Oral selective estrogen receptor degraders (SERDs): The new emperors in breast cancer clinical practice?

Endocrine therapy (ET) targeting estrogen receptor (ER) signaling is still the mainstay treatment option for early or advanced ER-positive breast cancer (BC) and may involve suppressing estrogen production by means of aromatase inhibitors or directly blocking the ER pathway through selective estrogen receptor modulators such as tamoxifen or selective estrogen receptor degraders such as fulvestrant. However, despite the availability of this armamentarium in clinical practice, de novo or acquired resistance to ET is the main cause of endocrine-based treatment failure leading to the progression of the BC. Recent advances in targeting, modulating, and degrading ERs have led to the development of new drugs capable of overcoming intrinsic or acquired ET resistance related to alterations in the ESR1 gene. The new oral selective estrogen receptor degraders, which are capable of reducing ER protein expression and blocking estrogen-dependent and -independent ER signaling, have a broader spectrum of activity against ESR1 mutations and seem to be a promising means of overcoming the failure of standard ET. The aim of this review is to summarize the development of oral selective estrogen receptor degraders, their current status, and their future perspectives.

Assessment of DXA derived bone quality indexes and bone geometry parameters in early breast cancer patients: A single center cross-sectional study.

Background: Bone mineral density (BMD) lacks sensitivity in individual fracture risk assessment in early breast cancer (EBC) patients treated with aromatase inhibitors (AIs). New dual-energy X-ray absorptiometry (DXA) based risk factors are needed. Methods: Trabecular bone score (TBS), bone strain index (BSI) and DXA parameters of bone geometry were evaluated in postmenopausal women diagnosed with EBC. The aim was to explore their association with morphometric vertebral fractures (VFs). Subjects were categorized in 3 groups in order to evaluate the impact of AIs and denosumab on bone geometry: AI-naive, AI-treated minus (AIDen-) or plus (AIDen+) denosumab. Results: A total of 610 EBC patients entered the study: 305 were AI-naive, 187 AIDen-, and 118 AIDen+. In the AI-naive group, the presence of VFs was associated with lower total hip BMD and T-score and higher femoral BSI. As regards as bone geometry parameters, AI-naive fractured patients reported a significant increase in femoral narrow neck (NN) endocortical width, femoral NN subperiosteal width, intertrochanteric buckling ratio (BR), intertrochanteric endocortical width, femoral shaft (FS) BR and endocortical width, as compared to non-fractured patients. Intertrochanteric BR and intertrochanteric cortical thickness significantly increased in the presence of VFs in AIDen- patients, not in AIDen+ ones. An increase in cross-sectional area and cross-sectional moment of inertia, both intertrochanteric and at FS, significantly correlated with VFs only in AIDen+. No association with VFs was found for either lumbar BSI or TBS in all groups. Conclusions: Bone geometry parameters are variably associated with VFs in EBC patients, either AI-naive or AI treated in combination with denosumab. These data suggest a tailored choice of fracture risk parameters in the 3 subgroups of EBC patients.

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

BACKGROUND: KRAS is the most frequently mutated gene in non-small cell lung cancer (NSCLC), however conflicting data are available on its role as a biomarker. OBJECTIVE: The aim of our work was to investigate the impact of KRAS mutations on response and survival outcomes in advanced non-squamous NSCLC patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy. PATIENTS AND METHODS: We retrospectively identified 119 patients, most of whom (58%) were KRAS wild type. For each patient we evaluated overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). An exploratory analysis was performed among KRAS mutated patients to investigate the impact of specific KRAS mutations on response and survival outcomes. RESULTS: After a median follow-up of 10.3 months, the median OS was 14.9 months (95% confidence interval [CI] 7.6-22.7) in wild-type KRAS patients versus 14.7 months (95% CI 8.0-19.5) in mutated KRAS patients (p = 0.529). No differences were detected between the two groups in terms of PFS and DCR. Patients with a KRAS G12C mutation reported survival and response outcomes that were not statistically different from those of patients with other KRAS mutations. CONCLUSION: Our data confirmed that KRAS mutational status is not associated with survival and response outcomes in advanced non-squamous NSCLC patients treated with immunotherapy alone or combined with chemotherapy.

Sleep disturbances and restless legs syndrome in postmenopausal women with early breast cancer given adjuvant aromatase inhibitor therapy.

INTRODUCTION: Whether adjuvant therapy with aromatase inhibitors (AIs) causes sleep disturbances or not in postmenopausal women with early breast cancer (EBC) is still a controversial issue. METHODS: Between March 2014 and November 2017, validated questionnaires for assessing insomnia, anxiety, depression, quality of life (QoL) and restless legs syndrome (RLS) were administered to 160 EBC patients at baseline and after 3, 6, 12, and 24 months of AI therapy. RESULTS: AI therapy significantly decreased the patients' QoL, but did not influence insomnia, anxiety or depression. However, it significantly increased the frequency and severity of RLS. Patients with RLS at baseline (19%) or who developed RLS during AI therapy (26.3%) reported statistically lower quality of sleep, higher anxiety and depression, and worse QoL compared to patients who never reported RLS (54.7%). CONCLUSION: Although AI therapy does not affect sleep quality, it may increase RLS frequency. The presence of RLS could identify a group of EBC patients who may benefit from psychological support.

Taste Alterations Do Not Affect Change in Food Habits and Body Weight in Breast Cancer Patients.

BACKGROUND/AIM: Chemotherapy-induced taste alterations (TAs) affect approximately 53-84% of breast cancer patients with significant consequences on flavor perception, possibly leading to food aversion and changes in daily dietary habits. The aim of this study was to investigate the relationship between TAs and changes in food habits and body weight among early breast cancer (EBC) patients undergoing adjuvant chemotherapy. PATIENTS AND METHODS: TAs were prospectively evaluated in 182 EBC patients from April 2014 to June 2018. TAs, dietary habits, and body weight were collected by a trained dietician. TAs were classified into different subtypes according to the following basic taste perception: metallic, sweet, bitter, salty, sour, and umami taste. RESULTS: During adjuvant chemotherapy, a significant reduction in the consumption of bread, breadsticks, red meat, fat salami, snacks, added sugar, milk, and alcoholic beverages was observed, regardless of TAs onset. No correlation between these dietary changes and different TAs subtypes was found. Body weight remained stable in most EBC patients (71.4%) and was not influenced by TAs onset and by different TAs subtypes. CONCLUSION: EBC patients change their dietary habits during adjuvant chemotherapy, mostly following the World Cancer Research Fund recommendations, irrespective of TAs onset and without affecting body weight.

Taste alterations during neo/adjuvant chemotherapy and subsequent follow-up in breast cancer patients: a prospective single-center clinical study.

PURPOSE: Dysgeusia and taste alterations (TAs) are side effects of cytotoxic chemotherapy and affect patients' quality of life; however, the prevalence, types, and duration of TAs and their potential relationship with other clinical disturbances are not well-described. Our primary aim was to prospectively evaluate the characteristics of TAs in early breast cancer (EBC) patients during (neo)adjuvant chemotherapy and up to 1 year after its completion. METHODS: From April 2014 to June 2018, 182 EBC patients entered the study and received (neo)adjuvant chemotherapy, mostly with taxane and anthracycline-containing regimens (65% of cases). A dietitian performed TAs assessment through the Common Terminology Criteria for Adverse Event v4.0 (CTCAE) and the Chemotherapy-induced Taste Alteration Scale (CiTAS) questionnaire during chemotherapy and follow-up according to defined time points: at baseline (T0, before starting chemotherapy); at the first follow-up visit, (T1, 2 months after starting chemotherapy); at the final follow-up visit (T2, 1 week after completing chemotherapy); after that, every 3 months up to 12 months. RESULTS: Dysgeusia was reported by 69.8% of patients at T1 and declined subsequently; salty flavor distortion was the most frequently reported TA (51.6% of cases). CiTAS was significantly different between T0 and T2 (p < 0.001). Dysgeusia occurred more frequently in patients reporting nausea, mucositis, diarrhea, and appetite modification. CONCLUSIONS: TAs are common but transient during chemotherapy and occurred frequently with other distressing gastrointestinal side effects. The assessment of these side effects is crucial in managing EBC patients during (neo)adjuvant chemotherapy.

Accurate Triage of Oncological Patients for Safely Continuing Cancer Therapy During the SARS-CoV-2 Pandemic.

OBJECTIVE: To evaluate the efficacy of clinical triage of oncological patients for safe continuation of cancer therapy implemented during the first SARS-CoV-2 outbreak. METHODS: Between 25 February and 21 April 2020, patients attending the Medical Oncology Unit, Spedali Civili Hospital, Brescia (Italy) for cancer therapy underwent triage to identify those with no signs and symptoms suspicious for SARS-CoV-2 infection in which antineoplastic treatment could be continued as scheduled. Triage questions investigated common symptoms (e.g., fever, cough, dyspnea, anosmia, dysgeusia, headache, nasal congestion, conjunctival congestion, sore throat, diarrhea, nausea and vomiting); body temperature and pulse oximetry were also recorded. All patients were followed-up for overt SARS-CoV-2 through to 18th May 2020. RESULTS: Overall, 1180 patients (median age 65 years) underwent triage during the study period. The most frequent primary malignances were breast (32%), gastrointestinal (18%), and lung (16.5%) cancer. Thirty-one (2.5%) presented with clinically evident SARS-CoV-2 infection and tested positive on nasopharyngeal swab testing and/or radiological imaging. Triage identified 69 (6%) grey zone patients with symptoms suspicious for SARS-CoV-2; 5 (7.2%) subsequently developed symptomatic disease. Neither the symptomatic nor the grey zone patients received their scheduled treatment; instead, they were referred for hospitalization or home quarantine. CONCLUSION: Triage of oncological patients at our Unit provided for safe continuation of scheduled cancer treatment in 91.5% of patients during the initial SARS-CoV-2 outbreak.

Changes in eating habits and food preferences in breast cancer patients undergoing adjuvant chemotherapy.

Change in eating habits in early breast cancer (EBC) patients during chemotherapy has been poorly studied in the literature. The primary aim of this study was to prospectively evaluate food preferences and weight change in EBC patients before and after adjuvant chemotherapy. From April 2014 to June 2018, 205 EBC patients underwent a dietary assessment according to the following timeline: baseline evaluation (one week before starting chemotherapy, T0); first follow-up (approximately 2-3 months after starting chemotherapy, T1); final follow-up (one week after chemotherapy end, T2). A statistically significant reduction of the following foods was reported after the start of chemotherapy: pasta or rice, bread, breadsticks/crackers, red meat, fat and lean salami, fresh and aged cheese, milk, yogurt, added sugar, soft drinks, alcoholic beverages (wine, beer, and schnapps), and condiments (oil and butter). Conversely, fruit consumption consistently increased. As a result of these changes, a Healthy Eating Index (HEI) specifically developed for this study and suggestive of a balanced diet, significantly increased. Body weight did not increase, despite reduction in physical activity. This prospective study shows that EBC patients tend to adopt "healthier dietary patterns" during adjuvant chemotherapy, leading to a non-change in weight, despite reduction in physical activity.

The Interaction of Lean Body Mass With Fat Body Mass Is Associated With Vertebral Fracture Prevalence in Women With Early Breast Cancer Undergoing Aromatase Inhibitor Therapy.

Aromatase inhibitors (AIs) induce depletion of estrogen levels, causing bone loss and increased fracture risk in women with breast cancer. High-fat body mass (FBM) emerged as an independent factor associated with the prevalence of morphometric vertebral fractures (VFs) in patients undergoing AIs. We explored the role of lean body mass (LBM) and the interaction of LBM with FBM in predicting the occurrence of VFs in postmenopausal women who were either AI-naïve or AI-treated. A total of 684 consecutive breast cancer patients were enrolled in this cross-sectional study. Each woman underwent a dual-energy X-ray absorptiometry (DXA) scan, measuring bone mineral density (BMD), LBM, and FBM; VFs were assessed using a quantitative morphometric analysis of DXA images. After propensity score matching, the study population was restricted to 480 women, 240 AI-naïve and 240 AI-treated. We used multivariable logistic regression models to explore the associations between baseline characteristics, VF prevalence and the interaction between LBM, FBM and AI therapy. No interaction between LBM and AI therapy on VF prevalence was shown. Conversely, we reported a significant interaction between LBM, FBM and AI therapy (p = .0311). Among AI-treated women having LBM below and FBM above or equal the median value, VF prevalence was numerically higher (15/31; 48.4%) than in other subgroups (VF prevalence: 35.7% in high-LBM and low-FBM group, 23.2% in high-LBM and high-FBM group, and 19.8% in low-LBM and low-FBM group). Among AI-naïve women, the greatest VF proportion was observed in the subgroup with LBM and FBM below median value (25/92; 27.2%). This study suggests a synergism between LBM and FBM in predicting the morphometric VF in women with early breast cancer undergoing AIs. This observation is new and deserves further investigation. The assessment of body composition by DXA might be useful when estimating fracture risk in this population. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

The Spread of SARS-CoV-2 Infection Among the Medical Oncology Staff of ASST Spedali Civili of Brescia: Efficacy of Preventive Measures.

Patients with cancer are at a higher risk of developing serious disease-related complications in case of contracting SARS-CoV-2. Oncology units should implement all possible preventive measures to reduce the risk of viral transmission by healthcare professionals (HCPs) to patients. We conducted a surveillance for SARS-CoV-2 infection among the staff members of the Medical Oncology Unit of ASST Spedali Civili in Brescia, one of the Italian areas most affected by the SARS-CoV-2 pandemic. The aim of this study was to demonstrate whether the recommended preventive measures, promptly implemented by the unit, have been effective in reducing the spread of the virus among the HCPs. Between February 24 and May 19, 2020, SARS-CoV-2 infection was detected in 10 out of 76 healthy HCPs (13%). Six of them developed a symptomatic disease, leading to home quarantine, and four remained asymptomatic. The infection was revealed when a serology test was performed on all staff members of the unit. In seven HCPs, in which it was possible to trace the person-to-person infection, the contagion occurred as a result of unprotected contacts or partially protected with surgical masks. In particular, four asymptomatic HCPs did not stop working, but a widespread outbreak in the unit was avoided. Adherence to the recommended preventive strategies, in particular, wearing of surgical masks by both the HCPs and the patients, is effective in reducing and preventing the viral spread.

Efficacy of Eribulin mesylate in older patients with breast cancer: A pooled analysis of clinical trial and real-world data.

PURPOSE: Eribulin mesylate (EM) is a non-taxane microtubule inhibitor approved for use in patients with metastatic breast cancer. With this pooled analysis of retrospective studies, we evaluated the efficacy and toxicity profile of EM in older patients with breast cancer in the real-world setting. METHODS: We performed a systematic database search for studies published up to March 2019 and reporting outcome and adverse events with EM in older patients (≥70 years). Overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) were described and aggregated in a pooled analysis. Main toxicity rates (G1-2 and G3-4) were also described. RESULTS: The analysis included five studies for a total of 301 patients. The median age was 71 to 74 years. Pooled ORR, median PFS and OS were 23.2%, 4.8 and 13.1 months, respectively. The disease control rate was 47%. Grade 3-4 neutropenia was 0 to 49%, G3-4 anemia and thrombocytopenia were rare. The most frequent G3-4 adverse events among non-hematological toxicities were fatigue (5-16.5%) and neurotoxicity (0-10.1%). Dose reduction rate was reported in three studies and carried out in 40% of patients (18.6-84%). CONCLUSIONS: This pooled analysis shows that the median OS in older patients with breast cancer is 13 months, with an ORR of 23%. Control of disease was achieved in about 50% of patients. Dose reduction was relatively frequent and severe toxicities were rare. EM treatment of older patients with breast cancer is feasible and reflects the outcomes for the general population.

Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non-small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy.

BACKGROUND: Clinical-pathologic predictors of acquired T790M epidermal growth factor receptor (EGFR) mutation in Caucasian patients with non-small-cell lung cancer (NSCLC) progressing after first-/second-generation tyrosine kinase inhibitors (TKIs) is an open field for research. Similarly, the best time point for T790M detection by liquid or tissue biopsy after disease progression is currently matter of debate. PATIENTS AND METHODS: This is an observational study at 7 Italian centers enrolling patients with EGFR-mutant NSCLC progressing after first-/second-generation EGFR TKIs, between 2014 and 2018, aiming at comparing baseline clinical-pathologic features and progression patterns in acquired T790M-positive compared with T790M-negative cases. RESULTS: A total of 235 patients received first-line treatment with gefitinib (N = 126; 53%), erlotinib (N = 51; 22%), or afatinib (N = 58; 25%). In 120 (51%) cases, T790M was detected in liquid biopsy, tissue biopsy, or both. Age younger than 65 years (P = .037), the presence of common mutations (P = .004), and better response to first-line TKI (P = .023) were correlated with T790M positivity. T790M detection was associated with higher number of new progressing sites (P = .04), liver progression (P = .002), and a lower frequency of lung metastases (P = .027). When serial liquid biopsies were performed (N = 15), an oligoprogressive disease was correlated with a negative test outcome, whereas systemic progression was observed at the time of T790M positivity. CONCLUSION: This study on a Caucasian population showed that age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.

Association of Fat Body Mass With Vertebral Fractures in Postmenopausal Women With Early Breast Cancer Undergoing Adjuvant Aromatase Inhibitor Therapy.

Importance: Aromatase inhibitors induce a profound depletion in serum estrogen levels. Postmenopausal obese women receiving aromatase inhibitor therapy may be at increased risk of bone fractures owing to the detrimental association of adiposity with bone quality and the loss of the protective effect of estrogens on bone mineral density. Objective: To determine whether fat body mass (FBM), as measured by dual-energy x-ray absorptiometry, is associated with vertebral fracture prevalence in postmenopausal women undergoing adjuvant aromatase inhibitor therapy for breast cancer. Design, Setting, and Participants: In this single-center, cross-sectional study, 556 postmenopausal women with early-stage breast cancer were consecutively enrolled from October 15, 2013, to June 30, 2018, and stratified according to whether they were aromatase inhibitor-naive or aromatase inhibitor-treated for at least 2 years. The database was locked on December 31, 2018, and data analysis was completed on February 28, 2019. Eligible patients in both groups had normal renal function, no metabolic diseases, and no previous or current treatment with antiosteoporotic drugs or glucocorticoids. Previous chemotherapy, but not tamoxifen, was permitted. Data were gathered once, at baseline. Main Outcomes and Measures: Vertebral fracture prevalence associated with FBM in aromatase inhibitor-naive and aromatase inhibitor-treated patients. Results: Of the 556 women enrolled, the mean age was 63.0 years (95% CI, 62.2-63.8 years). The 195 aromatase inhibitor-treated patients were older than the 361 aromatase inhibitor-naive patients (mean age, 66.1 vs 61.3 years; P < .001), had a higher body mass index (mean, 26.4 vs 25.3; P = .009), were less likely to engage in physical activity (65.3% vs 73.7%; P = .03), and were less likely to consume alcoholic beverages (68.4% vs 80.9%; P = .001). Among the aromatase inhibitor-naive patients, the vertebral fracture prevalence was higher in the subgroup with FBM below the median value than in those with high FBM, but the difference was not statistically significant (19.2% vs 13.3%; P = .13). Conversely, the proportion of vertebral fractures in the aromatase inhibitor-treated group was 20.0% in patients with low FBM vs 33.3% in patients with high FBM (P = .04). An opposite trend in the association of FBM with vertebral fracture prevalence according to aromatase inhibitor group was shown by multivariable analysis in the propensity score-matched sample: odds ratio, 0.38 (95% CI, 0.12-1.19) and 1.94 (95% CI, 0.67-5.64) in the aromatase inhibitor-naive and aromatase inhibitor-treated groups, respectively (odds ratio for the interaction, 5.77 [95% CI, 1.08-30.81]; P for interaction term = .03). Conclusions and Relevance: Fat body mass may be associated with fragility-related fractures in patients with breast cancer who undergo aromatase inhibitor therapy. If these data are confirmed, obesity could be included in the algorithm for assessing fracture risk and selecting patients to receive bone resorption inhibitors.

PD-L1 for selecting non-small-cell lung cancer patients for first-line immuno-chemotherapy combination: a systematic review and meta-analysis.

Aim: With the final aim to explore the first-line treatment options for non-small-cell lung cancer (NSCLC) patients, we performed a systematic review and literature-based meta-analysis of available clinical trials exploring immunotherapy in combination versus standard histology-based chemotherapy. Materials & methods: We evaluated interactions according to type of treatment-add-on strategy: immunotherapy in combination versus standard chemotherapy-based regimens. Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were extracted and cumulated. Results: Seven trials (4278 patients) were included. The addition of immunotherapy to standard chemotherapy-based regimens significantly increased OS (HR 0.74; p = 0.001) and PFS (HR 0.61; p < 0.0001) compared with standard-of-care in NSCLC patients in first-line setting. Conclusion: Immunotherapy-based regimens constantly improved OS and PFS compared with chemotherapy in first-line treatment of nononcogene-addicted NSCLC.

Clinical implication of changes in body composition and weight in patients with early-stage and metastatic breast cancer.

Breast cancer represents the most frequent cancer among women in Western countries. Although physicians and patients have witnessed a significant evolution in both treatment strategies and personalized medicine (the identification of featured patients' subsets such as HER2-driven disease), the identification of additional prognostic clinical predictors referring to patients' dietary habits represents a research area aiming to further improve the overall management of this disease. In this regard, body composition (i.e. the relative proportion of fat and muscles) and its changes have recently generated growing interest. A large body of evidence supports the relationship between overweight or weight gain and poor outcome in patients with early-stage breast cancer during adjuvant, and more recently, also neoadjuvant therapy. Nevertheless, available data on post-diagnosis weight variations and mortality report controversial results. Indeed, the limited data produced in the metastatic setting do not indicate an impact of body size on the outcome of these patients. With these perspectives, this review aims to elucidate the complex association between weight, body composition and breast cancer outcome, across the different settings of such disease. The more recent and important findings are highlighted, emphasizing the potential role of body composition assessment to predict individualize chemotherapy dosing, toxicity and efficacy, in order to improve the overall health status and prognosis of such still to date growing patients' population.

Morphometric vertebral fractures in breast cancer patients treated with adjuvant aromatase inhibitor therapy: A cross-sectional study.

BACKGROUND: The impact of long-term adjuvant therapy with aromatase inhibitors (AIs) on vertebral fracture (VF) risk is still unclear. OBJECTIVE: In this cross-sectional study, we explored the prevalence and determinants of VFs in breast cancer (BC) patients before and during AI therapy. Each woman underwent a dual-energy X-ray absorptiometry (DXA) to evaluate bone mineral density (BMD) and identify VFs by a quantitative morphometric approach. Blood samples were collected to measure serum hormone and calcium levels. RESULTS: We consecutively included 263 postmenopausal women with hormone receptor-positive early BC. One-hundred-sixty-nine women were AI-naïve, and 94 were AI-treated. AI-treated patients had lower BMD at total hip (p=0.01) and lumbar spine (p=0.03), higher serum vitamin D (p<0.001) and parathyroid hormone (p=0.006) values as compared to AI-naïve patients. The prevalence of VFs was 18.9% in AI-naïve patients, and 31.2% in those assessed during AI therapy (odds ratio 1.90, 95% CI 1.1-3.5, p=0.03). In AI-naïve patients, VFs were associated with older age (p=0.002) and lower BMD values at femoral neck (p=0.04) and total hip (p=0.007), whereas VFs occurred without association with any parameter analyzed in AI-treated patients. In AI-treated group, the prevalence of VFs was not significantly different between patients with osteoporosis and those with normal BMD (36.7% vs. 20.0%; p=0.31). CONCLUSIONS: In women with early BC, AI therapy is associated with high prevalence of radiological VFs, which were shown to be independent of BMD values during the adjuvant treatment. These findings may be clinically relevant since they may lead to a change in management of AI-induced skeletal fragility. Specifically, the results of this study provide a rationale for performing a morphometric evaluation of VFs in all women undergoing treatment with AIs.