stimulated growth. If tamoxifen is stopped, tumors regrow. These results suggest that adjuvant tamoxifen therapy should involve long treatment periods (even lifetime) to prevent tumor recurrence. Unfortunately resistance to therapy and patient relapse inevitably occur, and such disease recurrence involving tamoxifen resistance is difficult to treat successfully. A laboratory model of endocrine therapy failure has been developed. When athymic mice with MCF-7 tumors are treated for 6–8 months with tamoxifen, several tumors grew and continued to grow in tamoxifen-treated mice. These estrogen receptor-positive tumors grow with either tamoxifen or estradiol. Tamoxifen-stimulated tumor growth has been observed in human endometrial tumors implanted into athymic animals. Growth of these tamoxifen-stimulated tumors can be inhibited with the pure antiestrogen ICI 164,384 upon withdrawal of tamoxifen. These data are discussed in terms of treatment strategies for tamoxifen-failed patients.

Epidermal growth factor receptor (EGFr) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer.

We have used primary endocrine therapy for 61 elderly women with operable breast cancer (median age 77 years). Eleven patients (18%) had complete and 24 (39%) partial tumour regression, 12 (20%) had stable disease for a minimum of six months and 14 (23%) no response. Salvage surgery was undertaken in the 14 with no response and 8/9 with progressive disease following initial response, thus samples were available from relapse patients only. Assays for EGFr (two point radioreceptor assay) and oestrogen receptors (ER) (dextran coated charcoal method and an immunohistochemical method) were performed on 20/22 patients. Ten of these 20 tumours were EGFr+ (greater than 10 fmol mg-1 binding) and 9/13 patients progressing within six months had EGFr+ tumours. 15/22 were available for ER evaluation and there was no such association with ER status. EGFr status was also associated with early recurrence after surgery and death in the endocrine failure group (P less than 0.005 and P less than 0.05 respectively). Of a control population of 33 patients (median age 72 years) treated by primary surgery, only 6 were EGFr+. In this group early relapse was predicted by EGFr status, but not by ER status (median disease free survival for EGFr+ patients 15 months, and for EGFr- patients 40 months, P less than 0.01, logrank test). There was a significantly higher proportion of EGFr+ tumours in the endocrine failure group compared with the control population (P less than 0.001). EGFr status is a marker for rapid early progression on primary endocrine therapy and the development of non-excisional methods of EGFr analysis would allow better directed therapeutic decisions.

Effectiveness of steroid and imidazole drugs in inhibiting aromatase activity

Tamoxifen is the endocrine treatment of choice for breast cancer. In several laboratory models in vivo tamoxifen is a tumoristatic agent. When MCF-7 breast cancer cells are inoculated into athymic mice, palpable tumors do not grow unless the animals are treated with estrogen, and tamoxifen inhibits estrogen-stimulated growth. If tamoxifen is stopped, tumors regrow. These results suggest that adjuvant tamoxifen therapy should involve long treatment periods (even lifetime) to prevent tumor recurrence. Unfortunately resistance to therapy and patient relapse inevitably occur, and such disease recurrence involving tamoxifen resistance is difficult to treat successfully. A laboratory model of endocrine therapy failure has been developed. When athymic mice with MCF-7 tumors are treated for 6–8 months with tamoxifen, several tumors grew and continued to grow in tamoxifen-treated mice. These estrogen receptor-positive tumors grow with either tamoxifen or estradiol. Tamoxifen-stimulated tumor growth has been observed in human endometrial tumors implanted into athymic animals. Growth of these tamoxifen-stimulated tumors can be inhibited with the pure antiestrogen ICI 164,384 upon withdrawal of tamoxifen. These data are discussed in terms of treatment strategies for tamoxifen-failed patients.

Ultrastructural comparison of endometriotic implants and eutopic endometrium

Ultrastructural features of endometriotic implants suggest an incomplete response to the prevalent hormonal milieu. The cyclic changes, especially in the secretory phase, appear to depend more on the morphologic differentiation of the ectopic implants than on the hormonal stimulus. The endometriotic tissue encompassed a wide range of morphologic development from poorly to highly differentiated glands. Variations occurred from gland to gland and even within the same gland. Complete proliferative development was found only in some of the patients and full secretory transformation was absent in all. The incomplete morphologic response to cyclic hormonal changes may explain the frequent failure of endocrine therapy.

Studies on estrogen receptors and regression in human breast cancer.

Estradiol receptors were studied both qualitatively and quantitatively in 650 cases of breast cancer to obtain information on molecular forms and relationship with response to endocrine therapy. Cytosol estradiol receptor (ERC) was assayed by a charcoal method following incubations with 3H-estradiol and also by chromatography on Sephacryl columns. Results were classified as positive (10 fmoles/mg P and up), borderline (3-10 fmoles) and negative (0-3 fmoles). It was found that 44.6% of tumors were positive, 14.15% were borderline, and 41.2% were negative. Qualitatively, two major molecular forms of ERC were identified with molecular weights 31,000 and approximately 250,000. ERC level and response to endocrine therapy were correlated in a group of 52 patients. Response rate to hormonal therapy only was 59% in the ERC-positive, 28% in the borderline, and 9% in the ERC-negative group. Combination therapy, including endocrine manipulation, chemotherapy, and/or radiation improved response rates to 66% in the ERC-positive, 40% in the borderline, and 33% in the ERC-negative group. Defects in the translocation of the cytosol estradiol receptor (ERC)-estradiol complex to the nucleus could partly explain the failure of endocrine therapy in 40% of patients with significant ERC. To examine this possibility, 98 cases of breast cancer were examined for both ERC and nuclear translocation of estradiol (ERN). Nuclei were isolated from the low speed sediment and incubated with the ERC-3H-estradiol complex in the presence and absence of an estrogen competitor. After incubation, ERN was extracted from the nuclei and expressed as specifically bound estradiol, fmoles/mg DNA. Of 44 cases with significant ERC, nine had no ERN (20%). In the borderline group of 23 cases, eight had no ERN (34%), and of the 31 cases with zero or negligible ERC 27 had no ERN (87%). Results indicate that ERC-negative cases should be excluded from hormonal therapy and appear to benefit most from chemo- and/or radiation therapy. The absence of ERN in a significant proportion of ERC-positive cases probably contributes to the failure of hormonal manipulation in such patients. The results indicate that the determination of both ERC and ERN could improve the selection of patients for endocrine therapy.

Studies on cytosol and nuclear binding of estradiol in human breast cancer

Defects in the translocation of the cytosol estradiol receptor (ERC)-estradiol complex to the nucleus could partly explain the failure of endocrine therapy in 40% of breast cancer patients with significant ERC. To examine this possibility, 98 cases of human breast cancer were investigated for cytoplasmic and nuclear (ERN) estradiol receptors. ERC was assayed by a charcoal method following incubation with [ 3H]-estradiol. Nuclei were isolated from the low speed sediment and incubated at 30°C with the ERC-[ 3H]-estradiol complex in the presence and absence of an estrogen competitor. ERN was extracted from the nuclei with 0.4 M KCl and expressed as specifically bound estradiol, fmol/mg DNA. The quantity of ERN ranged between 0–746 fmol/mg DNA. Of 50 cases with significant ERC activity, 11 had no ERN (24%). In the borderline ERC group of 17 tumors, 5 had no ERN (29%), while of the 31 cases with zero or negligible ERC, 27 eases had no ERN (87%). Characteristics of ERC are different from the classical model. Chromatography of ERC on Sephacryl-S-200 columns and sucrose gradient sedimentation values indicate that the original form has an approximate molecular weight of 35,600, which on warming is transformed into an even smaller form (mol. wt — 22,700). The larger form of ERC (mol. wt ∼- 250,000) is produced by aggregation in low ionic strength media. The major form of the ERN complex has a molecular weight of 35,600, the same as that of the cytosolic receptor complex. It appears that the absence of ERN in a significant proportion of ERC positive tumors could contribute to the failure of endocrine therapy in such patients. Results indicate that the determination of both ERC and ERN could improve the selection of patients for endocrine therapy.

Steroids and human breast cancer

Estrogen receptor is present in the rat in target tissues, including mammary gland and hormone dependent mammary tumors, but is absent in non-target tissues and in many autonomous tumors. In human tissues, estrogen receptor behaves much like that of the rat. Its absence in a breast tumor specimen predicts the failure of hormone therapy, as shown by data collected from many sources, and this fact will be useful to clinicians in selecting therapy for metastatic breast cancer patients. The receptor is present, however, in a substantial number of nonresponsive tumors. These tumors may contain defects in the normal nuclear localization or action of the receptor-estrogen complex or even in the functions of other hormones which affect the mammary gland. These defects will have to be identified for a complete biochemical prognosis for endocrine therapy in breast cancer.

The failure of hormone therapy to induce an early lamb crop.

The failure of hormone therapy to induce an early lamb crop.