By Cancer Rose, 4th January 2026
Since the 1990s, breast cancer treatment therapies have evolved considerably. In particular, over the last 25 years, cancer treatments have been revolutionized by innovations such as targeted therapies (drug action against a specific characteristic of the cancer cell), immunotherapy (also a targeted therapy, such as monoclonal antibodies that attack a specific protein of the cancer cell to block its growth), or even genetically modified lymphocytes that recognize the diseased cell and become selective killers in the patient’s body.
Currently, kinase inhibitors, and more specifically CDK4/6 (cyclin-dependent kinases), are real blockbusters in anticancer therapies and are gaining an important place in the oncology drug market.
These are very effective drugs for metastatic breast cancer, but they are not at all effective for non-metastatic breast cancer with a high risk of recurrence, as defined in two clinical trials (Natalee and MonarchE).
In the MonarchE trial, high risk of recurrence is defined as patients with 4 or more positive axillary lymph nodes on the same side, or 1 to 3 axillary lymph nodes on the same side with at least one of the following two criteria: histological grade 3 or primary tumour size ≥ 5 cm.
In Natalee, high risk of recurrence is defined as patients with anatomical stage IIB-III cancer, or anatomical stage IIA cancer that is either:
o With lymph node involvement
or without lymph node involvement, with: – Histological grade 3, or – Histological grade 2, with one of the following criteria: – Ki67 ≥ 20% – High risk according to genomic signature
(Clinical trials are listed at the end of the article)
Two public health whistleblowers have published a memo (available for download at the end of this article) calling for an immediate safety plan for this class of drugs, and we are relaying their appeal. They are Carine Cohen, a pharmacoepidemiologist speaking as a patient, and Dr. Jean-Pierre Thierry, a public health physician.
Kinase inhibitors, mechanisms of action
How does it work?
Simply put, kinases are enzymes that add phosphates to other molecules within a cell. They trigger the transfer of a phosphate group from a donor molecule, usually ATP (adenosine triphosphate), to a target molecule, often a protein. ( Adenosine triphosphate (ATP) is a molecule used in all living organisms to provide energy for metabolic reactions.)
These alterations (phosphorylation) in cancer cells potentially affect the ability of diseased cells to divide, invade tissues, and form distant metastases.
Two molecules are primarily used and widely available: ribociclib ( Kiskali ) and abemaciclib ( Vernezio ) . These molecules can be used as adjuvant therapy (i.e., in addition to usual post-surgical treatments such as radiotherapy and hormone therapy), or as neoadjuvant therapy (i.e., before the main treatment, before surgery or radiotherapy), mainly to reduce tumor size in cases of large, aggressive cancers.
That’s what they did.
However, the two authors of the note warn of several problems inherent not only in the molecules themselves, but also in the lack of information provided to women targeted by these therapies about adverse effects, and in addition to the methodological biases that plague clinical trials in which women are enrolled, with a consent form that does not clearly contain the considerable adverse effects to which they are exposed.
The major problems raised by the warning note
1/ Massive toxicities , including several undiagnosed fatal adverse effects, poorly assessed in the long term, namely cardiovascular, hepatic and hematological (neutropenia, i.e. a decrease in white blood cells).
2/ Acquired resistance to treatments , in case of recurrence of the disease, with a more rapid progression towards triple negative breast cancer, which is much more difficult to treat and has a poor prognosis.
3/ No efficacy on overall survival (false efficacy), and perhaps even a negative impact due to treatment escape and the selection of cell clones resistant to chemotherapy . (We will return to this point below)
4/ For abemaciclib , there may be an inverse dose-effect relationship, meaning that the drug may work during the first few weeks before acquired resistance develops, which women are not alerted to during the two years of treatment, increasing the risk of fatal adverse effects.
5/A massive controversy over clinical trials in which patients are included, concerning the ethical aspect of the information given to patients, concerning the problem of the modalities of inclusion of new patients in these clinical trials, and concerning the honesty in what is promised to patients, that is to say the display of an objective of “therapeutic de-escalation” by replacing chemotherapies which would be more toxic, which is very questionable.
WHAT DOES THE HAS (HIGH AUTHORITY FOR HEALTH) SAY IN FRANCE?
Regarding Ribociclib , the HAS (French National Authority for Health) opinion specifies that ” ribociclib has no place in the therapeutic strategy for early breast cancer ,” notably because ribociclib presents greater toxicity than the chemotherapy it is intended to replace.
The note explains that in July 2025, the French National Authority for Health issued an unfavorable opinion regarding reimbursement for ribociclib ( Kisqali® ). The Transparency Committee, based on clinical trial data, therefore judged that the Medical Benefit Rendered by this drug was insufficient ( SMRI ) and thus “has no place in the therapeutic strategy” for early breast cancer, given the following factors:
o Very modest amount of effect
o Major methodological biases creating significant uncertainty about actual effectiveness
o Lack of robust data on overall survival
o Concerning tolerability profile with an unacceptable increase in toxicity in adjuvant therapy (more toxic than standard treatments, particularly chemotherapy).
Regarding abemaciclib ( Verzenios® ) , it received a favorable opinion from the HAS (French National Authority for Health). According to the report from the two whistleblowers, “the HAS considered on May 24, 2023, that abemaciclib provided a moderate medical benefit (SMR) and did not offer any improvement in medical benefit compared to the current standard treatment, namely hormone therapy after surgery, chemotherapy, and radiotherapy if necessary.”
The serious side effects described
A – Cardiovascular toxicity
As adjuvant therapy, data from the US FDA (Food and Drug Administration) and the European EMA (European Medicines Agency) have revealed fatal toxicity of ribociclib The toxicity is at least double that of standard chemotherapy. It is primarily cardiovascular, including QT interval prolongation (an abnormality that increases the risk of rapid heart rhythms such as ventricular tachycardia).
The risk of death is increased fourfold.
It should be noted that adverse drug events are classified by grade. Grade 5 events are fatal adverse events.
However, the EMA (European Medicines Agency) report attributes 16 deaths in the Natalee clinical trial to adverse effects of ribociclib, of the 16 deaths reported in 2023, 5 had already occurred after the end of exposure to ribociclib. These events are minimised and their causality with the treatment denied in the trial, as the two whistleblowers point out, ‘this discrepancy between the concordant assessment of the regulatory authorities, notably via the FDA package insert, and the scientific communication raises questions about the transparency and ethics of the information’ in the Natalee trial.
https://case.edu/cancer/sites/default/files/2018-06/Adverse-Effects.pdf
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical intervention; asymptomatic laboratory findings only; marginal clinical relevance)
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; non-invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation).
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring hospitalization or invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation).
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, lifethreatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive care or emergent invasive procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation).
Grades 5 are fatal adverse event resulting in death.
B-other toxicities
Neutropenia (a decrease in white blood cells) is significant, as is liver toxicity.
Patients also report significant fatigue, all of which can impact treatment adherence. Furthermore, the lack of physical activity induced by this excessive fatigue leads to a de facto lack of physical activity, increasing the cardiac toxicity of the standard chemotherapies prescribed concurrently.
C- Tumor escape
What is it?
Sometimes, suddenly, treatment—whether chemotherapy or targeted therapy—stops “working.” Several factors are responsible: first, the tumor burden, meaning the number of cancer cells. The higher the number of cancer cells, the greater the risk that one of them will become resistant to treatment.
Furthermore, a cancerous tumor is not a collection of identical cells. It is composed of a kind of “mosaic” of cells with different molecular characteristics, giving the tumor intratumoral heterogeneity .
If there is a subpopulation of cells within the tumor carrying a gene for resistance to chemotherapy, these resistant cells will be “selected” when chemotherapy is administered and will have an advantage. predominant over others.
As in the animal world, the best-adapted organisms and cells survive, and therefore only these cancer cells resistant to chemotherapy or kinase inhibitor therapy will persist after treatment and multiply. This is the phenomenon of primary resistance.
On the other hand, the genome (the complete set of chromosomes and genes of an individual) of cancer cells can mutate and acquire new molecular properties. The treatment itself can thus induce characteristics that promote resistance in cancer cells. It is not the sequence of genes in cancer cells that is altered, but rather the way in which these genes are expressed.
The phenomenon of drug escape is well known as an adverse effect of this class of drugs and affects both products.
In the context of neoadjuvant therapy, this phenomenon of drug escape for ribociclib still affects 66-73% of treated patients.
We can no longer speak of “therapeutic de-escalation” in the treatment of so-called early cancer if, on the one hand, we observe a loss of life expectancy of at least 12 to 14 months, corresponding to the overall survival benefit of CDK4/6 in cases of metastatic cancers, if on the other hand we even observe cross-resistance to several therapies or if the selection of cell clones produces even more aggressive metastases that have become triple negative!
D- Overall survival and quality of life
The various trials do not show any improvement in overall survival with kinase inhibitors compared to chemotherapies, and some of these trials even show a negative effect on survival.
The report by Carine Cohen and Jean-Pierre Thierry even notes that on social media, particularly Facebook, “institutional communication evokes a ‘therapeutic de-escalation’ and an improvement in ‘quality of life,’ arguing for less toxicity compared to standard chemotherapy.” This terminology, the authors state, is found in institutional communication concerning a clinical trial (the NoLEEta study ) promoted by the UCBG (French Breast Cancer InterGroup) . Unicancer Chemotherapy is thus presented as more dangerous than ribociclib , when in fact the opposite is true: the mortality rate linked to kinase inhibitor toxicity is higher, as are hospitalization rates and data on liver and hematological toxicity.
All this is presented in the complete absence of any demonstration of improved overall survival or quality of life. The use of the term “therapeutic de-escalation” appears misleading in this context. No benefit on overall survival is expected during at least the first four or five years, which are crucial for patients, given that life expectancy is already compromised in the most aggressive forms of the disease.
E-information owed to women
The report even highlights how misleading and contrary to the ethical principles of information and informed consent are in communicating this information to women, given that quality-of-life data is not included in the ribociclib ( Kisqali® ) product information leaflet.
The FDA issued a warning to the company in 2024, prohibiting it from directly promoting the product to patients by invoking “quality of life.”
F- Clinical trial bias
In some international clinical trials ( ManarchE and Natalee trials ), overall survival data are heavily biased in the control group, that is, the group of women used as a comparator to the “intervention” group, where the product is tested.
While these drugs have demonstrated their efficacy in the treatment of metastatic breast cancer, some patients assigned to the control group in these clinical trials did not have access to kinase inhibitors when their cancer recurred or when metastases appeared (they had received adjuvant hormone therapy alone). This represents a missed opportunity for these women because this lack of treatment artificially accelerates mortality in the control group, compared to countries where these treatments are available, including France.
The note points out that “hundreds and potentially thousands of patients are still exposed in clinical trials… and in routine clinical practice, including off-label or off-reimbursement, while clinical trials are the source of a contradictory scientific debate, and above all, independently of this particular context, without adequate information on the known risks and hypothetical expected benefits being communicated to them .”
In the Ribolaris trial , all patients are exposed to 2.5 years of adjuvant ribociclib , including the 60% of women identified as having developed resistance during the neoadjuvant phase (“non-responders”). Not only is there an additive effect of toxic effects, but there is also a worsening of acquired resistance through the selection of increasingly aggressive tumor clones, as explained above. The Ribolaris trial is investigating ribociclib as neoadjuvant and adjuvant therapy combined with endocrine therapy for the treatment of early, high-risk breast cancer.
The “PAM50 test,” used in the trial, is a genomic test, or genetic test of the cancer cell, to predict the effectiveness of treatments. It allows for the classification of different types of cancer and guides therapeutic decisions. However, this test has not been approved by the French National Authority for Health (HAS) for use at the time of diagnosis. The trial strategy using the test imposes ribociclib and possibly chemotherapy on women who could avoid them, and deprives some of chemotherapy they could benefit from, for example in case of lymph node progression, a case where PAM50 prohibits chemotherapy.
Women with a genetic risk factor, such as the BRCA mutation, are denied BRCA testing to include them in the Ribolaris trial .
The pre-treatment information given to patients is incomplete or not prominent, particularly regarding increased resistance acquired during the neoadjuvant phase with the addition of ribociclib , as well as the significantly higher toxicity of ribociclib compared to standard chemotherapy.
In short, faced with overwhelming methodological biases, a lack of transparency, ethics and patient information, more and more independent international experts are opposing the current systematic use of CDK4/6 in adjuvant or neoadjuvant treatment .
G- Lack of information
During the recruitment of patients for ongoing clinical trials, the authors of the report warn of the lack of accurate information regarding:
– Toxicity compared to standard chemotherapy in the treatment of non-metastatic breast cancer
– The lack of demonstrated benefit on overall survival during the first four or five years
– The known risk of therapeutic impasse in the event of metastatic recurrence
– The available therapeutic alternatives that patients might prefer
– The opinions of the High Authority for Health following the comparative evaluation with standards of care, as well as on the use of genomic tests
However, the note emphasizes that women must be informed of the risks of potentially fatal toxicity in the short and long term, and obtain full information regarding the specific reasons for the Insufficient Medical Service Rendered by the HAS for ribociclib in non-metastatic breast cancer.
How many women are affected?
According to the lead author of the note, Ms Carine Cohen, 85 French women were included in the Calhys trial, 1,100 potential victims were recruited for the Ribolaris trial, about half of whom were in Spain (difficult to quantify because it is not known whether the French National Agency for Medicines Safety (ANSM) decision to suspend the inclusion of women in the trial between July 2024 and February 2025 was also followed in Spain).
There could be 3,900 women involved in the NoLEETa trial, including a first victim recruited at the Curie Institute.
It is difficult to obtain information on the number of victims in other countries where the trials have been conducted.
Other countries participating in the NoLEETa trial include Germany, the Netherlands, Spain, Switzerland, Italy, Brazil and Canada.
According to the note from the two authors (pages 1 and 2), “
Similarly to other countries, the affected patient populations in France for this indication are significant and allow us to assess the stakes:
• _The ribociclib indication concerns moderate to high-risk breast cancers representing approximately 30 to 43% of incident breast cancers (approximately 14,000 potentially eligible patients per year).
• _The abemaciclib indication potentially concerns 14% to 18% of breast cancers (approximately 6,000 potentially eligible patients per year).
These numbers represent theoretical eligibility based on general biological and clinical criteria. Actual eligibility, after considering contraindications, comorbidities, and other criteria favoring individualization of therapeutic strategies, should be substantially more restricted. In practice, eligible populations can be estimated at approximately 10,000 patients/year for ribociclib and 4,500 patients/year for abemaciclib in France.
Worldwide, about 300,000 patients could be eligible for ribociclib.”
CONCLUSION
A growing number of independent international experts recommend against using CDK4/6 in non-metastatic breast cancer, based on the following findings:
– The mechanisms of acquired resistance and the resulting therapeutic impasse
– The confirmed failure of Palbociclib as an adjuvant (this is a third specialty alongside ribociclib and abemociclib , which we have not discussed, because its failure is confirmed by two studies).
– The negative conclusions of the use of these molecules in neoadjuvant therapy due to tumor escape (in two other studies), and greater toxicity than standard chemotherapy.
– Data on lethal toxicity, particularly cardiovascular toxicity, which is common to this entire class of drugs.
Ms. Carine Cohen and Dr. Jean-Pierre Thierry are calling for a moratorium allowing for the immediate suspension of exposure in studies with ribociclib (RIBOLARIS, CALHYS, and NoLEEta ), as well as the reassessment of all patients exposed or currently undergoing treatment. This approach requires systematically informing all patients exposed to CDK4/6 inhibitors in the adjuvant/ neoadjuvant setting .
According to them, the urgency of the situation demands immediate action from health authorities. “Without major changes, thousands of women will remain exposed to treatments whose rapid effectiveness in overall survival is unproven, with lethal toxicities and documented but unreported acquired resistance, all while being given a false sense of security through a proposed ‘de-escalation’.”
Furthermore, enhanced pharmacovigilance must be implemented. “The use of ribociclib and other CDK4/6 inhibitors in adjuvant and neoadjuvant settings must be reassessed in light of the documented adverse events not only in ribociclib trials, but also in cases of routine prescribing.”
Note on the Use of CDK4/6 Inhibitors in Adjuvant and Neoadjuvant Treatment of early Breast Cancer
The clinical trials
Natalee trial: Phase III, multicentre, randomised, open-label study to evaluate the efficacy and tolerability of ribociclib with endocrine therapy as adjuvant treatment in patients with early-stage hormone receptor-positive, HER2-negative breast cancer / Novartis
MonarchE trial: Phase III, randomised, open-label study evaluating abemaciclib in combination with standard anti-hormonal therapy versus standard anti-hormonal therapy alone in the adjuvant setting in patients with early-stage breast cancer at high risk of recurrence, with lymph node involvement, HER2- and RH+ / Lilly
Adaptcycle study: Phase III study investigating whether CDK4/6 inhibition plus hormone therapy (HT) could replace chemotherapy in early-stage RH+/HER2- breast cancer with moderate to high risk. / West German Study Group/Novartis/Genomic Health
Feline trial: study of the efficacy of neoadjuvant anti-aromatase therapy (hormone therapy) with or without ribociclib for hormone-dependent breast cancers / Novartis
Ribolaris trial: Study of RIBOCICLIB as neoadjuvant and adjuvant therapy with endocrine therapy (or hormone therapy) for the treatment of high-risk RE+/HER2- breast cancer /Novartis / Unicancer
Calhys trial: Phase I/II study of the safety and efficacy of ribociclib in combination with hormone therapy and hypofractionated radiotherapy in hormone receptor-positive, HER2-negative breast cancer in elderly, newly diagnosed patients who are not immediately operable. / Antoine Lacassagne Cancer Centre – CLCC Nice
NoLEEta trial: Global phase III non-inferiority trial to demonstrate that patients with early-stage ER+ HER2- breast cancer at intermediate risk treated with ribociclib could be spared the side effects of chemotherapy with similar survival outcomes. / Unicancer
CORALLEEN trial: a multicentre, randomised, two-arm study in postmenopausal women with primary Luminal B HR+/HER2- breast cancer, to explore whether the combination of ribociclib and letrozole (hormone therapy) offers a clinical benefit at least comparable to that of standard chemotherapy. / SOLTI Breast Cancer Research Group / Novartis
Carabela trial: Phase II trial to study the efficacy, in terms of residual disease and tumour proliferation, of neoadjuvant treatment combining abemaciclib and letrozole (hormone therapy) compared to chemotherapy.
Lidera trial: Phase 3, randomised study evaluating the efficacy and safety of Giredestrant as an adjuvant compared to adjuvant hormone therapy chosen by the physician in patients with early-stage, oestrogen receptor-positive, HER2-negative breast cancer. / Roche
Señorita programme: A care pathway created at the Toulouse Oncopole for patients with non-metastatic breast cancer who are eligible for a CDK4-6 inhibitor combined with adjuvant hormone therapy. To improve patient support for better management of adverse effects, better treatment adherence and greater safety.
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