Introduction

Preventive therapy or chemoprevention is a medical approach aimed at reducing the risk of common tumors and is particularly studied in the field of breast cancer. This term was coined by Michael Sporn to define the inhibition or reversal of carcinogenesis by the use of noncytotoxic nutrients or pharmacologic compounds that protect against the development and progression of mutant clones of malignant cells1,2,3. Currently, preventive therapy is a recognized useful measure to effectively reduce the incidence of breast cancer4, the most commonly diagnosed cancer in female patients, accounting for 23.8% of total female cases5.

Several endocrine therapies used in the adjuvant setting of breast cancer patients have been approved for prevention6,7.

Tamoxifen is a well-established selective estrogen receptor (ER) modulator widely used to manage ER-positive breast cancer patients at a standard dose of 20 mg a day, with a benefit in reducing mortality in the adjuvant setting8. In rat models, tamoxifen induced long-lasting chemopreventive action on chemically-induced breast cancer, both benign tumors and cancers9,10. However, due to its partial estrogenic activity in the uterus and on platelets, tamoxifen use is associated with an increased risk of endometrial tumors and venous thromboembolic events.

Window of opportunity (WOO) trials are a very useful study design to evaluate, ex vivo, several aims. Among these, are tissue drug bioavailability, pharmacokinetic, and biological drug activity. In particular, our main interest is focused on investigating novel strategies for preventive therapy. To examine if efficacy could be maintained while reducing the dose, tamoxifen has been studied through WOO trials, which are pre-surgical studies of short duration used to screen the preventive role of candidate drugs and better define their optimal dosing. In ER-positive breast cancer patients, our group randomly assessed different tamoxifen doses in a WOO trial and showed comparability of 5 mg/day versus 20 mg/day in decreasing proliferation as measured by the Ki-67 labeling index (LI)11. Breast intraepithelial neoplasia (IEN) is a part of breast cancer landscape encompassing different histological forms, such as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Overall, women with these precancerous lesions have a 5–10 times higher risk of developing invasive breast cancer forms compared with the general population, and these lesions account for 15–25% of all breast tumors in the current era of screening mammography12. As illustrated in the Fig. 1 the WOO trials provide the chance to study the drug activity not only on the tumor tissue, but also on the adjacent DCIS/LCIS and ADH, when present, and in the normal tissue. This proved to be an important objective to elucidate the potential preventive activity by measuring changes in biomarkers, such as Ki-67 LI and other biomarkers involved in carcinogenesis. The development of chemotherapeutics and, subsequently, targeted agents, biologics, and immunotherapies, has been notoriously driven by the search for the maximum tolerated dose (MTD) traditionally used to select chemotherapy agents, generally located at the upper level of a safe therapeutic range13, despite the substantial mechanistic difference between chemotherapy and other agents, including endocrine agents. However, real-world data show a high rate of dose reduction in several well-known approved targeted agents14. It has been demonstrated that doses generated from phase I studies underestimate the toxicity and up to 45% of patients in phase III studies require dose modification due to toxicity15. Accordingly, increasing awareness has suggested that MTD can potentially compromise the opportunity to discover lower yet active and safer doses of anticancer drugs. Therefore, “less is more” has become a paradigm shift for the development of new cancer medicines14. Based on these concepts, in the last few years, the Food and Drug Administration (FDA) announced the international Project Optimus program, to reform the process of dose optimization by selecting the most appropriate dose16,17.

Fig. 1: The WOO model reveals the field cancerization effect and may be relevant to preventive therapy.
Fig. 1: The WOO model reveals the field cancerization effect and may be relevant to preventive therapy.The alternative text for this image may have been generated using AI.
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A WOO study exploits the presence of a mammary field cancerization to draw signals on cancer tissue biomarker changes (red circles) and on adjacent pre-cancer lesions including DCIS/LCIS and ADH (blue circles). A main objective of a WOO study is to measure Ki-67 LI and percentage of precancer lesions to draw preventive activity of drugs.

In this article, we summarize the scientific evidence regarding the utility of WOO trials to screen agents and optimize doses for preventive therapy for breast cancer.

Selection Criteria

We selected a list of reference articles according to the following criteria: (i) randomized clinical trials, (ii) usual timeline of WOO trials (a range of 1–10 weeks), (iii) “pure” WOO trials, and not just considered as a “window phase” preceding neoadjuvant treatments, (iv) full text available.

According to these criteria, we screened a total of 55 records, 20 of which were single-arm trials18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37 and 6 of which as trials with non-classical WOO design38,39,40,41,42,43, respectively, were excluded from the final selection. We ultimately selected 29 WOO trials with different treatments, as reported below.

Goals of window-of-opportunity trials in early-stage breast cancer patients

WOO trials are nontherapeutic phase II drug studies used to screen an investigational drug alone or in combination with other drugs over a short period, usually from 1 to 10 weeks duration, between biopsy and surgery. Eligible patients for WOO trials are operable individuals who are non-candidate for neoadjuvant treatments. WOO trials have been actively incorporated into drug development as a unique opportunity to investigate the pharmacodynamic effects of therapy in treatment-naïve patients whose tumors are “de facto” unperturbed, without having developed mechanisms of resistance or heterogeneity from previous treatments.

The main goals of WOO trials are (i) to optimize dose drug selection towards the minimal effective dose in cancer and precancerous tissue lesions using pre-post treatment biomarkers change (i.e. Ki-67 LI), (ii) to assess biomarkers changes in adjacent precancerous lesions and distant hyperplasia, and (iii) to enable academic research to address important medical questions typically overlooked by the pharmaceutical industry, such as drug repurposing or dose optimization of generic drugs44. Furthermore, an early understanding of the pharmacodynamic effects of anticancer drugs could allow (i) to confirm target therapies, (ii) optimize patient selection for subsequent clinical trials, (iii) obtain early insights regarding primary resistance, and, finally, (iv) get clues regarding subsequent treatment combinations. Of note, tumor shrinkage and pathological complete response are not instead the main endpoints of WOO trials.

Main endpoint for WOO trials

The Ki-67 LI is a biomarker of proliferation that tends to increase as carcinogenesis progresses. WOO trials predominantly use tumor Ki-67 LI as a surrogate biomarker of reduced cancer cell proliferation after short-term therapy. Smith et al. demonstrated that changes in Ki-67 LI over 2 weeks correlated with the prediction of the effectiveness of aromatase inhibitors (letrozole or anastrozole) in ER-positive early breast cancer patients43. In women with ADH, Ki-67 LI appeared as a time-varying biomarker of risk prediction for breast cancer development over a time period of 20 years45. In a cohort of women with benign proliferative breast lesions, Shaaban et al. observed that women who subsequently developed breast cancer had significantly higher levels of Ki-67 LI in foci of ductal hyperplasia without atypia (DH)46. Preoperative studies have demonstrated that higher Ki-67 LI following short-term endocrine therapy may significantly improve the prediction of recurrence-free survival in women with breast cancer38,47.

In operable ER-positive early breast cancer patients, we demonstrated that post treatment Ki-67 LI value was significantly associated with recurrence-free survival, and that patients after tamoxifen with Ki-67 LI levels >20% (versus those with Ki-67 < 20%) had a 5.5-fold increased risk of death. Furthermore, we found that the confirmed prognostic role of Ki-67 LI value in terms of survival outcome is an indirect measure of the usefulness of low-dose tamoxifen as an alternative to the standard dose48.

In 2011, a group of investigators with expertize in Ki-67 LI measurement made recommendations regarding preanalytical and analytical evaluation, as well as interpretation and scoring of Ki-67 LI. In full sections, at least three high-power (×40 objective) fields should be selected to represent the spectrum of staining seen in the initial overview of the whole section. For prognostic evaluation, the invasive edge of the tumor should be scored. If pharmacodynamic comparisons must be between core cuts and sections from the excision, assessment of the latter should be across the whole tumor. Scoring should involve the counting of at least 500 malignant invasive cells (and preferably at least 1000 cells)49.

While image analysis methods for Ki-67 LI remain to be proven for use in clinical practice, concerns over the reproducibility and variability of semiquantitative measurements have been raised. Recently, a Norwegian study comparing automated and digital image analysis (DIA) and manual methods in 367 ER-positive HER2 negative early breast cancer patients50 showed that DIA scoring correlated with greater prognostic value for distant metastases-free survival using a 14% cutoff as compared to manual scoring. In another study, image analysis allows for standardized automated Ki-67 LI scoring that accurately replicates previously clinically validated and calibrated manual scores51.

WOO trials with hormonal treatments

In Table 111,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67 we report all the trials with hormonal treatments, here we briefly describe some of them.

Table 1 Randomized Window-of-opportunity trials with hormonal treatments in patients with early-stage breast cancer
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One of the first WOO trials of tamoxifen in primary breast cancer patients was published in 1993. Patients treated with tamoxifen displayed a drop of KI-67 LI level, from 5.6% to 3.0% (p < .001), whereas no significant difference was found in placebo patients. The authors suggested that Ki-67 LI is a useful measure in monitoring response to tamoxifen treatment in early breast cancer patients52.

Raloxifene, another selective ER modulator, when administered at 60 mg daily induced a decrease in Ki-67 LI by 21% (p = 0.015) in ER-positive breast cancer patients. Importantly, the dose of 600 mg per day did not attain a significant Ki-67 LI reduction, illustrating the lack of a dose response effect. The authors concluded that 60 mg/day of raloxifene is the optimal dose for future prevention studies53.

Three different doses of tamoxifen were investigated in ER-positive breast cancer patients and the results demonstrated that lower doses of tamoxifen (1 mg/day and 5 mg/day) were comparable to 20 mg/day in decreasing Ki-67 LI levels. The authors concluded that a lower dose of tamoxifen should be selected for a phase III prevention study11.

The pure anti-oestrogen Fulvestrant compared with daily tamoxifen proved to be active in reducing the expression of ER and Ki-67 values in premenopausal women with ER-positive breast cancer65.

The steroidal aromatase inhibitor exemestane, whose action is an irreversible binding to the aromatase enzyme, has shown efficacy in the adjuvant ER-positive breast cancer setting at a dose of 25 mg daily, as well as a strong preventive effect in the MAP.3 trial3. However, uptake has been limited mostly due to concerns about adverse events and decreased quality of life68. Two alternative schedules of exemestane were assessed in women with ER-positive early breast cancer (mostly with invasive tumors). Exemestane 3-times per week was non-inferior to daily exemestane in reducing circulating ultrasensitive estradiol, while the once-weekly schedule was to some extent less effective55.

The novel selective ER degrader amcenestrant was recently investigated in women with ER-positive early breast cancer. The main finding of the study was that the relative change from baseline in Ki67 LI was −75.9% for amcenestrant 400 mg, -68.2% for amcenestrant 200 mg, and −77.7% for letrozole. There was no evidence of dose-response for amcenestrant56.

Transdermal 4-hydroxytamoxifen gel, applied to the breast skin, versus oral tamoxifen, was investigated for the possible lower systemic toxicity by the topical agent. In women with DCIS, an absolute change in Ki-67 LI of −3.4 in women in the 4-hydroxytamoxifen gel group and −5.1 in women in the oral tamoxifen group was observed63.

A few years later, a larger noninferiority trial demonstrated that the Ki-67 LI absolute change was −1.0 in women receiving 4-hydroxytamoxifen gel whereas it was −4.8 in the oral tamoxifen arm rejecting the noninferiority hypothesis64.

Recently, a phase I WOO trial of transdermal endoxifen applied to both breasts pointed out that no dermal or systemic toxicity occurred with endoxifen-gel when compared with placebo. A non-significant overall reduction of Ki-67 LI was noted, while a significant downregulation of gene signatures prone to stimulate cancer invasion was observed66.

WOO trials with hormonal and non-hormonal treatments

Several trials have studied hormonal and non-hormonal agents, either in comparison to each other or in combination (Table 2)69,70,71,72.

Table 2 Randomized Window-of-Opportunity trials with hormonal and non-hormonal treatments in Patients with early-stage Breast Cancer
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In ER-positive early breast cancer women, our group observed that exemestane displayed a highly significant median 10% absolute reduction in Ki-67 LI, whereas no change there was with celecoxib or placebo69.

The PI3K pathway has been shown to have a critical signaling role in ER-positive breast cancer73,74. The combination of anastrozole plus the PI3K inhibitor pictilisib was associated with greater reduction in Ki-67 LI levels than with anastrozole alone (p = 0.004)71, supporting subsequent phase III treatment trials.

WOO trials with molecularly targeted agents

The oral reversible TKI lapatinib, targeting both HER2 and EGFR tyrosine kinases, was tested by our group in HER2-positive early breast cancer patients. Of interest, ER-negative tumors displayed a more significant reduction in Ki-67 LI after lapatinib compared to ER-positive. In surgical specimens after treatment, the prevalence of DCIS in both arms was similar (70%–76%), with a median Ki-67 LI of 15% (range, 5%–35%) on lapatinib versus 20% (5%–60%) on placebo (p = 0.067), as well as the prevalence of ductal hyperplasia similar in both arms (>90%) with a median Ki-67 LI of 1% (1%–7%) on lapatinib versus 3% (1%–5%) on placebo (p = 0.006)75.

Table 3 summarizes WOO trials with molecularly targeted agents75,76,77,78,79.

Table 3 Randomized Window-of-opportunity trials with molecularly targeted agents in patients with early-stage breast cancer
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WOO trials with metformin

Preclinical studies in breast cancer cell lines have observed that metformin, an oral biguanide commonly used for patients with type 2 diabetes, may inhibit cancer cell proliferation and stimulate apoptosis80,81. Furthermore, epidemiologic data suggest that metformin use is associated with decreased proliferation or incidence of breast cancer in women with diabetes in some82, but not all studies83.

Hadad et al. evaluated the effects of metformin on Ki-67 LI modulation in nondiabetic women with operable breast cancer. A significant reduction of Ki-67 LI levels was observed, indicating an antiproliferative action of metformin in these patients84.

Along this line, our group investigated the antiproliferative activity of metformin by Ki-67 LI changes in nondiabetic early-stage, mainly ER-positive breast cancer patients. There was a significant effect modification by insulin resistance status with a reduction of Ki-67 LI in insulin-resistant or overweight/obese women85.

Table 4 summarizes WOO trials with metformin84,85,86.

Table 4 Randomized Window-of-opportunity trials with metformin in patients with early-stage breast cancer
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Translating WOO trials to phase III

Based on the promising tamoxifen data summarized above, we performed a randomized phase III trial (TAM-01) to assess whether tamoxifen 5 mg per day versus placebo administered for 3 years after surgery in 500 women with ER-positive/unknown breast IEN (including ADH, LCIS and mainly DCIS) was able to reduce the incidence of invasive breast cancer or DCIS. After a mean 5-years of follow-up, 28 breast events (disease recurrence or IEN) in the placebo arm and 14 in the tamoxifen arm (hazard ratio 0.48; 95% CI, 0.26–0.92; p = 0.02) were documented, with cumulative incidence rates of 11% and 6%, respectively. Patients on tamoxifen had a 75% reduction of contralateral breast events (hazard ratio 0.25; 95% CI, 0.07–0.88; p = 0.02). The majority of recurrences were infiltrating carcinomas. Patient-reported outcomes did not significantly differ overall between the two arms, except for slightly increased hot flashes (less than one per day) with tamoxifen treatment (p = 0.02)87.

The 10-year follow-up analysis of TAM-01 study has recently been reported. A total of 66 breast cancer events was documented, 15 of which were in situ lesions, while 51 were invasive forms: 25 of 66 events occurred in the tamoxifen group, the remaining 41 events in the placebo group (hazard ratio, 0.58; 95% CI, 0.35–0.95; p = 0.03). The majority of recurrences occurred ipsilaterally. Contralateral breast cancer events occurred in 6 cases in the tamoxifen group and 16 in the placebo group (hazard ratio, 0.36; 95% CI, 0.14–0.92; p = 0.025). In the DCIS cohort, representing 70% of the patient population, the use of tamoxifen reduced the risk of relapse by 50% (hazard ratio, 0.50; 95% CI, 0.28–0.91; p = 0.02)88. In an accompanying editorial, Carol Fabian pointed out study strengths, including (i) the idea that modulation of risk biomarkers within breast tissue in WOO early-phase studies can hypothesize efficacy outcomes in further studies involved in cancer incidence; (ii) the fewer serious adverse events while maintaining at the same time optimal efficacy; (iii) a total of 5 years is not required for obtaining a significant risk reduction. Overall, there is the potential to amplify tamoxifen uptake in the setting of breast cancer risk reduction in healthy women at high risk89.

Conclusions

This literature review of WOO trials suggests that several agents both hormonal and nonhormonal have the potential to be promising actors within future preventive trials for breast cancer risk reduction.

Tamoxifen at 5 mg daily offers a significant benefit in preventing local and contralateral recurrences in women with IEN87. According to these data, ASCO clinical practice guidelines has incorporated low-dose tamoxifen as an option in women with IEN6. The effective role of low-dose tamoxifen after IEN was also implemented by the NCCN guidelines in case the patient suffers from side effects with the dosage of 20 mg or is unable to take the conventional dose90. Recent real-world studies have highlighted low-dose tamoxifen as the most popular choice of preventive therapy for high-risk women91,92,93. Notably, tamoxifen has a long time to Cmax concentrations and plasma half-life of approximately 5–7 days, while its active metabolite, endoxifen, has an even longer half-life of 7–14 days. As a result, steady-state plasma concentrations are typically achieved only after 4–6 weeks of continuous administration94,95. This delay in reaching steady-state can influence the biological response observed in short-duration WOO trials, potentially underestimating the full pharmacodynamic impact of tamoxifen. To address this, alternative pharmacokinetic modeling approaches or prolonged intervention periods should be considered in future WOO studies to ensure accurate assessment of drug efficacy96.

Along the line of hormonal treatments, exemestane 3 times a week has been documented to be non-inferior to exemestane daily in decreasing ultrasensitive estradiol and Ki-67 LI levels in women with ER-positive early breast cancer55. These results may also help to increase compliance and improve prognosis in intolerant women in the adjuvant setting97. In addition, in a comparison WOO trial with celecoxib, exemestane correlated with an antiproliferative effect whereas celecoxib did not affect breast cancer proliferation, further supporting the use of exemestane as an effective agent in the prevention setting69. Based on these promising results, a comparison between exemestane given every other day versus low-dose tamoxifen every other day in high-risk women has been launched (BabyTears, NCT06364267).

Among WOO trials with molecularly targeted agents selected in this review, lapatinib successfully resulted to reduce cell proliferation in women with premalignant breast lesions and HER2-positive breast cancer, thus supporting its role in the preventive therapy of HER-2 positive IEN75.

As regards to selected WOO trials with metformin, we observed that metformin reduced Ki-67 LI in patients with HER2-positive tumors and in adjacent DCIS86, further supporting its potential role in the tertiary prevention of HER2-positive invasive tumors98 and HER2-positive DCIS.

One point to make is the difference in outcome of phase III trials between metformin and low-dose tamoxifen. Indeed, the MA-32 trial98, a large adjuvant study of metformin, failed to show a benefit on disease free survival and overall survival in high-risk patients with early breast cancer, although there was a significant prolongation of invasive disease-free survival and overall survival in HER2 positive disease, in line with WOO trials. One reason might be that the WOO trials may be more predictive for subsequent phase III prevention trials, as opposed to adjuvant trials, although the evidence for this translation is still limited. Another explanation is the deep effect of tamoxifen and other hormonal agents on cancer proliferation assessed by Ki-67 LI as opposed to the weak effect of metformin.

Another point to remark of this literature review of WOO trials is that Ki-67 LI continues to be the leading surrogate biomarker of cancer cell proliferation in these types of trials. This assumption is also supported by the results of the POETIC phase III trial, in which Ki-67 LI changes during a window of 14 days before surgery were associated with prediction of efficacy of aromatase inhibitor therapies in postmenopausal ER-positive early breast cancer women99. In WOO trials, core-cut biopsies used for baseline measurement and surgical specimens for post-treatment analysis may introduce significant fixation-related artifacts, thus originating a significant limitation in such type of trials. Differences in fixation duration and processing conditions can alter biomarker expression, leading to inconsistencies in results. The POETIC study revealed that Ki-67 assessments were affected by such artifacts due to variations in fixation completeness, highlighting the need for standardized fixation protocols. To minimize these effects, we recommend harmonized pre-analytical conditions, such as controlled fixation times and optimized tissue processing workflows, to ensure reproducible biomarker assessment in WOO trials49. From this, although Ki-67 LI is widely used as a surrogate endpoint in WOO trials, it may not be suitable for all drug classes. For example, COX-2 inhibitors and other non-hormonal agents may exhibit preventive effects without significantly altering Ki-67 LI levels. This limitation has been observed in trials assessing the preventive potential of COX-2 inhibitors, such as celecoxib, where the absence of Ki-67 LI reduction did not correlate with a lack of clinical benefit69. Therefore, alternative biomarkers should be considered for evaluating the efficacy of non-hormonal interventions. Future WOO trials should incorporate a broader panel of mechanistic biomarkers, including inflammation markers, apoptosis indicators, and metabolic profiling, to better capture the full range of drug effects.

Preventive therapy for risk reduction of breast cancer is associated with robust data on effectiveness2,3,6,7, there are, however, conflicting data on its uptake in the clinical practice, with fear of adverse events and loss of quality of life playing a crucial role in this regard100,101,102,103. A survey through questionnaires to physicians involved in breast cancer has documented that the main reasons for the low uptake of tamoxifen/raloxifene were found to be (i) the fear of adverse events, (ii) the lack of easy risk models and uncertainty in defining the most appropriate physician for counseling, (iii) the lack of short-term surrogate biomarkers and (iv) lack of commercial interest in preventive therapy68. A systematic review and meta-analysis in individuals at increased risk of breast cancer has demonstrated a very low uptake of breast cancer-preventive therapy (pooled uptake estimated at 16.3%), with significantly higher uptake in trials than in non-trial patients104. In a controlled UK pilot study of women at increased risk of developing breast cancer, only 8% (14 women) accepted preventive therapy, and frequent reasons for refusing it were distrust of taking medication and unsuitable moments of life105. A questionnaire-based survey among 360 women at increased risk for breast cancer has underlined that the primary physician recommendation resulted to be the most important factor influencing women’s decisions to accept a prevention trial106.

From our point-of-view, the need to optimize dose selection in cancer drug development has now reached a point that requires novel trial designs, from early trials searching for the MTD to current models including a randomized approach of optimal dosing to select the minimal effective dose in breast cancer prevention/interception setting. WOO trials may therefore minimize important clinical toxicity. While most WOO trials involve well-characterized agents with known safety profiles, some studies have tested drugs in early development stages, such as fulvestrant. In these cases, ensuring robust preclinical and early-phase safety data is crucial to minimize risks for participants who may not directly benefit from the intervention97,98. Investigational drugs used in WOO trials should have completed at least phase I safety studies with a well-documented toxicity profile before administration in a pre-surgical setting60. Additionally, careful patient selection and monitoring protocols should be implemented to mitigate potential adverse effects in high-risk populations97. Future WOO trial designs should incorporate clear safety monitoring guidelines, including predefined stopping criteria based on toxicity thresholds.

FDA’s project Optimus can reinforce and reasonably standardize this strategy from WOO trials to phase III trials as a novel drug development path107. Overall, project Optimus is an opportunity to stimulate changes in study development, through (i) smarter designs to allow more efficient patient participation, (ii) comprehensive drug assessment, and (iii) greater availability of pharmacokinetic/ pharmacodynamic data by intra-patient comparisons. The goal is therefore to educate, innovate, and collaborate with companies, academia, professional societies, international regulatory authorities, and patients to move forward with a dose-finding and dose optimization paradigm across oncology that emphasizes selection of a dose or doses that maximizes not only the efficacy of a drug but the safety and tolerability as well.

In the present article, we have elaborated on the rationale for focusing on the primary tumor Ki-67 LI, the primary endpoint, explaining that tumor tissue reflects real-time responses to intervention and is a gold standard to measure drug activity in WOO trials. Additionally, we have discussed how Ki-67 LI in adjacent premalignant lesions, a key secondary endpoint, may also yield important insights into early molecular changes associated with cancer development. Indeed, while tumor tissue provides direct insights into drug efficacy, the analysis of premalignant lesions and surrounding normal tissue is essential for assessing the broader impact of preventive interventions. Changes in the microenvironment, such as alterations in inflammatory markers or stromal interactions, may provide additional insights and serve therefore as early indicators of carcinogenesis45,108. Future WOO trials should consider integrating multi-tissue analysis to optimize the predictive value of biomarker responses across different histological stages. Key points of this review are summarized in Fig. 2.

Fig. 2: Key points summarizing current evidence and strategies in endocrine prevention of breast cancer.
Fig. 2: Key points summarizing current evidence and strategies in endocrine prevention of breast cancer.The alternative text for this image may have been generated using AI.
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This figure outlines major concepts in endocrine prevention for high-risk breast cancer women. Topics include the clinical benefit and challenges of endocrine preventive therapy (A), dose optimization through window-of-opportunity trials (B), the role of Ki-67 LI as a prognostic biomarker (C), guideline-approved use of low-dose tamoxifen (D), novel dosing schedules of exemestane (E), and the FDA's project Optimus for dose selection standardization (F).

To conclude, WOO trials can help to elucidate the minimal effective dose and obtain clues on drug preventive potential through the measurement of biomarker proliferation in the adjacent IEN.