Progesterone and not estrogens or androgens cause breast cancer

In May 2023, we published a scientific paper entitled “Progesterone from ovulatory menstrual cycles is an important cause of breast cancer” in the journal “Breast Cancer Research” (BCR: Impact Factor 11.2) by Herjan J. T. Coelingh Bennink, Iman J. Schultz, Marcus Schmidt, V. Craig Jordan, Paula Briggs, Jan F. M. Egberts, Kristina Gemzell‑Danielsson, Ludwig Kiesel, Kirsten Kluivers, Jan Krijgh, Tommaso Simoncini, Frank Z. Stanczyk and Robert D. Langer.

In September 2023 the journal “Climacteric” (Impact Factor 3.0) published a critical paper commenting on our BCR paper entitled “Lack of evidence that progesterone in ovulatory cycles causes breast cancer” by A. Gompel, V. Seifert-Klauss, J. A. Simon & J. C. Prior.

We were pleased that the Editor-in-Chief of Climacteric, Rod Baber, provided us with the opportunity to publish a full length paper as “Letter to the Editor” as rebuttal to the Gompel et al paper.
This rebuttal entitled “Progesterone and not estrogens or androgens cause breast cancer” has been published on 10 January 2024 in Climacteric by Herjan J.T. Coelingh Bennink and Frank Z. Stanczyk on behalf of all BCR authors.

A tumor cell specific Zona Pellucida glycoprotein 3 RNA transcript encodes an intracellular cancer antigen

Our peer-reviewed paper entitled “A tumor cell specific Zona Pellucida glycoprotein 3 RNA transcript encodes an intracellular cancer antigen” has just been published in Frontiers in Oncology!

It describes the presence and cancer-specific expression of a novel ZP3 transcript we call ‘ZP3-Cancer’ that is a highly interesting target for the development of an mRNA-based Cancer Vaccine.

Expression of ZP3-Cancer is strongly enriched in patients with ovarian cancer, colorectal cancer and in patients with a particular subtype of lung cancer. Pantarhei will strive to make a ZP3-Cancer based treatment available for patients suffering from these types of cancer.

Interview met Herjan Coelingh Bennink, Olav Andriesse en Nathalie Bries in BiotechNEWS & Life Sciences

Pantarhei Bioscience: Eigen. Gedurfd. En uiteindelijk uitermate succesvol.

Pantarhei heeft in haar 23-jarig bestaan mooie stappen gezet. Maar bovenal draait medicijnontwikkeling om geduld en geld. Van allebei liefst veel. Prof. dr. Herjan Coelingh Bennink kan erover mee praten. Maar zijn team en hij geloven onvoorwaardelijk in de toepassingen van Estetrol (E4), ARC (Androgen Restored Contraception) en Zona Pellucida 3 Cancer (ZP3C).

Lees hier het interview met Herjan Coelingh Bennink, Olav Andriesse en Nathalie Bries in BiotechNEWS & Life Sciences.

 

 

Progesterone from ovulatory menstrual cycles is an important cause of breast cancer

On May 30, 2023 the leading scientific journal dealing with basic and clinical breast cancer research “Breast Cancer Research (BCR)” published the Perspective Review paper  “Progesterone from ovulatory menstrual cycles is an important cause of breast cancer” by Herjan J.T. Coelingh Bennink, Iman J. Schultz, Marcus Schmidt, V. Craig Jordan, Paula Briggs, Jan F.M. Egberts, Kristina Gemzell-Danielsson, Ludwig Kiesel, Kirsten Kluivers, Jan Krijgh, Tommaso Simoncini, Frank Z. Stanczyk and Robert D. Langer.

The most important message of this narrative review paper is that progesterone from normal menstrual cycles causes most BCs, whereas estrogens and androgens may stimulate existing hormone receptor positive BC, but do not cause BC. Four authors of this paper are related to Pantarhei (HCB, IJS, JFME and JK) and the other nine authors are experts in the field of Reproductive Endocrinology and Oncology, supporting this rather thought-provoking paper, that will hopefully lead to a reappraisal and a turnaround of the medical view and opinion on the cause of breast cancer and change the negative perception of estrogens.

Abstract: Many factors, including reproductive hormones, have been linked to a woman’s risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting an essential role of P4. During the MC, P4 has a strong proliferative effect on normal breast epithelium, whereas estradiol (E2) has only a minimal effect. The origin of BC has been strongly linked to proliferation associated DNA replication errors, and the repeated stimulation of the breast epithelium by P4 with each MC is likely to impact the epithelial mutational burden. Long-lived cells, such as stem cells, present in the breast epithelium, can carry mutations forward for an extended period of time, and studies show that breast tumours tend to take decades to develop before detection. We therefore postulate that P4 is an important factor in a woman’s lifetime risk of developing BC, and that breast tumours arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.

 

Treatment of serious COVID-19 infection by combining suppression of testosterone and using a high dose of estrogens

Pantarhei Oncology announces the publication of its scientific paper “Testosterone suppression combined with high-dose estrogen as potential treatment of serious COVID-19 infection” (Heliyon 8 (2022) e12376)

COVID-19 infections are more serious and have a higher mortality in males compared to females especially at ages above 50 years. This is related to the 10-20x higher testosterone (T) levels in males. Suppression of T in males with serious COVID-19 has no consistent effect on the clinical outcome. However, by suppressing T in males, also their estrogen levels are decreased while estrogens have a favorable inhibitory effect on the factors responsible for the COVID-19 infection. Therefore, we hypothesize that a combination of T suppression by androgen-deprivation therapy (ADT) and high-dose estrogen (HDE) treatment may be an effective treatment of serious COVID-19, to be confirmed in in seriously ill COVID-19 patients.

The scientific background of this hypothesis

Most studies report a higher incidence of serious COVID-19 infections in males compared to females especially at ages above 50 years, which may be due to sex-related immunomodulation. A resulting higher mortality rate has been published in Maturitas, both in a meta-analysis performed in May 2020 and in a recent retrospective analysis. These observations could be associated with the 10-20x higher testosterone level in males, since testosterone has unfavourable effects on the immune system, and also stimulates angiotensin converting enzyme-2 (ACE2) and the androgen-regulated protease transmembrane protease serine 2 (TMPRSS2), which both facilitate the entry of the COVID-19 virus into the cell. Testosterone suppression by ADT decreases the effects of ACE2 and TMPRSS2. Estrogen treatment (ET) has the same beneficial suppressive effect on ACE2 and TMPRSS2 as ADT. Both ADT and ET (ADET) have been investigated separately as possible treatments of SARS-CoV-2. We hypothesize that the ADET combination may be more effective than its components alone, as also suggested in our Research Letter in European Urology (2021), entitled ‘Treatment of Serious COVID-19 with Testosterone Suppression and High-dose Estrogen (HDE) Therapy‘. The ADET co-treatment has been investigated successfully by Pantarhei Oncology in patients with advanced prostate cancer (Eur Urol Open Science, 2021 & 2022). We searched the literature for evidence of COVID-19 treatment benefits with estrogens, progesterone, androgen deprivation, and anti-androgens. Data supporting the effect of ADT on SARS-CoV-2 are sparse, but the favorable effects of estrogens in relation to COVID-19 have been shown in various cohort studies.

Based on the outcome of our review and the mode of action of the ADET combination, we hypothesize that a combination of ADT and HDE may be an effective and safe treatment of serious SARS-CoV-2 and we propose to test this ADET hypothesis in a clinical trial.

 

“Maintaining bone health by estrogen therapy in patients with advanced prostate cancer: a narrative review”

Pantarhei Oncology proudly announces that its paper “Maintaining bone health by estrogen therapy in patients with advanced prostate cancer: a narrative review” “Maintaining bone health by estrogen therapy in patients with advanced prostate cancer: a narrative review” has been published in the journal Endocrine Connections after comprehensive review. This journal is an international peer-reviewed, scientific, open access journal in the field of endocrinology.

In this paper we review the new and safer estrogen therapies, including high dose estetrol (HDE4), to maintain bone mass and prevent fractures in advanced prostate cancer patients treated with androgen deprivation therapy (ADT).

 

Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study

Pantarhei Oncology proudly announces that its paper ‘Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study’ has been published in the journal European Urology Open Science after comprehensive review. This journal is an international peer-reviewed, scientific, open access journal in the field of urology.

This paper summarises the very important data on the beneficial effects of high dose estetrol (HDE4) on the Quality of Life of prostate cancer patients treated with androgen deprivation therapy (ADT).

 

Positive results of E4 co-treatment with androgen deprivation therapy for advanced prostate cancer has been published in European Urology Open Science

Positive results of E4 co-treatment with androgen deprivation therapy for advanced prostate cancer has been published in European Urology Open Science

Pantarhei Oncology proudly announces that its paper ‘Estetrol Cotreatment of Androgen Deprivation Therapy in Infiltrating or Metastatic, Castration-sensitive Prostate Cancer: A Randomized, Double-blind, Phase II Trial (PCombi)’ has been published in the journal European Urology Open Science after comprehensive review. This journal is an international peer-reviewed, scientific, open access journal in the field of urology.

The research paper reports the results of the PCombi study, a phase II, double-blind, randomised, placebo-controlled, multi-centre study in males recently diagnosed with locally advanced or metastatic prostate cancer, who started ADT treatment with an LHRH agonist. The ADT-treated patients were co-treated for 24-weeks with 40 mg E4 or placebo. The high dose E4 treatment was well-tolerated and no treatment-related cardiovascular adverse events were observed. Patient treated with E4 reported fewer complaints of estrogen deficiency symptoms and better quality of life than patients who received placebo. With E4, 6% of the patients reported hot flushes compared to 55% of patients treated with placebo. Total and free testosterone, prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH) were suppressed more rapid and profound, suggesting enhanced disease control by E4. In addition, bone turnover was substantially reduced in the E4-treated patient implicating a bone-sparing effect. The study results have now been published in European Urology Open Science (EUROS).

Research paper on positive results treatment for advanced breast cancer with the fetal estrogen estetrol (E4) has been accepted for publication in the Journal of Cancer Research and Clinical Oncology

Pantarhei Oncology proudly announces that its paper ‘Tumor Suppression, Dose Limiting Toxicity and Wellbeing with the Fetal Estrogen Estetrol (E4) in patients with advanced breast cancer’ has been accepted for publication in the Journal of Cancer Research and Clinical Oncology after comprehensive review. The Journal of Cancer Research and Clinical Oncology is an international peer-reviewed scientific journal in the field of oncology.

The research paper states that treating postmenopausal women diagnosed with advanced breast cancer can be treated safely with high doses of E4. All 12 patients enrolled had progressive, heavily pre-treated advanced breast cancer. No treatment-related serious adverse events  or doses of limiting toxicity (DLTs) occurred during the first 4 weeks of E4 treatment allowing further investigation of all three doses. Five of nine patients completing 12 weeks of E4 treatment showed objective anti-tumor effects and six of nine patients reported improved wellbeing.

Schmidt_et_al-2020-Journal_of_Cancer_Research_and_Clinical_Oncology

Review paper on the risk of breast cancer in relation to gender, breast development and gonadal function published in JCEM

The Journal of Clinical Endocrinology & Metabolism has accepted the manuscript “Breast Cancer and Major Deviations of Genetic and Gender-related Structures and Function” by Herjan J.T. Coelingh Bennink, Jan F.M. Egberts, Jan A. Mol, Kit C.B. Roes, Paul J. van Diest for publication. The review reports of the risk of breast cancer (BC) in relation to gender, breast development and gonadal function in eight populations with different genetic conditions. Main three conclusions are: 1) the presence of an Y chromosome protects against the development of BC; 2) Without menstrual cycles, BC hardly occurs with an incidence comparable to males; 3) BC has been reported only once in genetic females with the Mayer-Rokitansky-Küster-Hauser syndrome, who have normal breasts and ovulating ovaries with normal levels of estrogens and progesterone.

For more information, please read the abstract.