scholarly journals 50th anniversary of the first clinical trial with ICI 46,474 (tamoxifen): then what happened?

2021 ◽  
Vol 28 (1) ◽  
pp. R11-R30
Author(s):  
V Craig Jordan
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Incidence ◽  
50Th Anniversary ◽  
Stage Iv ◽  
Research Strategy ◽  
Laboratory Animals ◽  
High Dose ◽  
Radium Institute ◽  
Stage Iv Breast Cancer ◽  
The World

Following the discovery and approval of the oral contraceptive, the pharmaceutical industry sought new opportunities for the regulation of reproduction. The discovery of the first non-steroidal anti-oestrogen MER25, with antifertility properties in laboratory animals, started a search for ‘morning-after pills’. There were multiple options in the 1960s, however, one compound ICI 46,474 was investigated, but found to induce ovulation in subfertile women. A second option was to treat stage IV breast cancer. Although the patent for ICI 46,474 was awarded in the early 1960s in the UK and around the world, a patent in the USA was denied on the basis that the claims for breast cancer treatment were not supported by evidence. A trial at the Christie Hospital and Holt Radium Institute in Manchester, published in 1971, showed activity compared with alternatives: high-dose oestrogen or androgen treatment, but the US Patent Office was unswayed until 1985! The future of tamoxifen to be, was in the balance in 1972 but the project went forward as an orphan drug looking for applications and a translational research strategy was needed. Today, tamoxifen is known as the first targeted therapy in cancer with successful applications to treat all stages of breast cancer, male breast cancer, and the first medicine for the reduction of breast cancer incidence in high-risk pre- and post-menopausal women. This is the unlikely story of how an orphan medicine changed medical practice around the world, with millions of women’s lives extended.

Breast Cancer

2018 ◽  
Author(s):  
Nancy E Davidson
Keyword(s):  
Breast Cancer ◽  
United States ◽  
Cancer Incidence ◽  
Hormone Replacement ◽  
Breast Cancer Incidence ◽  
Stage Iv ◽  
The United States ◽  
Rate Of Increase ◽  
Stage Iv Breast Cancer ◽  
Incidence And Mortality

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 266,120 In 2018, along with 63,960 new cases of non-invasive (in situ) breast cancer. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

scholarly journals Difficulty Diagnosing a Brain Tumor during Clinical Maintenance of a Complete Response to anti-HER2 Treatments for Metastatic Breast Cancer: A Case Report

2020 ◽  
Vol 13 (3) ◽  
pp. 1311-1316
Author(s):  
Ryoko Semba ◽  
Yoshiya Horimoto ◽  
Atsushi Arakawa ◽  
Yoko Edahiro ◽  
Tomoiku Takaku ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumor ◽  
Ductal Carcinoma ◽  
Metastatic Breast ◽  
Stage Iv ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Her2 Positive ◽  
Stage Iv Breast Cancer ◽  
The Right

A 46-year-old woman with erythema of the right breast presented to our hospital and was diagnosed with stage IV breast cancer (HER2-positive invasive ductal carcinoma). She received 4 courses of anthracycline-based regimens and 4 courses of trastuzumab + pertuzumab + docetaxel (Tmab + Pmab + DTX). Since she responded well to these therapies, only Tmab + Pmab was continued thereafter. Twenty-three months after starting treatment, she developed a headache. A tumor was identified in the right temporal lobe. Craniotomy was performed for definitive diagnosis. Intraoperative pathological assessment suggested the tumor to be brain metastasis of breast cancer. However, the final pathological diagnosis was diffuse large B-cell lymphoma of central nervous system (DLBCL-CNS) based on re-assessment with immunohistochemical examinations. Therefore, the Tmab + Pmab was discontinued, and 6 courses of high-dose methotrexate therapy were administered. This case highlights the importance of considering rare entities, such as DLBCL, when diagnosing a solitary brain tumor in a patient with a primary cancer, based on imaging and pathological findings.

Breast Cancer

2017 ◽  
Author(s):  
Nancy E Davidson
Keyword(s):  
Breast Cancer ◽  
United States ◽  
Hormone Replacement ◽  
Breast Cancer Incidence ◽  
Metastatic Breast ◽  
Stage Iv ◽  
The United States ◽  
Rate Of Increase ◽  
Stage Iv Breast Cancer ◽  
Incidence And Mortality

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 235,000 women in this country in 2013 and is expected to result in approximately 40,000 deaths. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

High-dose consolidation therapy with autologous stem-cell rescue in stage IV breast cancer: follow-up report.

1992 ◽  
Vol 10 (11) ◽  
pp. 1743-1747 ◽  
Author(s):  
S F Williams ◽  
T Gilewski ◽  
R Mick ◽  
J D Bitran
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Median Time ◽  
Metastatic Breast ◽  
Stage Iv ◽  
High Dose ◽  
Dose Intensification ◽  
Stem Cell Rescue ◽  
Stage Iv Breast Cancer ◽  
Time To Treatment Failure

PURPOSE Fifty-nine patients with newly diagnosed metastatic breast cancer were treated with induction chemotherapy followed by high-dose intensification and autologous stem-cell rescue (ASCR) to determine therapeutic efficacy. PATIENTS AND METHODS Induction consisted of cyclophosphamide, doxorubicin, vincristine, and methotrexate with leucovorin rescue (LOMAC) in 27 patients, or fluorouracil, cisplatin, doxorubicin, and cyclophosphamide (FCAP) in 32 patients. Intensification after LOMAC was cyclophosphamide and thiotepa (CyTepa) with ASCR, and after FCAP it was cyclophosphamide, thiotepa, and carmustine (BCNU) in all but eight patients who received CyTepa. RESULTS Median survival from study entry for the entire group was 13.3 months. Median time to progression from reinfusion for the 45 patients who underwent intensification was 7.5 months. After LOMAC and intensification, there were 12 complete responses (CR) (nine partial responses [PRs] after induction converted to CRs). Responses after FCAP and intensification were eight CRs (two PRs after induction converted to CRs). Median time to treatment failure from reinfusion was 5.4 months for LOMAC and intensification, and was 10.5 months for FCAP and intensification. Median survival from study entry was 15.1 months for all 27 LOMAC patients and 9.3 months for all 32 FCAP patients. Median time to treatment failure from reinfusion for 11 patients who were CRs at intensification has not been reached and is more than 13 months compared with a median of 5.5 months for the 23 patients in partial remission at intensification. CONCLUSIONS High-dose intensification therapy has led to increased CR rates in metastatic breast cancer. The role of such therapy in the treatment of stage IV breast cancer requires further refinement.

Breast Cancer

2018 ◽  
Author(s):  
Nancy E Davidson
Keyword(s):  
Breast Cancer ◽  
United States ◽  
Hormone Replacement ◽  
Breast Cancer Incidence ◽  
Metastatic Breast ◽  
Stage Iv ◽  
The United States ◽  
Rate Of Increase ◽  
Stage Iv Breast Cancer ◽  
Incidence And Mortality

Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 235,000 women in this country in 2013 and is expected to result in approximately 40,000 deaths. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States. This review contains 2 highly rendered figures, 8 tables, and 108 references.

High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer.

1989 ◽  
Vol 7 (12) ◽  
pp. 1824-1830 ◽  
Author(s):  
S F Williams ◽  
R Mick ◽  
R Desser ◽  
J Golick ◽  
J Beschorner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Induction Chemotherapy ◽  
Disease Free Survival ◽  
Stage Iv ◽  
Complete Response ◽  
High Dose ◽  
Stem Cell Rescue ◽  
Stage Iv Breast Cancer ◽  
Autologous Stem Cell Rescue

We designed a phase II study to determine whether induction chemotherapy (CT) consisting of leucovorin, vincristine, methotrexate, doxorubicin, and cyclophosphamide (LOMAC) followed by high-dose intensification chemotherapy (ICT) with cyclophosphamide, thiotepa, and autologous stem cell rescue (ASCR) could increase the complete response (CR) rate and survival in women with stage IV breast cancer. Twenty-nine women were enrolled on study; 16 patients had received prior adjuvant chemotherapy and no patient had received chemotherapy for stage IV disease. Two patients were found to be ineligible and excluded from further analysis. Of the 27 patients treated, four (15%) obtained a CR and 15 (56%) a partial response (PR) after LOMAC induction, for an overall response rate of 70%. Of the 22 patients treated with ICT, 12 patients had a CR, and nine were in PR after induction and converted to CR after ICT. The toxicities included nausea/vomiting, mucositis, diarrhea, dermatitis, alopecia, and infections secondary to neutropenia. The 1-year survival is 60%; the median has not yet been reached. The time to treatment failure for patients on study is 10 months. The treatment approach of ICT and ASCR following induction chemotherapy can lead to an improved CR rate in stage IV breast cancer. How this increased CR rate leads to a prolonged disease-free survival requires further follow-up.

Estimation of maximum tolerated dose and minimum efficient dose of BP-C1 in the treatment of stage IV breast cancer patients: A phase I response surface pathway designed study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11022-e11022
Author(s):  
Stig Einride Larsen ◽  
Sagita Dewi ◽  
Vichien Srimuninnimit ◽  
Yen-Shen Lu ◽  
Tjakra Manuaba ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cumulative Dose ◽  
Dose Group ◽  
Low Dose ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
High Dose Group ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Stage Iv Breast Cancer

e11022 Background: The aims were to establish a treatment routine and to estimate the Maximum Tolerated Dose (MTD) and the Minimum Efficient Dose (MED) of a novel anti-cancer agent named BP-C1. Methods: The material consists of 15 Stage IV breast cancer patients with a mean age of 51 years. The study was performed as a non-randomized multi-centre trial with between patient 3-level Response Surface Pathway design. BP-C1 was given intramuscularly once daily during 32 days. The given cumulative dose window was 0.16 to 1.12 mg/kg bw, resulting in a starting dose of 0.64 mg/kg bw. The main variable was the National Cancer Institute common toxicity criteria (NCI-CTC) Bethesda. If the increase in toxicity was classified as moderate or less, the next patient in the sequence was allocated to an increased dose. In case of severe toxicity increase, the dose was reduced. Patients receiving cumulative dose of 0.96 mg/kg bw or higher was defines as the high-dose group. Results: Three of the five patients on the first design level recorded unchanged toxicity, one mild and one moderate increased Max NCI-CTC. Of the four patients receiving 0.96 mg/kg bw, three obtained no change and one a mild toxicity increase. The four patients on the third design level received the maximal dose of 1.12 mg/kg bw without any change in Max NCI-CTC. The Sum NCI-CTC increased (p= 0.07) in the low-dose group, but reduced (p=0.09) in the high-dose group. The cumulative dose of BP-C1 was found significantly (p=0.048) and negatively correlated (r = - 0.52) to the increase in toxicity. Only mild to moderate Adverse Events were reported and the prevalence was found largest in the high dose group (p=0.06). In the high-dose group 62.5% of the patients were classified as responders compared to 28.6% in the low-dose group. One of the patients in the high-dose group was classified as complete responder. The development in both Karnofsky Scale of Performance Status and patient wellbeing was found obviously better in the high-dose group. Conclusions: BP-C1 can safely be administrated continuously during a period of 32 days. The MTD seem to be at least 1.12 mg/kg bw and the MED to be 0.96 mg/kg bw.

Treatment of estrogen receptor-negative or hormonally refractory breast cancer with double high-dose chemotherapy intensification and bone marrow support.

1990 ◽  
Vol 8 (7) ◽  
pp. 1207-1216 ◽  
Author(s):  
F R Dunphy ◽  
G Spitzer ◽  
A U Buzdar ◽  
G N Hortobagyi ◽  
L J Horwitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Estrogen Receptor ◽  
Menopausal Status ◽  
Stage Iv ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Stage Iv Breast Cancer ◽  
Estrogen Receptor Negative

We have used high-dose therapy followed by randomization to receive or not receive autologous bone marrow infusion in 58 stage IV breast cancer patients (all were estrogen receptor-negative [ER-] or primary hormonal refractory). Patients received a median of four courses of induction chemotherapy and if stable or responding received two courses of intensive therapy with cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 180 mg/m2 (CVP). The complete remission (CR) rate after completion of the induction and intensive phases was 55%. Median progression-free interval from induction is 57 weeks with a projected 2-year progression-free survival of approximately 25%. Six of seven patients followed for greater than 2 years are still progression-free. Three favorable features predicted for improved progression-free survival are the following: (1) absent liver involvement, (2) absent soft tissue involvement, and (3) less than or equal to two disease sites (P values of .001, .013, and .048, respectively). Hormonal and menopausal status did not predict for progression-free survival. Major toxicities were infectious secondary to neutropenia, with a 93% incidence of fever and a 38% incidence of sepsis. The treatment-related mortality rate was 9%, with three infectious, one coronary, and one late hemorrhage-related death of unknown cause. Longer follow-up is still needed to truly evaluate the possibility of long-term disease-free survival, but further studies of this approach to high-dose intensification in poor prognostic groups of stage IV breast cancer appear warranted.

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