Breast cancer prevention remains an important opportunity to move care earlier in the disease continuum, particularly by addressing measurable risk factors such as mammographic breast density (MBD). In this editorial, Steven Quay, M.D., Ph.D., examines the potential role of low-dose (Z)-endoxifen and findings from the phase 2 KARISMA-Endoxifen trial as part of a broader shift toward prevention and early intervention.
Key Takeaways
- Mammographic breast density is both a breast cancer risk factor and a challenge for mammographic detection, making it an important consideration in prevention and risk assessment.
- MBD is a measurable pharmacodynamic marker that may provide an objective indication of biological response to endocrine risk-reduction therapy.
- The KARISMA-Endoxifen trial evaluated low-dose (Z)-endoxifen, a selective estrogen receptor modulator and degrader (SERM/SERD) also known as 4-hydroxy-N-desmethyltamoxifen, in 240 healthy, premenopausal women and reported reductions in MBD with both 1 mg and 2 mg daily doses compared with placebo.
- A broader prevention-focused approach to breast cancer care emphasizes therapies designed to address risk before breast cancer develops rather than relying primarily on treatment after diagnosis.
A gap in our armor
The fight against breast cancer has largely followed a reactive approach that focuses on improving treatment, refining surgeries, and chasing cures. While these monumental strides in advanced care deserve our celebration, they also expose a gap in our armor. There is still room to deploy our best tools to further prioritize prevention and early intervention.
To truly reshape the future of breast oncology, we must pivot from treatment to true prevention. The key to unlocking this proactive future lies in tackling a deeper understanding of the biological indicators associated with breast cancer risk. For years, high mammographic breast density (MBD) was viewed as a fixed obstacle. Today, data from the KARISMA trial (NCT05068388) show that low-dose (Z)-endoxifen* can reduce this density while offering greater safety and tolerability than conventional treatments.
By aggressively embracing these targeted risk-reduction strategies, we may finally be able to intervene at the cellular level, altering a patient’s trajectory long before a tumor ever has the chance to form, initiating intervention earlier in a patient’s journey, and potentially altering the course of the disease before advanced progression occurs.
The Density Dilemma
To revolutionize prevention, we must first master the biological risk, starting with high MBD.
As a well-recognized and independent risk factor for breast cancer, MBD presents a dual challenge in breast cancer. It can lead to patients becoming more susceptible to developing the disease. [1] First, it creates a dangerous ‘masking effect’ as dense fibroglandular tissues can obscure tumors in mammograms, rendering detection more difficult for radiologists as it essentially camouflages early-stage tumors. When these early-stage tumors are left unidentified, it can result in a delay of life-saving diagnoses.[2]
Beyond its role as a diagnostic obstacle in cancer detection and risk stratification, elevated MBD possesses an even more powerful, proactive attribute, serving as a critical pharmacodynamic marker of response to endocrine risk-reduction therapies. [3] In preventive medicine, rather than treating asymptomatic patients with therapies to mitigate a future symptom or diagnosis from occurring, MBD acts as a visible, measurable window into the drug’s biological efficiency.
When an endocrine risk-reduction therapy successfully reduces breast density over time, it provides objective proof that we are successfully lowering that patient’s systemic breast cancer risk. In other words, yielding a measurable indicator of a corresponding reduction.
The Tamoxifen Paradox
For decades, the gold standard treatment for chemical breast cancer risk reduction has been tamoxifen, a Selective Estrogen Receptor Modulator (SERM) approved by the U.S. Food and Drug Administration (FDA) in 1977. [4] In reality, it represents a profound paradox: a powerful preventive player for many high-risk patients. However, as pharmaceutical advancements persist, innovations are successfully addressing the limitations found within the preexisting therapies.
The flaw lies not in tamoxifen’s intent, but in its biological architecture. Rather than serving as a functional drug that is effective immediately upon administration, tamoxifen is a pro-drug that requires biological conversion.
When ingested, tamoxifen is pharmacologically inactive and must travel to the liver, where it undergoes a complex enzymatic pathway to be converted into active cancer-fighting metabolites, such as (Z)-endoxifen. Because human genetics vary wildly, this conversion process is notoriously unpredictable. Tamoxifen relies entirely on the body’s makeup to become effective, and as metabolism varies from patient to patient, the variables of genetics play a significant role. Poor metabolizers may never achieve therapeutic levels of the active drug, rendering the treatment ineffective. Conversely, for those who do metabolize it fully,
The standard-dose 20mg tamoxifen can inflict intolerable tolls on daily well-being with side effects including severe hot flashes, nausea, night sweats, and more. The result is dismally low patient acceptance and high discontinuation rates. [5] While tamoxifen has proved to reduce the risk of recurrence in patients with breast cancer and is approved for prevention of breast cancer in women at increased risk, its limitations in tolerability, variable metabolism, and patient acceptance prove there is room for further innovation.
As precision medicine continues to reshape modern healthcare, relying on a pro-drug with heterogeneous predictability and toxicity is no longer sufficient. To truly protect high-risk patients, we must transition to therapies that bypass the liver’s genetic lottery entirely, delivering a biologically efficient, highly tolerable mechanism for modern patients and broader use.
A New Path Forward: Low-Dose (Z)-Endoxifen
To mitigate limitations associated with tamoxifen’s indirect pathways, low-dose (Z)-endoxifen therapy offers a direct approach and is less susceptible to genetic variability in liver metabolism. The Phase 2 KARISMA-Endoxifen trial evaluated if low-dose (Z)-endoxifen could reduce MBD in healthy, premenopausal women. [6] The double-blind, placebo-controlled study included 240 women in Sweden who were randomly assigned to placebo, 1 mg, or 2 mg daily doses of (Z)-endoxifen for six months.
The results showed significant changes in MBD in both groups taking (Z)-endoxifen compared with those taking placebo. Those who received 1 mg of (Z)-endoxifen experienced an approximately 19% reduction, and those receiving 2 mg achieved an approximately 26% reduction compared with placebo. These reductions were broadly consistent with those historically observed with standard-dose tamoxifen, but achieved using a compound that does not require metabolic activation and upheld a safety and tolerability profile virtually identical to a placebo.
This innovation in preventive care is biologically effective enough to lower risk, but gentle enough to stay on the drug long term. Through direct delivery of (Z)-endoxifen to the body instead of relying of the liver to create (Z)-endoxifen to do so, we can use a fraction of the dose to get the same, if not better, results as traditional therapies. These results reinforce the concept that meaningful reductions in MBD may represent a measurable pathway toward lowering future breast cancer risk and advancing prevention-focused care.
From Treatment to True Prevention
The paradigm of breast health must fundamentally reorient. We must no longer accept being masters of cancer treatment. We must become architects of cancer prevention.
The data from the KARISMA trial provides far more than a clinical signal that we are on the right track to advancing and further enhancing the foundations established in the industry thus far. It offers a blueprint for a proactive future. For preventive breast oncology to achieve widespread adoption, our tools must fit the lives of the asymptomatic patients we seek to protect. Armed with predictable, low-toxicity risk-reduction strategies, we may finally have the means to intervene before the crisis begins.
It is time to step out of the shadow of reactive medicine and endeavor to not simply survive breast cancer, but prevent it entirely.
Note
* In the United States and other major markets, proprietary oral formulations of (Z)-endoxifen (such as those being developed by Atossa Therapeutics) are currently investigational and not yet approved by the FDA for commercial sale or specific oncology/rare disease indications.
Clinical Trials
Effect of Oral (Z)-Endoxifen in Premenopausal Women With Measurable Breast Density – ClinicalTrials.gov ID NCT05068388
Highlights of Prescribing Information
Tamoxifen (Nolvadex®; AstraZeneca)[Prescribing Information]
Tamoxifen (Soltamox®; Mayne Pharma)[Prescribing Information]
Reference
[1] Dense Breasts. US Centers for Disease Control and Prevention (CDC) Online. Last accessed on September 25, 2026
[2] Lange JM, Gard CC, O’Meara ES, Miglioretti DL, Etzioni R. Breast density and risk of breast cancer: masking and detection bias. Am J Epidemiol. 2025 Feb 5;194(2):441-448. doi: 10.1093/aje/kwae245. PMID: 39098823; PMCID: PMC11815494.
[3] Bodewes FTH, van Asselt AA, Dorrius MD, Greuter MJW, de Bock GH. Mammographic breast density and the risk of breast cancer: A systematic review and meta-analysis. Breast. 2022 Dec;66:62-68. doi: 10.1016/j.breast.2022.09.007. Epub 2022 Sep 26. PMID: 36183671; PMCID: PMC9530665.
[4] Researchers leverage tamoxifen’s active metabolite to improve breast cancer prevention. Karolinska Institutet. May 4 2026. Online. Last accessed on September 25, 2026
[5] Tamoxifen. MedlinePlus.January 15, 2018. Online. Last accessed on September 25, 2026.
[6] Hall P, Hammarström M, Bergqvist J, Czene K, Eriksson M, Gabrielson M, Tapia J, Quay S, Nash S, Bäcklund M. Endoxifen for mammographic density reduction-results from the KARISMA endoxifen trial. J Natl Cancer Inst. 2026 Apr 27:djag087. doi: 10.1093/jnci/djag087. Epub ahead of print. PMID: 42070780.
Featured image: © 2026 CHA ONC JONC. Used with permission.
DOI
