Therapy In Postmenopausal Patients Research Articles

Abstract PO2-02-05: CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial

Abstract Background: Patients with HR-positive, HER2-negative breast cancer respond poorly to neoadjuvant chemotherapy. The phase 3 DAWNA-1 and DAWNA-2 studies have proved that adding dalpiciclib (a CDK4/6 inhibitor) to endocrine therapy can significantly improve progression-free survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, the evidence of dalpiciclib in the neoadjuvant setting is limited. This study aimed to explore the efficacy and safety of dalpiciclib plus letrozole as neoadjuvant therapy in in patients with HR-positive, HER2-negative stage II-III breast cancer. Methods: In this multicenter, single-arm exploratory trial (NCT05512780), adult postmenopausal women with HR-positive (estrogen receptor >10%), HER2-negative stage II-III invasive breast cancer were enrolled. Patients received oral dalpiciclib (150 mg on days 1-21 of each 28-day cycle) and oral letrozole (2.5 mg once daily) for 4 cycles, followed by surgery. The primary endpoint was objective response rate (ORR), assessed by investigator according to the Response Evaluation Criteria In Solid Tumors version 1.1. Secondary endpoints included complete cell cycle arrest (CCCA, defined as Ki-67 < 2.7% on day 15 of the first cycle) rate, total pathological complete response (tpCR; ypT0/is ypN0) rate, residual cancer burden (RCB) 0-I rate, and safety. Results: Between June 2022 and January 2023, 41 patients were screened at 9 sites, and 35 patients were enrolled and received at least one dose of study drug. The median age was 66 years (range, 52-83), and the median baseline Ki-67 level was 20% (range, 4%-40%). The majority of patients had T2 disease (65.7%), lymph node-positive disease (88.6%), and stage II disease (IIA: 45.7%; IIB: 40.0%). The ORR was 35.5% (11/31) at 8 weeks and 51.7% (15/29) at 16 weeks in patients with evaluable response. The CCCA rate was 70.0% (21/30) in patients with available data. Four patients refused surgery and chose to continue the drug therapy. Of 27 patients who had undergone surgery, one (3.7%) patient had tpCR and RCB 0. Of 35 patients, the most common adverse events were neutrophil count decreased (74.3%), white blood cell decreased (68.6%), anemia (34.3%), and fatigue (31.4%). The most common grade 3 or higher adverse event was neutrophil count decreased (45.7%). No febrile neutropenia or treatment-related deaths occurred. Conclusions: This is the first prospective study of neoadjuvant dalpiciclib in patients with HR-positive, HER2-negative breast cancer. The findings suggest the promising tumor response to neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR-positive, HER2-negative breast cancer, with a manageable safety profile. This combination can effectively suppress the tumor cell proliferation, as reflected by change in Ki-67 level. Citation Format: Lina Zhang, Chao Yang, Jie Ma, Yuntao Li, Ruizhen Luo, Jianjun Han, Xiaochun Wang, Zhisheng Zhang, Li Ma, Haifeng Cai, Xiangshun Kong, Zunyi Wang, Xinping Zhou, Yueping Liu, JiaJie Shi, Yanshou Zhang, Meiqi Wang, Jiaxing Wang, Cuizhi Geng. CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-05.

Abstract P3-07-07: The use of ribociclib/letrozole combination as an alternative for neoadjuvant chemotherapy in selected patients with early luminal breast cancer

Abstract Introduction In hormone receptor-positive, HER2-negative early-stage breast cancer (BC), cyclin-dependent kinases 4 and 6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) could represent an alternative to neoadjuvant chemotherapy (NAC). Methods NEOLBC is a randomized phase II trial that tailored neoadjuvant therapy in postmenopausal patients with early, luminal (ER >50%, PR any), HER2-negative, stage II/III BC based on the percentage of Ki67 positive cancer cells after a window of opportunity of two weeks letrozole. Patients with a Ki67 >= 1% after 2 weeks were randomized between ribociclib plus letrozole (RL) and chemotherapy (CT; AC-T regimen). The primary objective was to determine if RL gives a doubling in complete cell cycle arrest (CCCA; Ki67 < 1% on IHC) as compared to CT in the surgical specimen (70% vs. 35% of patients, respectively). Secondary endpoints included pathological response, toxicity and ER pathway activity (measured by the OncoSIGNal qPCR test). Results Out of 161 registered patients, 70 patients were randomized and 66 patients started treatment; 34 RL and 32 CT. Patient characteristics were equally distributed between the two groups, except for the PR status (RL 23.5% negative vs. 50.0% negative in the CT group). In the intention to treat analysis, the CCCA in the surgical specimen was similar for both groups: 35.3% in the RL vs. 31.3% in the CT group (p = 0.73). The pathological complete response (pCR) in the breast was not significantly different between the two groups (11.8% vs. 3.1%, p = 0.36) nor was the pCR rate in breast plus lymph nodes (8.8% vs. 3.1%, p = 0.61) for the RL vs. CT group, respectively. An explorative analysis on the difference in Ki67% (decline, no change, increase) from baseline to surgery showed a decline in 73.5% vs. 50.0%, no change in 17.6% vs. 31.3% and an increase in 8.8% vs. 18.8% of patients (p = 0.06) for the RL vs. CT group, respectively. In the RL group eight patients (23.5%) discontinued ribociclib early due to toxicity (two SAE’s were observed) vs. 10 patients (31.3%) discontinuing treatment in the CT group (one SAE was observed). Secondary endpoints, including the ER pathway activity analysis, will be presented in-depth during the meeting. Conclusion Although the primary endpoint was not met, the NEOLBC trial showed a similar CCCA and pathological response at surgery for RL vs. CT. Therefore, RL as an alternative for NAC merits further investigation in follow-up studies. ClinicalTrials.gov: NCT03283384 Citation Format: Anne Florine de Groot, Danielle Cohen, Joan B. Heijns, Caroline Mandigers, Diederick M. Keizer, Hein Putter, Elma Meershoek-Klein Kranenbarg, Marjolijn Duijm-de Carpentier, Kyra Dijkstra, Elise van Leeuwen-Stok, Gerrit-Jan Liefers, Sabine Linn, Judith Kroep. The use of ribociclib/letrozole combination as an alternative for neoadjuvant chemotherapy in selected patients with early luminal breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-07.

Ovarian function suppression as a potential mechanism of chemotherapy.

Ovarian function suppression as a potential mechanism of chemotherapy.

Abstract B19: The impact of circulating tumor cells on treatment response in early breast cancer patients with hormone receptor-positive and HER2 positive who underwent the neoadjuvant therapy

Abstract Introduction: Accumulating evidence has described that circulating tumor cells (CTCs) imply a poor prognosis in patients with early breast cancer. In this study, we evaluated the association between CTCs and response of neoadjuvant therapy in patients with hormone receptor (HR)-positive and HER2-positive breast cancer. Method: The HERAKLES study was a prospective single-arm, multicenter, phase II trial designed to evaluate the efficacy and safety of letrozole and trastuzumab for neoadjuvant therapy in postmenopausal patients with HR-positive and HER2-positive breast cancer (NCT02214004). All patients received trastuzumab every 3 weeks for eight cycles and daily letrozole for 24 weeks, followed by the surgery. After neoadjuvant therapy, the clinical response was assessed by the radiologic modalities. The CTCs were investigated by using a microfabricated porous filter in which the size of the square pores was optimized as 8.5 × 8.5 μm for the nickel electroformed membrane filter from 10mL of whole blood. Then, immunofluorescence staining was conducted with antibodies against CD45, EpCAM, cytokeratins, and then counterstained with DAPI. The CTCs were determined as DAPI-positive, EpCAM-positive, CK-positive, and CD45-negative cells. The CTCs analysis before and after neoadjuvant therapy was performed in 21 patients. In addition, we classified the patients into 4 groups: Group A, CTC-negative at both times (n=4); Group B, presence of CTC at pretreatment and CTC-negative at post-treatment (n=4); Group C, CTC-negative at pretreatment and presence of CTC at post-treatment (n=6); Group D, presence of CTC at both times (n=7). Results: The CTCs were detected in 11 (52.4%; median CTCs count, 2; range, 1-26) patients at pre-treatment and 13 (61.9%; median CTCs count, 4; range, 1-11) patients at post-treatment. CTC detection and CTC changes after neoadjuvant therapy were not associated with primary tumor characteristics. There was no patient with disease progression after neoadjuvant therapy in group A and B. However, the disease progression was observed in one (16.7%) patient in group C and two (28.6%) patients in group D (p=0.470). When the CTC was analyzed as continuous value, the CTCs were increased in all (the average change of CTCs, +6.0) patients with disease progression after neoadjuvant therapy, although the CTCs were increased in 7 (38.9%; the average change of CTCs, -1.3) of 18 patients without progression disease (p=0.09). Conclusions: The increase in CTCs after neoadjuvant treatment, including aromatase inhibitor and trastuzumab, tended to be correlated with poor treatment response in HR+/HER2+ breast cancer patients, although it remains underpowered. Our results supported that the monitoring of CTCs may reflect the response to neoadjuvant aromatase inhibitor and trastuzumab therapy in HR+/HER2+ breast cancer. Citation Format: Soong June Bae, Soeun Park, Chi Hwan Cha, Dooreh Kim, Janghee Lee, Sung Gwe Ahn, Joon Jeong. The impact of circulating tumor cells on treatment response in early breast cancer patients with hormone receptor-positive and HER2 positive who underwent the neoadjuvant therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B19.

B12Y12 (Y: N, P) fullerene-like cages for exemestane-delivery; molecular modeling investigation

The present study aimed to assess the adsorption of Exemestane (Aromasin: AMS) drug on the boron nitride (B12N12) and boron phosphide (B12P12) fullerene-like cages in the solvent (water) and vacuum environments at the PBE/6-311 + G∗∗ and MPW1PW91/6-311 + G∗∗ theoretical levels. AMS drug can adsorbed on the B12N12 and B12P12 fullerene-like cages generally via their CO and C–H groups. The strong adsorption of AMS drug (state II) is observed through a carbonyl involves a σ bond and a π bond involving the 2p orbitals on the boron atoms of the B12N12 in the water environment compared to vacuum environment. Phosphorous substituted doping in the B12N12 has little influence on the adsorption of AMS for both environments. The electronic and structural features of the B12N12 in comparison with B12P12 can be enhanced when AMS drug adsorbed on it. The adsorption of the AMS to the B12N12 changes the polarity of the pure fullerene-like cage as displayed by the calculated dipole moment values. The calculated solvation energies reveal that the solubility of AMS interacting with B12N12 is enhanced to a greater extent compared with the pure one. B12N12 can thus function as a drug delivery carrier in the therapy of postmenopausal patients with advanced breast cancer.

CYCLIN-EPENDENT KINASES 4/6 INHIBITORS IN COMBINATION WITH AROMATASE INHIBITORS IN TREATMENT OF METASTATIC BREAST CANCER (clinical observation)

It is known that a complete recovery in patients with generalized tumor is impossible, but the use of effective treatment regimens can significantly inhibit the development of the disease. The main goal of treatment of metastatic breast cancer is to increase overall survival, time to disease progression, improvethe quality of life, to prevent serious complications. In recent years, the standard of first−line hormone therapy in postmenopausal patients has been the use of aromatase inhibitors. Recently, a new class of drugs has emerged that can increase the effectiveness of hormone therapy, which significantly strengthens the position of this method in metastatic breast cancer. A clinical trial of PALOMA−2 and its findings are presented: the palbociclib + letrozole protocol as first−line therapy in postmenopausal patients with estrogen−positive Her2 new negative advanced breast cancer improves the objective response rate and clinical efficacy compared to letrozole monotherapy. The overall incidence of adverse responses was higher in patients treated with palbociclib + letrozole compared with placebo + letrozole. This clinical case demonstrates the possibility of long−term effective disease control in metastatic breast cancer. Literature data and personal experience show high efficacy of the combined protocol of hormone therapy and inhibitors of cyclin−dependent kinases 4/6. The use of such protocols is advisable in patients with multiple bone metastases, while achieving an effective reduction of pain. The use of such regimens is possible in patients with a low ECOG score who cannot tolerate chemotherapy with more severe toxicity. Key words: metastatic breast cancer, aromatase inhibitors, palbociclib.

Abstract P3-07-05: Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study

Abstract Background: Oncotype DX Recurrence Score (RS), Prosigna PAM50 ROR score, the EndoPredict score (EP, EPclin) and the Breast Cancer Index (BCI) all provide substantial molecular prognostic information and are used in clinical practice for guiding the treatment for large numbers of patients with primary ER+/HER2- breast cancer. Despite this, there is incomplete information on the concordance between these scores and very little understanding of the molecular features that drive the individual scores. Here we report from a unique database (i) the correlation between all 4 scores when measured by the respective manufacturers in the TransATAC set of samples and (ii) the degree to which each of the scores is driven by proliferation, oestrogen signalling, HER2 signalling and invasive properties insomuch as these are reflected by each component module of the RS test (PM, EM, HM and IM, respectively). Methods: The TransATAC tumour sample set was collected from patients in the tamoxifen or anastrozole arms from the ATAC clinical trial of 5 years of endocrine therapy in postmenopausal patients with primary hormone receptor positive breast cancer. Cases were included if HER2- and all 4 scores were available. None of the patients received adjuvant chemotherapy. EP and ROR both include some clinical features in their final score but components were excluded for the purposes of this study. The RS module scores were provided by the manufacturer. The genes that contribute to the module scores are as follows: PM: Ki67, STK15, Survivin, CCNB1, MYBL2; EM: ER, PGR, BCL2, SCUBE2; HM: GRB7, HER2; IM: MMP11, CTSL2). Spearman rank correlation was used to study the association between molecular components. Results: Data was available for all four molecular scores for 785 TransATAC patients. Correlations were moderate to strong for RS vs EP (r=0.63), ROR vs EP (r=0.68), ROR vs BCI (r=0.74) and EP vs BCI (r=0.67) but were weak for RS vs ROR (r=0.32) and RS vs BCI (r=0.35). The correlation between each score with the RS module scores are shown in the Table. Molecular scoreRS moduleRSROREPBCIPM0.360.860.710.74EM-0.790.00-0.38-0.10HM-0.04-0.14-0.15-0.18IM0.260.380.340.32 The RS had a strong negative correlation with its EM (r= -0.79) and a weak positive correlation with its PM (r= 0.36) although the latter was stronger when the PM was thresholded; 78% of the cases had a PM score below the threshold of 6.5 and were assigned a value of 6.5 in the RS with no correlation between RS and PM in these samples (r=-0.03). ROR showed a very strong correlation with the PM (r=0.86), but none with the EM (r: 0.00). EP and BCI both showed strong correlation with the PM (r= 0.71 and 0.74, respectively) and with low or near absent correlation with EM (r= -0.38 and -0.10, respectively). There was little correlation between the HM with each of the scores while the IM correlation was similar for each score varying from 0.26 to 0.38. Of the two module components of BCI, MGI was strongly associated with the PM (r= 0.84) and not at all with the EM while H/I moderately correlated with PM (r=0.51) and weakly correlated with EM (r= -0.31). Conclusion: EP scores are moderately correlated with each of the other 3 scores while RS scores are dissimilar to those from the ROR and BCI. In contrast to common thinking the RS is driven only weakly by proliferative features and more by those related to ER/PR pathways. The EP, BCI and particularly ROR are dominated by proliferative features. These relationships provide and explanation for the differences that we and others have reported in the prognostic performance of the tests for both early and late recurrence. Citation Format: Richard Buus, Ivana Sestak, Mitch Dowsett, Ralf Kronenwett, Sean Ferree, Catherine Schnabel, Frederick L Baehner, Jack Cuzick. Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-05.

First-line endocrine therapy for postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a systematic review and meta-analysis

BackgroundIn establishing the 2018 Breast Cancer Practice Guidelines of the Japan Breast Cancer Society, we explored the optimal first-line endocrine therapy for advanced postmenopausal hormone receptor-positive breast cancer.MethodsWe performed a systematic review of relevant reports from randomized-controlled studies published prior to November 2016 found using medical journal search engines. The main outcomes which we evaluated were progression-free survival (PFS), objective response rate (ORR), disease control rate (CBR), and toxicity.ResultsFour controlled trials comparing aromatase inhibitors (AI) and cyclin-dependent kinase (CDK)4/6 inhibitor combination therapy to AI monotherapy, and two controlled trials comparing anastrozole to fulvestrant 500 mg were analyzed. AI/CDK4/6 inhibitor combination therapy significantly improved PFS (Risk Ratio: 0.67, 95%CI 0.60–0.73), increased ORR (Risk Difference: 0.11, 95% CI 0.07–0.16), and increased CBR (Risk Difference: 0.11, 95% CI 0.07–0.15), compared with AI monotherapy. Patients who received this combination therapy had a higher grade ≥ 3 adverse event rate more than those who received AI monotherapy (Risk Difference: 43%, 95%CI: 0.39–0.47). Fulvestrant 500 mg alone significantly improved PFS (risk ratio: 0.85, 95%CI 0.72–0.98), but ORR and CBR were similar to those of anastrozole alone.ConclusionIn the first-line treatment for advanced postmenopausal hormone receptor-positive breast cancer, a combination therapy of CDK4/6 inhibitors and AI showed significant improvement of PFS, ORR, and CBR but with significant increased toxicities compared with AI alone. Fulvestrant 500 mg monotherapy significantly prolonged PFS compared with AI monotherapy. We must wait for the results of the studies with longer follow-up period.

CLINICO-MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL ASPECTS OF ENDOMETRIAL POLYP PATHOGENESIS IN POSTMENOPAUSE

To study hypoxia-inducible transcription factor HIF-1α expression in endometrial polyps (EP) considering their clinical-morphological and immunological features during postmenopause. A complex clinical and laboratory examination of 120 postmenopausal patients was carried out. 90 of them developed EP, whereas 30 had morphologically unchanged endometrium. Immune histochemical (ICH) testing was used to evaluate HIF-1α expression in epithelial and stromal cells of polyps in adjacent and control endometrium. A complex of the most significant risk factors in EP genesis such as high rate of inflammatory disorders of genital organs (IDGO), extragenital, metabolic and endocrine disorders and intrauterine contraception (IUC) was found. High expression of HIF-1α in epithelial cells and in the area of inflammatory infiltrate of glandular fibrous EP stroma was established as compared with control endometrium. HIF-1α expression in epithelial cells and in the area of inflammatory infiltrate of EP glandular fibrous stroma against the background of inflammatory, metabolic and endocrine, immunological changes and age-related involutional processes indicated local hypoxia. Epigenetic changes can develop in the processes of proliferation and apoptosis and in the processes that control neoplastic transformation. The obtained data can provide grounds for patient-tailored EP therapy in postmenopausal patients.

Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer

Patients with estrogen receptor (ER)-positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood. To compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype. Secondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node-negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018. Patients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy. Distant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics. In the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, P < .001 [luminal A subtype, n = 336], P = .04 [luminal B subtype, n = 126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59). Patients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.

Abstract P4-14-11: No impact of osteoporosis or bisphosphonate use for osteoporosis on breast cancer outcome: A sub-study of the DATA trial

Abstract Background: The phase III DATA study (NCT00301457) investigates the efficacy of 6 versus 3 years of adjuvant anastrozole after an initial 2-3 year treatment with tamoxifen in postmenopausal women with breast cancer. A reduced bone mineral density (BMD) is associated with a lower risk of breast cancer. Bisphosphonates as adjuvant therapy in postmenopausal patients have been shown to prevent (distant) breast cancer recurrences. In this planned side-study of the DATA trial we assessed the relationship between osteoporosis and distant recurrence free survival (DRFS), and evaluated the effect of bisphosphonate use for reduced BMD in general on DRFS. Methods: Decisions on BMD measurements and bisphosphonate use in the DATA study were left to the treating physician. We registered all BMD measurements and start of bisphosphonate-use. BMD was measured by a dual-energy x-ray absorptiometry (DEXA) scan of the lumbar spine/hip. We used a landmark of 3 years beyond the start of anastrozole, to create 3 different groups by BMD values based on DEXA scans made before the landmark and before a DRFS event (normal T score &amp;gt;-1.0, osteopenia T score &amp;lt;-1.0, osteoporosis T score &amp;lt;-2.5). Kaplan Meier methodology was used for analyzing the DRFS for these groups. The events ending a period of DRFS were defined according to the STEEP criteria. For analyzing the relationship between bisphosphonate use and DRFS, overall bisphosphonate use was integrated as a time dependent covariate. Results: Of the 1860 DATA patients, 1142 (65.5% in the 6-year arm and 62.9% in the 3-year arm) had a DEXA scan within the first 3 years after randomization. A normal BMD was diagnosed in 436 (38.2%) patients, osteopenia in 565 (49.5%), and osteoporosis in 141 (12.3%). Of the latter group, 112 (80.9%) used bisphosphonates. In the total study population (n=1860), bisphosphonates were overall used over time before a DRFS event in 226 patients (24.2%) in the 6-year arm and 201 patients (21.7%) in the 3-year arm. During the study, only 46 patients used bisphosphonates without a diagnosis of osteopenia/osteoporosis. After a median follow up of 5.0 years from the landmark (interquartile range 4.3-5.7), osteoporosis (n=141) did not have a significant impact on DRFS when compared with the group without osteoporosis (normal/osteopenia (n=1001)) (HR 1.19, p=0.24 in the 6-year arm and HR=0.79, P=0.56 in the 3-year arm, P interaction=0.45). Neither when compared with only the group with a normal BMD (n=436) (HR=1.15, p=0.72 in the 6-year arm and HR=0.67, p=0.34 in the 3-year arm, P interaction=0.35). Within the group with osteoporosis, bisphosphonate use did not lead to a better DRFS (HR=1.47, P=0.72 in the 6-year arm and HR 0.65, P=0.61 in the 3-year arm, P interaction=0.55). Bisphosphonate use in general was also not associated with DRFS (HR 1.31, P=0.13 in the 6-year arm and HR 0.88, P=0.52 in the 3-year arm, P interaction=0.14). Conclusion: In this DATA sub-study, we observed no association between the presence of osteoporosis before the landmark of 3 years after the start of anastrozole and DRFS. However, as most patients with early osteoporosis also were treated with bisphosphonates this may have influenced the results. At the conference additional analyses will be presented. Citation Format: van Hellemond IE, Smorenburg CH, Peer PG, Swinkels AC, Seynaeve CM, van der Sangen MJ, Kroep JR, de Graaf H, Honkoop AH, Erdkamp FL, van den Berkmortel FW, de Roos WK, Linn SC, Imholz AL, de Boer M, Tjan-Heijnen VC. No impact of osteoporosis or bisphosphonate use for osteoporosis on breast cancer outcome: A sub-study of the DATA trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-11.

Assessment of Long-term Distant Recurrence-Free Survival Associated with Tamoxifen Therapy in Postmenopausal Patients with Luminal A or Luminal B Breast Cancer

Assessment of Long-term Distant Recurrence-Free Survival Associated with Tamoxifen Therapy in Postmenopausal Patients with Luminal A or Luminal B Breast Cancer

Association of Somatic Driver Alterations With Prognosis in Postmenopausal, Hormone Receptor–Positive, HER2-Negative Early Breast Cancer

A range of somatic driver alterations has been described in estrogen receptor-positive, HER2-negative (ER+/HER2-) early breast cancer (BC); however, the clinical relevance is unknown. To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole. The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptor-positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next-generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible patients with ER+/HER2- BC, with 841 distant recurrences after a median of 8.1 years of follow-up. To correct for the oversampling of distant recurrences, weighted analysis methods were used. This analysis was conducted from April 4, 2016, to November 30, 2016. The prevalence of driver alterations, associations with clinicopathologic factors, distant recurrence-free interval, and treatment interactions were analyzed. Multivariable analyses were performed to adjust for clinicopathologic factors. Of 764 samples, 538 (70.4%), including 140 distant recurrence events, were successfully sequenced. Nineteen driver alterations were observed with 5% or greater frequency, with a mean of 4 alterations (range, 0-15) per tumor. PIK3CA mutations were the most common (49%) and were significantly associated with reduction in the risk for distant recurrence (hazard ratio [HR], 0.57; 95% CI, 0.38-0.85; P = .006). TP53 mutations (HR, 1.92; 95% CI, 1.21-3.04; P = .006), amplifications on 11q13 (HR, 2.14; 95% CI, 1.36-3.37; P = .001) and 8p11 (HR, 3.02; 95% CI, 1.88-4.84; P < .001), and increasing number of driver alterations (HR per additional alteration, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with significantly greater risk. Amplifications on 11q13 and 8p11 remained significant predictors in multivariable analysis, but not PIK3CA and TP53 mutations. Patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not (P interaction = .002). In ER+/HER2- postmenopausal, early-stage BC, amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence and PIK3CA mutations were predictive of greater magnitude of benefit from letrozole. With these findings, DNA-based classification may aid adjuvant treatment decision making in this setting. ClinicalTrials.gov Identifier: NCT00004205.

A review of medical and surgical techniques for overcoming cervical stenosis

Cervical stenosis is anomalous narrowing or obstruction of any part or the entirety of the cervical canal. It may be congenital or acquired as the result of aging, nulliparity, use of progestins, curettage, cervical surgery or any combination of these factors. Cervical stenosis is challenging to gynecologists in that it presents an additional complication to the completion of procedures that require examination of or passage through the cervical canal. Limited literature on overcoming cervical stenosis recommends both medical therapy using laminaria or misoprostol (with additional estrogen therapy in postmenopausal patients) and surgical therapy using a variety of tools including hysteroscope, grasping forceps, scissors, bipolar electrode, hysteroscopic morcellator, resectoscope, LEEP and incision. We present an exemplar case where use of medical therapy might have eliminated the need for or at least reduced the risk of the surgical therapy that the patient actually received. We recommend that gynecologists become familiar with the variety of methods currently in use for resolving cervical stenosis so that they may best advise patients that need such treatment and that medical therapy be attempted before surgical therapy is applied whenever possible.

Abstract P1-10-07: Efficacy and safety results from a randomized, phase II study of CC-486 in combination with fulvestrant in postmenopausal women with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) metastatic breast cancer (MBC)

Abstract Background: Most patients diagnosed with breast cancer have ER+ tumors. Treatment of ER+ MBC typically involves endocrine therapy, including aromatase inhibitors and selective ER modulators such as tamoxifen; however, many patients develop resistance. Fulvestrant, an ER antagonist, is a commonly prescribed second- or third-line therapy for postmenopausal patients who have progressed on endocrine therapy; although, most patients will eventually develop resistance to this drug as well. It was hypothesized that CC-486, an oral formulation of azacitidine, may resensitize patients to endocrine therapy and possibly delay resistance to fulvestrant through the epigenetic regulation of certain genes. Methods: 97 postmenopausal female patients aged ≥ 18 years with ER+, HER2− MBC refractory to an aromatase inhibitor were randomized 1:1 to receive CC-486 300 mg on days 1 through 21 and fulvestrant 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent 28-day cycles or the same fulvestrant regimen alone. The primary endpoint was progression-free survival (PFS) based on investigator's assessment using RECIST version 1.1 and summarized by the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the hazard ratio (HR; including a 2-sided 95% CI), and a log-rank test was used to calculate P values for comparisons between treatment arms. Key secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. Results: 48 patients were included in the CC-486 + fulvestrant arm and 49 in the fulvestrant-alone arm. Median age was 63 years. Baseline characteristics were generally balanced between treatment groups, with some exceptions. The CC-486 + fulvestrant treatment cohort had fewer patients aged ≥ 65 years (40% vs 49%), with an ECOG PS of 1 (25% vs 57%), or with liver metastases (29% vs 43%) than did the fulvestrant-alone cohort. At the time of this analysis, 36 patients (75%) in the CC-486 + fulvestrant arm and 40 patients (82%) in the fulvestrant-alone arm had discontinued treatment, mostly due to progressive disease (81% and 90%, respectively). Median PFS was 5.5 months in both treatment groups (HR 0.87; 95% CI, 0.54 - 1.42; P = 0.599). ORR was 8.3% vs 2.0% in patients receiving CC-486 + fulvestrant vs fulvestrant alone, respectively. Median OS has not been reached. In patients who received CC-486 + fulvestrant, the most common any-grade nonhematologic treatment-emergent adverse events (TEAEs) were nausea (78%), vomiting (78%), diarrhea (44%), and constipation (41%), and the most frequent any-grade hematologic TEAE was neutropenia (26%). Of patients who discontinued due to AEs, most patients receiving CC-486 + fulvestrant treatment discontinued due to gastrointestinal (GI) TEAEs. Conclusion: The addition of CC-486 to fulvestrant did not improve PFS in patients with ER+, HER2− MBC compared with fulvestrant alone, and GI TEAEs were reported in a majority of patients. These results do not support further evaluation of this combination in this setting. Citation Format: Campone M, Sachdev J, Bianchi GV, Beck JT, Martínez-Jáñez N, Cortes J, Schmidt M, Zamagni C, Chen P, Miller J, Fandi A, Gianni L. Efficacy and safety results from a randomized, phase II study of CC-486 in combination with fulvestrant in postmenopausal women with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-07.

Abstract P3-13-06: Tailored neoadjuvant endocrine and chemo-endocrine therapy for postmenopausal patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative primary breast cancer

Abstract Aims We investigated the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane (EXE) alone followed by subsequent tailored treatment with EXE alone for responders or EXE plus oral metronomic cyclophosphamide (CPA) for non-responders. Methods In this multicenter open-label phase II study, we enrolled postmenopausal patients with primary invasive estrogen receptor (ER)-positive, HER2-negative, stage I–IIIA (T1c–T3 N0–2 M0) breast cancer and Ki67 index ≤ 30%. Patients first received EXE 25mg/day for 12 weeks. Based on clinical response and change in Ki67 index in response to the initial therapy, patients who achieved complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% both before and after treatment were defined as responders. Non-responders were defined as patients with PR and Ki67 index &amp;gt;5% after treatment, or SD and Ki67 index &amp;gt;5% before or after treatment. For the subsequent 24 weeks, responders continued the EXE monotherapy (continued EXE group), whereas non-responders switched to combination therapy with EXE plus CPA 50mg/day (EXE+CPA group). The primary endpoint was clinical response (CR and PR) at weeks 24 and 36. Results A total of 59 patients (median age 69 years, range 53–86 years) were enrolled between January 2011 and July 2015. After exclusion of 3 (2 with progressive disease, 1 with an adverse event, AE) who discontinued treatment in the initial 12-week EXE monotherapy period, 56 remained enrolled to receive subsequent treatment. After 8–12 weeks of the initial EXE monotherapy, 14 patients were classified as responders (9 with PR and Ki67 index ≤5% after treatment; 5 with SD and Ki67 index ≤5% before and after treatment), whereas 42 were classified as non-responders (3 with PR and Ki67 index &amp;gt;5% after treatment; 39 with SD and Ki67 index &amp;gt;5% before or after treatment). Clinical response rates at weeks 24 and 36 were 85% (12/14, 95%CI 57.2–98.2%) and 76% (10/13, 95%CI 46.2–95.0%), respectively, in the continued EXE group, and 56% (23/41, 95%CI 39.7–71.5%) and 76% (30/39, 95%CI 60.7–88.9%), respectively, in the EXE+CPA group. At week 36, no significant difference was found in median Ki67 index between the continued EXE and EXE+CPA groups (3.5% and 4.0%, respectively). The proportion of patients with preoperative endocrine prognostic index (PEPI) 0 was also similar between the continued EXE and EXE+CPA groups (21.4% and 23.8%, respectively). The breast-conserving surgery rate was 71.4% and 69.0%, respectively. Grade 3 AEs were elevated liver enzymes (1 patient) in the continued EXE group, and gastritis, hypertriglyceridemia, and bone mineral density loss (1 patient each) in the EXE+CPA group. Conclusion Switching from EXE monotherapy to EXE+CPA combination therapy based on clinical response and biological response (change in Ki67 index) to initial therapy improved subsequent clinical response in non-responders. Favorable clinical response to EXE alone was maintained in responders. Tailored neoadjuvant endocrine and chemo-endocrine therapy was shown to be effective in postmenopausal ER-positive breast cancer patients. (JBCRG-11CPA; UMIN000004751) Citation Format: Masuda N, Sato N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Yasojima H, Saji S, Sasano H, Morita S, Ohno S, Toi M. Tailored neoadjuvant endocrine and chemo-endocrine therapy for postmenopausal patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative primary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-13-06.

Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial

After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5-3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0-10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65-69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0·96, 0·88-1·05; p=0·39). The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. Pfizer, Dutch Cancer Foundation.

A Randomized Feasibility Study of 18F-Fluoroestradiol PET to Predict Pathologic Response to Neoadjuvant Therapy in Estrogen Receptor-Rich Postmenopausal Breast Cancer.

The aim of this study was to explore the ability of 18F-fluoroestradiol (18F-FES) PET/CT imaging to predict pathologic response to neoadjuvant therapy in postmenopausal women with estrogen receptor (ER)-rich breast cancer. Methods: This was a prospective, single-center study conducted as a substudy of the neoadjuvant study of chemotherapy versus endocrine therapy in postmenopausal patients with primary breast cancer (NEOCENT) trial. Patients with ER-rich breast cancer were randomized to neoadjuvant chemotherapy (NC) or neoadjuvant endocrine therapy (NET). The baseline SUVmax of 18F-FES PET/CT was measured. The pathologic response was assessed by the Miller-Payne system as nonresponse (grades 1 and 2) and response (grades 3-5). Results: Twenty-six patients were enrolled, with pathologic response achieved in 25 (NC, 12; NET, 13). Two patients achieved pathologic complete response after NC, but the remaining 23 patients had residual disease after NC or NET. Eight of 12 patients responded to NC, and 4 of 13 to NET; the difference was marginally significant (P = 0.07). In the NC group, the 2 patients with 18F-FES-negative tumors and none of the 10 patients with 18F-FES-avid tumors achieved pathologic complete response (P = 0.02). No difference in the SUVmax between responders and nonresponders was observed in either group. However, 5 of 7 NC patients with a baseline SUVmax of less than 7.3 achieved pathologic response, whereas none of the 5 NET patients with an SUVmax of less than 7.3 were responders (P = 0.03). The SUVmax values of the NC group were negatively correlated with percentage reduction of tumor cellularity (r = -0.63, P = 0.03), whereas those of the NET group showed positive correlation (r = 0.62, P = 0.02). During the median follow-up of 74 mo (range, 44-85 mo), recurrence occurred in only 4 NET patients. In patients with an SUVmax of less than 7.3, recurrence occurred in none of the 8 NC patients and 2 of the 5 NET patients (P = 0.13). Conclusion: Postmenopausal women who are ER-positive, but 18F-FES-negative, may benefit from NC rather than NET. 18F-FES PET/CT has the potential to predict response to neoadjuvant therapy in postmenopausal women with ER-rich breast cancer.

Abstract P1-09-09: Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07)

Abstract Background Endocrine therapy (E) has a major role in treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC). However, in contrast to western countries, premenopausal patients (PRE) more prevalent (50% of all breast cancer patients) and have less options of E than postmenopausal patients (POST) in Korea where the use of LHRH agonist in combination aromatase inhibitors (AIs) in PRE is restricted. Recently we have been successfully established nationwide cohort for the patients MBC (575 patients from 26 institutes). This study was designed to evaluate the role of E especially in PRE. Methods The patients with MBC were prospectively or retrospectively enrolled between September 2014 and May 2015. Only menopausal status-confirmed patients (296) were analyzed. Postmenopause was defined, based on NCCN guideline. Total duration of treatment was defined as the time from start day of any first treatment to end of any last treatment. Total duration of E was defined as the sum of time duration of each E. Overall survival was calculated from the start day of any treatment for MBC to any causes of death. This work is supported by National Strategic Coordinating Center for Clinical Research (H110C2020). Results A total of 296 patients with HR-positive MBC were analyzed [PRE, 169 (57.1%) and POST, 127 (42.9%)]. Except age (mean 44 and 60 years), baseline characteristics including in pathology, HER2 status, initial pathologic stage, de novo metastasis versus recurrence, surgery and adjuvant treatment (chemotherapy, endocrine therapy and radiotherapy) were well balanced. 92 (54.4%) of PRE and 77 (60.6%) of POST received at least one or more E through all treatment course. 41 (24.2%) of PRE and 44 (34.6%) received E as 1st-line treatment (p=0.034). Among PRE who received 1st-line of E, 30 (71.4%) and 9 (21.4%) of PRE received 2nd- and 3rd-line E. 20 (45.4%) and 10 (22.7%) of POST received 2nd- and 3rd- or more line of E. Most of PRE (54%) received tamoxifen+/-goserelin and 32% of PRE received AIs along with ovarian suppression. 71% of POST received AIs. As initial treatment, E was more frequently used in POST than in PRE (34.6% and 24.3%, p=0.053). Overall survival (OS) of all patients was 18.2 months (95% CI, 14.8-21.5). There was no difference in OS between PRE (17.8 months, 10.9-24.8) and POST (18.5 months, 95% CI, 13.2-23.9) (P=0.337). No difference of OS was observed (E, 18.1 moths, 95% CI, 13.0-23.3; chemotherapy 21.2 moths, 95% CI, 16.8-25.5), regardless of initial treatment. Total duration of treatment of PRE and POST were 15.2 and 13.6 months, respectively with no significant difference (p=0.389). PRE (8.3 moths, 95% CI,5.7-10.8) showed the trend toward longer duration of E in comparison with POST (5.5 moths, 95% CI,4.4-6.7), however the difference did not reach statistical significance (p=0.051). Conclusion E was more commonly used as 1st-line therapy in POST than in PRE. Although PRE had limited options of E, E was used in long duration of treatment especially in PRE. These findings suggested that E had a role in treatment for PRE with HR-positive MBC and could be used in treatment for PRE with good efficacy. Citation Format: Kim T-Y, Ahn J-H, Yoon JH, Sohn JH, Kim GM, Lee KH, Park YH, Koh S-J, Lee SE, Chae Y, Lee KS, Lee KE, Won HS, Kim JH, Jeong J, Park KH, Cho EK, Im Y-H, Im S-A, Jung KH. Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-09.

4P - Influence of anthracycline- and/or taxane-based chemotherapy on bone metabolism of patients with primary breast cancer

Background: Cancer therapy-induced bone loss (CTIBL) is well-known sequela of adjuvant endocrine therapy in postmenopausal patients (pts) with primary breast cancer (PBC). Pts exposed to chemotherapy (Ctx) with alkylators for lymphoma/leukemia own a high risk of premature CTIBL which as in premenopausal PBC pts may be mainly an indirect endocrine effect of Ctx. In contrast, data on direct effects of modern perioperative Ctx on bone metabolism are limited. This retrospective study was initiated to gain more detailed insights into the influence of perioperative anthracycline (A)- and/or taxane (T)-based Ctx on bone turnover of pts with pre- and postmenopausal PBC.Methods: A total of 109 pts (premenopausal: 49; postmenopausal: 60) receiving neoadjuvant or adjuvant A- and/or T-based Ctx were included. Serum markers of bone metabolism including C-telopeptide of type I collagen (ICTP) indicating the osteoclast activity, N-propeptide of type I collagen (P1NP) indicating the osteoblast activity, and bone alkaline phosphatase (BALP) were determined at baseline and prior to each subsequent Ctx cycle (C) up to C6. Changes of ICTP, P1NP, and BALP over time were analyzed by repeated-measure ANOVA.Results: A total of 600 Ctx cycles were analyzed. Baseline levels of ICTP, P1NP, and BALP were significantly higher in post- versus premenopausal pts. ICTP and BALP did not significantly change during Ctx. Both an increase of ICTP from baseline until C6 in premenopausal pts and a decrease in postmenopausal pts did not reach statistical significance. In contrast, P1NP significantly declined in postmenopausal pts from baseline to C6 (p = 0.0152). In premenopausal pts, P1NP declined from baseline to C3 and then increased until C6. These changes were highly significant (p = 0.0024).Conclusion: Our study demonstrates that A- and/or T-based Ctx for PBC exhibits direct effects on bone metabolism. In postmenopausal pts, Ctx was associated with a sustained suppression of osteoblast activity. In premenopausal pts, early osteoclast suppression completely recovered during C4-6. Whether these effects will translate into an increased risk to further develop CTIBL needs to be clarified by long-term observations.Disclosure: All authors have declared no conflicts of interest. Background: Cancer therapy-induced bone loss (CTIBL) is well-known sequela of adjuvant endocrine therapy in postmenopausal patients (pts) with primary breast cancer (PBC). Pts exposed to chemotherapy (Ctx) with alkylators for lymphoma/leukemia own a high risk of premature CTIBL which as in premenopausal PBC pts may be mainly an indirect endocrine effect of Ctx. In contrast, data on direct effects of modern perioperative Ctx on bone metabolism are limited. This retrospective study was initiated to gain more detailed insights into the influence of perioperative anthracycline (A)- and/or taxane (T)-based Ctx on bone turnover of pts with pre- and postmenopausal PBC. Methods: A total of 109 pts (premenopausal: 49; postmenopausal: 60) receiving neoadjuvant or adjuvant A- and/or T-based Ctx were included. Serum markers of bone metabolism including C-telopeptide of type I collagen (ICTP) indicating the osteoclast activity, N-propeptide of type I collagen (P1NP) indicating the osteoblast activity, and bone alkaline phosphatase (BALP) were determined at baseline and prior to each subsequent Ctx cycle (C) up to C6. Changes of ICTP, P1NP, and BALP over time were analyzed by repeated-measure ANOVA. Results: A total of 600 Ctx cycles were analyzed. Baseline levels of ICTP, P1NP, and BALP were significantly higher in post- versus premenopausal pts. ICTP and BALP did not significantly change during Ctx. Both an increase of ICTP from baseline until C6 in premenopausal pts and a decrease in postmenopausal pts did not reach statistical significance. In contrast, P1NP significantly declined in postmenopausal pts from baseline to C6 (p = 0.0152). In premenopausal pts, P1NP declined from baseline to C3 and then increased until C6. These changes were highly significant (p = 0.0024). Conclusion: Our study demonstrates that A- and/or T-based Ctx for PBC exhibits direct effects on bone metabolism. In postmenopausal pts, Ctx was associated with a sustained suppression of osteoblast activity. In premenopausal pts, early osteoclast suppression completely recovered during C4-6. Whether these effects will translate into an increased risk to further develop CTIBL needs to be clarified by long-term observations. Disclosure: All authors have declared no conflicts of interest.