Monitoring of the presence of EGFR-mutated DNA during EGFR-targeted therapy may assist in the prediction of treatment outcome.

The aim of our trial was to evaluate the prognostic significance of qualitative ctDNA analysis on different stages of EGFR mutated non-small cell lung cancer (NSCLC) treatment. We included 99 patients amendable for the first line treatment with either gefitinib/erlotinib (n = 87), afatinib (n = 10) or osimertinib (n = 2). Sequential qualitative analysis of ctDNA with cobas® EGFR Mutation Test v2 were performed before first dose, after 2 and 4 months of treatment, and on progression. Our analysis showed clinically significant heterogeneity of EGFR-mutated NSCLC treated with 1st line tyrosine kinase inhibitors (TKIs) in terms of progression-free and overall survival. When treated with conventional approach, i.e. monotherapy with TKIs, the patients falls into three subgroups based on ctDNA analysis before and after 2 months of treatment. Patients without detectable ctDNA at baseline (N = 32) possess the best prognosis on duration of treatment (PFS: 24.07 [16.8-31.3] and OS: 56.2 [21.8-90.7] months). Those who achieve clearance after two months of TKI (N = 42) have indistinguishably good PFS (19.0 [13.7 - 24.2]). Individuals who retain ctDNA after 2 months (N = 25) have the worst prognosis (PFS: 10.3 [7.0 - 13.5], p = 0.000). 9/25 patients did not develop ctDNA clearance at 4 months with no statistical difference in PFS from those without clearance at 2 months. Prognostic heterogeneity of EGFR-mutated NSCLC should be taken into consideration in planning further clinical trials and optimizing the outcome of patients.

CCND1 and FGFR1 gene amplifications are associated with reduced benefit from aromatase inhibitors in metastatic breast cancer

Purpose Endocrine therapy is a mainstay for the treatment of hormone receptor-positive breast cancer (BC); however, only a fraction of patients experience a pronounced response to antagonists of estrogen signaling. There is a need to identify predictors for efficacy of this treatment. Methods This study included 138 patients with newly diagnosed metastatic BC, who received upfront endocrine therapy. Archival biopsy specimens were tested for CCND1 and FGFR1 gene amplification and mRNA expression by PCR-based methods. Results CCND1 and FGFR1 amplification was detected in 24 (17.9%) and 28 (20.9%) of 134 evaluable cases, respectively; 9 carcinomas had concurrent alterations of these two genes. Presence of amplification in at least one locus was more common in tumors of higher grade (p = 0.018) and was associated with higher Ki-67 proliferation index (p = 0.036). CCND1 gene amplification was associated with shorter progression-free survival (PFS) in patients receiving aromatase inhibitors (AI) [16.0 months vs. 32.4 months, HR = 3.16 (95% CI 1.26–7.93), p = 0.014]. FGFR1 status did not significantly affect PFS of AI-treated women; however, objective response to AI was observed less frequently in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number [2/15 (13.3%) vs. 22/46 (47.8%), p = 0.031]. Meanwhile, CCND1/FGFR1 gene status did not influence the outcome of tamoxifen-treated patients. Conclusion Presence of CCND1 and/or FGFR1 amplification is associated with worse outcomes of AI therapy in patients with metastatic BC (AU)

CCND1 and FGFR1 gene amplifications are associated with reduced benefit from aromatase inhibitors in metastatic breast cancer.

PURPOSE: Endocrine therapy is a mainstay for the treatment of hormone receptor-positive breast cancer (BC); however, only a fraction of patients experience a pronounced response to antagonists of estrogen signaling. There is a need to identify predictors for efficacy of this treatment. METHODS: This study included 138 patients with newly diagnosed metastatic BC, who received upfront endocrine therapy. Archival biopsy specimens were tested for CCND1 and FGFR1 gene amplification and mRNA expression by PCR-based methods. RESULTS: CCND1 and FGFR1 amplification was detected in 24 (17.9%) and 28 (20.9%) of 134 evaluable cases, respectively; 9 carcinomas had concurrent alterations of these two genes. Presence of amplification in at least one locus was more common in tumors of higher grade (p = 0.018) and was associated with higher Ki-67 proliferation index (p = 0.036). CCND1 gene amplification was associated with shorter progression-free survival (PFS) in patients receiving aromatase inhibitors (AI) [16.0 months vs. 32.4 months, HR = 3.16 (95% CI 1.26-7.93), p = 0.014]. FGFR1 status did not significantly affect PFS of AI-treated women; however, objective response to AI was observed less frequently in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number [2/15 (13.3%) vs. 22/46 (47.8%), p = 0.031]. Meanwhile, CCND1/FGFR1 gene status did not influence the outcome of tamoxifen-treated patients. CONCLUSION: Presence of CCND1 and/or FGFR1 amplification is associated with worse outcomes of AI therapy in patients with metastatic BC.

Hereditary breast-ovarian cancer syndrome in Russia.

Hereditary breast-ovarian cancer syndrome contributes to as much as 5-7% of breast cancer (BC) and 10-15% of ovarian cancer (OC) incidence. Mutations in the "canonical" genesBRCA1andBRCA2occur in 20-30% of affected pedigrees. In addition toBRCA1andBRCA2 mutations, germ-line lesions in theCHEK2,NBS1, andPALB2genes also contribute to familial BC clustering. The epidemiology of hereditary breast-ovarian cancer in Russia has some specific features. The impact of the "founder" effect is surprisingly remarkable: a single mutation,BRCA15382insC, accounts for the vast majority ofBRCA1defects across the country. In addition, there are two other recurrentBRCA1alleles:BRCA14153delA andBRCA1185delAG. BesidesBRCA1, in Russia breast cancer is often caused by germ-line alterations in theCHEK2andNBS1genes. In contrast toBRCA1andBRCA2, theCHEK2andNBS1heterozygosity does not significantly increase the OC risk. Several Russian breast cancer clinics recently started to investigate the efficacy of cisplatin in the therapy ofBRCA1-related cancers; initial results show a unique sensitivity ofBRCA1-associated tumours to this compound.

Phase I/II trial of gene therapy with autologous tumor cells modified with tag7/PGRP-S gene in patients with disseminated solid tumors: miscellaneous tumors.

BACKGROUND: The use of genetically modified autologous tumor cells appears to be a promising approach for cancer therapy. A phase I/II trial was undertaken to define the feasibility, safety and antitumor effects of the autologous vaccine prepared by transferring tag7/PGRP-S gene into malignant melanoma and renal cell carcinoma cells. PATIENTS AND METHODS: Twenty-one patients (17 with disseminated malignant melanoma and four with metastatic renal cell carcinoma) were enrolled in this study. Cytoreduction was performed in all cases prior to therapy. Autologous tumor cells were transfected with the tag7/PGRP-S gene, irradiated and injected intradermally every 3 weeks. RESULTS: Vaccinations were well tolerated by all patients, without clinically significant signs of toxicity. Delayed-type hypersensitivity was observed in 48% of cases. Antitumor immune response was observed in 95% of patients. There were no complete or partial responses; however, a minor response was achieved in one patient with renal cell carcinoma. The stabilization of neoplastic disease was observed in eight patients (seven with malignant melanoma and one with renal cell carcinoma). Median time to tumor progression was 3 months. CONCLUSIONS: The approach suggested here appears to be well tolerated and produces a number of durable clinical effects. Further studies are required to determine whether promising effects on immune activation will result in an actual clinical benefit for patients with malignant melanoma and renal cell carcinoma.

High-dose toremifene in advanced renal-cell carcinoma.

Toremifene (Fareston)-a novel antiestrogenic drug with a triphenylethylene structure-is effective in the treatment of postmenopausal breast cancer patients. It can be safely given even at high doses of up to 300 mg/day. The purpose of the present study was to investigate the effect and tolerability of high-dose toremifene in the treatment of patients with advanced renal-cell carcinoma (RCC). A total of 36 patients started treatment with toremifene at 300 mg/day, including 26 men and 10 women. Their mean age was 56 years (range 35-75 years). In all, 19 patients were nephrectomized. One patient was not evaluable for response because of insufficient treatment time. The response rate was 17%, including one complete response (CR, 3%) lasting for 121+ weeks and five partial responses (PRs, 14%) with a mean duration of 40+ weeks. Ten cases of no change (NC, 28%) had a mean duration of 24 weeks. There was no significant difference in the response rate when patients with lung metastases alone were compared with patients showing metastases of other sites with or without lung metastases. Total pain control was achieved in 45% of the patients who had pain at the beginning of the treatment, and partial control was attained in 20%. Ten patients (28%) developed adverse reactions, which led to discontinuation of the treatment in one case. Blood samples were taken from 16 patients on days 0, 1, 3, 7, 14, and 28 for drug analyses. The concentration of toremifene and its main metabolites measured in serum were about 1.5 times that detected after a conventional dose of 60 mg/day. It can be concluded that high-dose toremifene is an effective and safe palliative treatment in advanced RCC.

Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer.

BACKGROUND: A phase III randomized trial was activated to evaluate the efficacy of preoperative combined chemotherapy and radiotherapy as compared to preoperative radiation therapy alone, in patients with breast cancer presenting with a clinical stage of IIb-IIIa (TNM classification). PATIENTS AND METHODS: From 1985 to 1990, 271 patients, aged 27-55 years, with stage IIb-IIIa breast cancer were randomized to receive either one or two courses of thiotepa 20 mg (i.m. injection) on the days 1, 3, 5, 7, 9, 11 (total dose per course 120 mg), methotrexate 40 mg/m2, i.v. on days 1 and 8, and 5-fluorouracil 500 mg/m2, i.v. on days 1 and 8 (TMF regimen) plus radiotherapy (Group I, 137 patients), or preoperative radiation therapy only (Group II, 134 patients). After the preoperative treatment all patients underwent mastectomy and complete axillary clearance, and then received 4-6 courses of TMF. The trial was conducted in a single institution (N.N. Petrov Research Institute of Oncology, St. Petersburg). RESULTS: Histopathological assessment of the mastectomy specimens showed complete regression of the tumour in 29.1% of the patients in group I and in 19.4% of the patients e.c. in group II. The estimated 5-year overall survival percentages were 86.1% for group I, and 78.3% for group II (P > 0.05). 5-year disease-free survival percentages were 81.0% and 71.6%, respectively (p < 0.05). CONCLUSIONS: Despite the low number of the patients included in the trial, we were able to detect a significant improvement in treatment results with a combination of chemotherapy and radiation therapy given prior to mastectomy over those of local therapy alone with radiation therapy followed by mastectomy, for average- and high-risk patients with operable breast cancer.

Study of the role of breast self-examination in the reduction of mortality from breast cancer. The Russian Federation/World Health Organization Study.

The protocol of a study, sponsored by the World Health Organization, of the role of breast self-examination (BSE) in reduction of mortality from breast cancer is presented. The major objective of the study is to determine the effect of a BSE programme on mortality from breast cancer. A population of of over 193,000 women aged 40 to 64 has been defined in Moscow and St Petersburg and randomised to study and control groups. In Moscow the education programme is based on a two-way communication principle allowing efficient person-to-person education in groups of up to 20 individuals and feedback information through specially designed personal calendars. In St Petersburg, class and individual instruction is carried out. After a 1-year feasibility study the project is planned to last for 15 years. It consists of an aggressive education programme, during and following which, all newly diagnosed breast cancers will be registered and treated, and followed up for 3 to 15 years. A key issue of the study is compliance of the population with BSE. The frequency and competence of BSE practice has been defined in subsamples of 400 randomly selected women by means of surveys at 6 months, 1, 2 and 3 years after the start of the project. The study is expected to result in the accrual of more than 1470 new breast cancer cases and 778 deaths from breast cancer. The power of the study is expected to permit detection of a 30% reduction in cumulative breast cancer mortality, assuming that 50-70% of the women in the study group practise BSE.

The role of breast self-examination in early breast cancer detection (results of the 5-years USSR/WHO randomized study in Leningrad).

A randomized population-based study has been carried out since 1985 in Leningrad in order to evaluate the efficacy of breast self-examination (BSE) in early breast cancer detection. The population under study covers 120,310 women aged 40-64 years with no history of breast cancer. About half of these women were exposed to BSE training (60,221) and 60,098 women constituted the control group. BSE teaching was carried out on a person-to-person basis and each patient received the BSE calendar. BSE education sessions resulted in a higher frequency of visits to specialists with complaints about "pathology" of the breast, a higher rate of referral to a specialized institution for an examination, and a higher number of excision biopsies due to a benign lesion (RR = 1.5; 95% C.I. = 1.1 - 1.9) as compared with the control group. As a result of examination, 190 breast cancer patients in the BSE group and 192 patients in the control group were detected. Comparisons of patients from both groups with regard to the size of primary tumor and the incidence of metastatic lesion in the regional lymph nodes showed no differences. The study is ongoing and all cases of breast cancer in the BSE group will be registered up to 1994 and followed-up to 1999; information will then be available on the impact of BSE upon breast cancer mortality.

Current evaluation of the contribution of self-examination to secondary prevention of breast cancer.

The "state of art" in the problem of BSE and its role in breast cancer early diagnoses in analysed. Advantages and disadvantages of this method and a complex of socio-psychologic problems arising in healthy population due to its introduction are discussed. The absence of scientifically grounded data on the importance of BSE for early diagnosis of breast cancer suggests the necessity of further investigations in order to identify its efficacy. Such data can be obtained only on the basis of randomized population study with estimation of efficacy by the decrease of breast cancer mortality in population. Under the auspices of the WHO such investigation has been conducted in Leningrad and in Moscow (USSR). Methods or investigation applied are described in short.

Clinical trials on adjuvant chemotherapy for breast cancer.

Clinical trial initiated in 1975 at the Petrov Research Institute of Oncology (Leningrad) included 1228 patients with breast cancer Stages I, II, and III. Adjuvant chemotherapy in patients with Stages I-II (P T0-2N0-1M0) leads to decrease in mortality rate by 24.3% in the case of monochemotherapy (thiotepa, six courses, 200 mg each course) and 32.4% in the case of polychemotherapy (thiotepa, methotrexate, 5-fluorouracil [TMF], cyclophosphamide, methotrexate, 5-fluorouracil [CMF], six course). There is a trend to higher (by 7.8%-9.8% versus control) rates of adjusted survival in the groups of patients with relatively early stages of breast cancer (P T0-2N0M0) subjected to adjuvant mono- and polychemotherapy. In the group of breast cancer patients (P T0-2N0-1M0) who received adjuvant polychemotherapy (TMF, CMF schemes) the survival rates are higher by 12.0%-16.6% than in the control group during the sixth, seventh, and eighth years of the follow-up. Favorable effect of adjuvant chemotherapy manifested by diminished mortality rate and prolonged survival was statistically significant only in the group of patients younger than 50 years.