Therapy For Early Breast Cancer Research Articles

Implications of obesity and insulin resistance for the treatment of oestrogen receptor-positive breast cancer

AbstractBreast cancer is the most common cancer in women, and incidence rates are rising, it is thought in part, due to increasing levels of obesity. Endocrine therapy (ET) remains the cornerstone of systemic therapy for early and advanced oestrogen receptor-positive (ER + ) breast cancer, but despite treatment advances, it is becoming more evident that obesity and insulin resistance are associated with worse outcomes. Here, we describe the current understanding of the relationship between both obesity and diabetes and the prevalence and outcomes for ER+ breast cancer. We also discuss the mechanisms associated with resistance to ET and the relationship to treatment toxicity.

A multidisciplinary team and patient perspective on omission of surgery after neoadjuvant systemic therapy for early breast cancer: A European Society of Surgical Oncology (ESSO) Research Academy survey

BackgroundSurgical de-escalation aims to reduce morbidity without compromising oncological outcomes. Trials to de-escalate breast cancer (BC) surgery among exceptional responders after neoadjuvant systemic therapy (NST) are ongoing. Combined patient and clinician insights on this strategy are unknown. MethodsThe European Society of Surgical Oncology Young Surgeons Alumni Club (EYSAC) performed an online survey to evaluate the perspective of multidisciplinary teams (MDTs) on omission of surgery (“no surgery”) following complete response to NST for early BC. The aim was to identify MDT considerations and perceived barriers to omission of BC surgery. Patient insights were obtained through a focused group discussion (FGD) with four members of the patient advocacy group, Guiding Researchers and Advocates to Scientific Partnerships (GRASP). ResultsThe MDT survey had 248 responses, with 229 included for analysis. Criteria for a “no surgery” approach included: patient's tumor and nodal status before (39.7 %) and after (45.9 %) NST and comorbidities (44.3 %). The majority chose standard surgery for hypothetical cases with a complete response to NST. Barriers for implementation were lack of definitive trials (55.9 %), “no surgery” not being discussed in MDTs (28.8 %) and lack of essential diagnostic or therapeutic options (24 %). Patients expressed communication gaps about BC surgery, lack of trust regarding accuracy of imaging, fear of regret and psychosocial burden of choosing less extensive surgery. ConclusionsBefore accepting “no surgery” after complete response to NST, MDTs and patients need level 1 evidence from clinical trials, access to standard diagnostic modalities and treatments. Patient's fear of regretting less surgery need to be acknowledged and addressed.

Endocrine therapy for early breast cancer in the era of oral selective estrogen receptor degraders: challenges and future perspectives.

Growth and survival of hormone receptor positive breast cancer cells are dependent on circulating hormones (e.g., estrogen and progesterone). Endocrine therapy improved outcomes in both early and advanced hormone receptor positive breast cancer. These treatments include drugs with different mechanisms of action, namely selective estrogen receptor modulators (SERM), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). SERDs represent estrogen receptor antagonists, favoring its degradation and thus interfering with proliferation genes transcription and activation. Fulvestrant is the first approved SERD, administered intramuscularly for treating advanced breast cancer. Oral SERDs have been tested to overcome the limitation of the intramuscular administration, and to increase SERD bioavailability. Recently, an oral SERD, Elacestrant, has been approved by the Food and Drug Administration (FDA) for patients carrying an ESR1 mutation. In fact, oral SERDs seem to be effective in tumors harboring ESR1 mutations, a well known mechanism of resistance to endocrine therapy (especially aromatase inhibitors). More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.

ASO Visual Abstract: Expanded Indications for Neoadjuvant Endocrine Therapy in Early Stage Breast Cancer During the COVID-19 Pandemic.

ASO Visual Abstract: Expanded Indications for Neoadjuvant Endocrine Therapy in Early Stage Breast Cancer During the COVID-19 Pandemic.

The cardiovascular and metabolic effects of ovarian suppression in combination with tamoxifen or an aromatase inhibitor as adjuvant therapy for early estrogen receptor-positive breast cancer: a systematic review

Adjuvant endocrine therapy is a key treatment in oestrogen receptor positive early breast cancer (BC). For premenopausal women ovarian function suppression (OFS) in combination either tamoxifen or aromatase inhibitor (AI) is utilised in high-risk cases. The resultant suppression of circulating oestradiol from OFS could have adverse cardiovascular and metabolic effects, subsequently increasing the risk of cardiovascular disease. Our study highlights the potential cardio-metabolic impact endocrine therapy and OFS have on premenopausal women with BC. It also highlights the pressing need for standardisation of routine collection and recording of cardiometabolic history and risk factors as part of baseline assessment and adverse event reporting to better understand the cardiometabolic impact these treatment has on our patients. Further studies, with particular focus on baseline and subsequent development of cardiovascular risk factors are needed to explore the impact of these drugs on the cardiovascular health of these young women with BC

CDK4/6 inhibitors as adjuvant therapy in early breast cancer? Uncertain benefits, guaranteed harms

CDK4/6 inhibitors are oral agents inhibiting key molecules of the cell cycle regulation. In patients with endocrine receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy is an effective treatment in the metastatic setting. Now, two studies in the adjuvant setting – MonarchE (2 years of abemaciclib) and NATALEE (3 years of ribociclib) – report positive invasive disease-free survival. Here, we re-evaluate these seminal trials. First, an excess drop-out or loss-to-follow up occurred early in the control arms of both studies. Since both trials are open-label, there is concern that the patients who drop-out do not do so at random but based on socioeconomic factors and alternative options. Is it possible that the results merely appear favorable due to loss to follow up? Based on re-constructed Kaplan-Meier curves, we concluded the results of these studies remain fragile, being prone to informative censoring. Secondly, adverse events were notably higher in both trials, and some of them, like COVID-19 related deaths in NATALEE, raise serious concerns. Third, the potential costs associated with CDK4/6 inhibition given as adjuvant therapy are unprecedented. The NATALEE strategy, in particular, could affect up to 35 % of patients with newly diagnosed breast cancer, which is the cancer with the highest incidence worldwide. Without confirmatory data based on a placebo-controlled trial, or better identification of patients that would benefit from the addition of CDK4/6 inhibitors in the adjuvant setting, we argue against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer.

Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial.

LBA1001 Background: The combination of CDK4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) is the standard first line treatment for HR+, HER2- advanced breast cancer (ABC). While disease progression occurs in nearly all patients (pts) with ABC, the optimal treatment for pts who experience progression on a CDK4/6i + ET remains uncertain. Real-world evidence suggests that use of abemaciclib after disease progression on a prior CDK4/6i prolongs progression-free survival (PFS) in ABC; however, Phase 2 trials with other CDK4/6i have generated mixed results. Here we present the primary outcome analysis for the Phase 3 postMONARCH trial (NCT05169567) of fulvestrant + abemaciclib or placebo in pts with HR+, HER2- ABC following disease progression on prior CDK4/6i + ET. Methods: postMONARCH was a global, double-blind, placebo-controlled study with pts randomized 1:1 to abemaciclib + fulvestrant or placebo + fulvestrant. Eligible pts had disease progression on a CDK4/6i + AI as initial therapy for ABC or relapse on/after a CDK4/6i + ET as adjuvant therapy for early breast cancer. No other prior treatment for ABC was permitted. Primary endpoint was investigator-assessed PFS; secondary endpoints included PFS by blinded independent central review (BICR), overall survival (OS), objective response rate (ORR), and safety. Assuming a hazard ratio (HR) of 0.7, the study had ~80% power to detect superiority for abemaciclib, with a cumulative 2-sided type I error of 0.05. Kaplan-Meier method was used to estimate PFS curves and treatment effect was estimated using a stratified Cox proportional hazard model. Results: A total of 368 pts were randomized to abemaciclib + fulvestrant (n = 182) or placebo + fulvestrant (n= 186). Most pts (99%) enrolled directly after CDK4/6i + ET as initial therapy for ABC. Prior CDK4/6i was 59% palbociclib, 33% ribociclib, and 8% abemaciclib. At interim analysis, the study reached the pre-specified criteria for significantly improved investigator-assessed PFS with abemaciclib + fulvestrant compared to placebo + fulvestrant (169 events, HR = 0.66; 95% CI 0.48 – 0.91; p = 0.01). At primary analysis (258 events), the HR was 0.73 (95% CI 0.57 – 0.95), with PFS rates at 6 months of 50% vs 37% for the abemaciclib and placebo arms, respectively. Consistent effect was seen across major clinical and genomic subgroups, including pts with baseline ESR1 or PIK3CA mutations. ORR was improved with abemaciclib compared to placebo (17% vs 7%, respectively, in pts with measurable disease). PFS according to BICR was also improved with HR = 0.55 (95% CI 0.39 - 0.77). OS remains immature (20.9% event rate). Safety was consistent with the known profile of abemaciclib. Conclusions: Abemaciclib + fulvestrant demonstrated statistically significant PFS improvement in pts with ABC progression on prior CDK4/6i-containing therapy. Clinical trial information: NCT05169567 .

Changes in body composition in early breast cancer patients treated with aromatase inhibitors

Abstract Purpose The aim of the study was to analyze the modification of total and regional body composition in early breast cancer patients treated with aromatase inhibitors (AIs). Methods This is a prospective, single-center, observational, longitudinal study. Four-hundred and twenty-eight patients treated with adjuvant aromatase inhibitors were enrolled at the Medical Oncology and Breast Unit of Spedali Civili Hospital in Brescia from September 2014 to June 2022. Several body composition parameters including total and regional fat and lean body mass were investigated with dual-energy X-ray absorptiometry (DXA) scan at baseline and after 18 months of treatment with aromatase inhibitors. Results A significant increase in fat body mass (mean + 7.2%, 95% confidence interval [CI]: 5.5;8.9%) and a reduction in lean body mass (mean −3.1%, 95% CI −3.9; −2.4) were documented in this population. The changes in fat and lean body mass varied considerably according to different body districts ranging between + 3.2% to + 10.9% and from−1.3% to −3.9%, respectively. Conclusion Aromatase inhibitor adjuvant therapy in early breast cancer is associated with changes in body composition, with a wide variability among different body districts, leading to a risk of sarcopenic obesity. Supervised physical exercise that focuses on single body parts that may display detrimental variations may be beneficial for AIs treated patients.

Wire-Free Targeted Axillary Dissection: A Pooled Analysis of 1300+ Cases Post-Neoadjuvant Systemic Therapy in Node-Positive Early Breast Cancer.

Recent advances in neoadjuvant systemic therapy (NST) have significantly improved pathologic complete response rates in early breast cancer, challenging the role of axillary lymph node dissection in nose-positive patients. Targeted axillary dissection (TAD) integrates marked lymph node biopsy (MLNB) and tracer-guided sentinel lymph node biopsy (SLNB). The introduction of new wire-free localisation markers (LMs) has streamlined TAD and increased its adoption. The primary endpoints include the successful localisation and retrieval rates of LMs. The secondary endpoints include the pathological complete response (pCR), SLNB, and MLNB concordance, as well as false-negative rates. Seventeen studies encompassing 1358 TAD procedures in 1355 met the inclusion criteria. The localisation and retrieval rate of LMs were 97% and 99%. A concordance rate of 67% (95% CI: 64-70) between SLNB and MLNB was demonstrated. Notably, 49 days (range: 0-272) was the average LM deployment time to surgery. pCR was observed in 46% (95% CI: 43-49) of cases, with no significant procedure-related complications. Omitting MLNB or SLNB would have under-staged the axilla in 15.2% or 5.4% (p = 0.0001) of cases, respectively. MLNB inclusion in axillary staging post-NST for initially node-positive patients is crucial. The radiation-free Savi Scout, with its minimal MRI artefacts, is the preferred technology for TAD.

Incidence and time to onset of immunotherapy-related adrenal insufficiency in the I-SPY2 trial.

584 Background: I-SPY2 was the first randomized trial to demonstrate an improvement in pCR and EFS when Immune Checkpoint Inhibitors (ICI) were added to standard neoadjuvant chemotherapy. This finding was validated in the phase 3 KEYNOTE 522 trial for triple-negative breast cancer, leading to approval of pembrolizumab (pembro) in this setting. ICIs add the risk of immune-related adverse events (irAEs); while most irAEs are reversible, endocrinopathies appear to persist. Higher rates of adrenal insufficiency (AI), either from primary adrenalitis or hypophysitis, have been reported with ICI-based therapy (tx) in early breast cancer (EBC) compared to advanced disease. Here we describe the incidence and time of onset of AI with ICI-based tx in I-SPY2. Methods: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone receptor, HER2, and MammaPrint status to evaluate novel agents in the neoadjuvant setting in patients (pts) with high-risk EBC. Treatment included weekly paclitaxel (T) plus ICI-based tx x 4 cycles, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. 6 completed investigational arms included ICIs: T+pembro x 4, T+pembro x 8 (+/- AC), T+pembro+SD101 (TLR9 agonist), T+durvalumab+olaparib, T+cemiplimab (cemi), and T+cemi+REGN3767 (anti-LAG-3). AI diagnoses were made by treating providers with review from two board certified endocrinologists. AI was defined as AM serum cortisol level < 3 mcg/dl in absence of recent glucocorticoid treatment. If ACTH was low or normal, pt was dx with hypophysitis; if ACTH was elevated, pt was dx with primary AI. Results: 442 pts in I-SPY2 received ICI-based tx; 11.8% (n=52) developed AI (primary+hypophysitis). Mean age of pts who developed AI was 47.3 vs 48.6 yrs in those who did not (p=0.44). Incidence of AI was highest in arms with dual immune modulation (18.1%) as compared to single ICI tx (8.5%). Median time to onset varied by arm, ranging from 92-204 days from first ICI dose. While some cases occurred during ICI tx (13.5%), the majority occurred between 12-24 wks after tx initiation, with 21.2% diagnosed after completion of all tx. The majority (94.2%) of pts with AI were symptomatic; the most common presenting symptoms included fatigue (59.6%), nausea (48.1%), and vomiting (34.6%). All pts with AI remain on glucocorticoid replacement tx. Conclusions: The incidence of AI in EBC is higher than has previously been reported in advanced disease, with higher rates observed in those tx with dual immune modulation. No correlation was observed with age; correlation of AI with response predictive subtype and other clinicopathologic features is ongoing and will be presented. Given the high incidence of AI in EBC, close monitoring in the peri/postoperative setting and education of pts and providers is critical, as risk persists even after completion of tx. Work to identify risk factors for AI is ongoing. Clinical trial information: NCT01042379 .

Neoadjuvant targeted therapy in early resectable HER2-mutant lobular breast cancer.

TPS630 Background: Invasive lobular carcinoma (ILC) accounts for approximately 10-15% of all breast cancers and is characterized by hormone receptor positivity (HR+), low Ki-67 score, and loss of cell adhesion receptors such as E-cadherin. While these tumors tend to be indolent initially, late recurrences and distant metastasis are common, and ILC has very low rates of pathologic complete response (pCR) to both neoadjuvant chemotherapy and endocrine therapy (ET). HER2 ( ERBB2) mutations are enriched in about 10% of unselected ILC, with some reports showing the prevalence as high as 27% in pleomorphic and higher grade ILCs. HER2 mutations in ILC are associated with ET resistance and a worse prognosis. Neratinib is a HER2 tyrosine kinase inhibitor (TKI) currently FDA-approved for adjuvant treatment of HER2-amplified (HER2+) early-stage breast cancer. It has shown safety and efficacy in combination with ET in metastatic HER2-mutant HR+ breast cancer. We hypothesize that neoadjuvant treatment with neratinib and ET will improve pathologic responses in newly diagnosed HER2-mutant HR+ ILC. Methods: This study (NCT05919108) is an open label multi-site Phase II clinical trial for 30 patients with Stage I-III ILCs and a HER2 activating mutation. Patients will be identified by next generation sequencing (NGS) of the diagnostic biopsy and randomized to 4 weeks of ET +/- neratinib; a biopsy will be done at the end of the lead-in phase. All patients will then receive ET and neratinib for 20 weeks prior to proceeding to surgery. To optimize tolerability, the first cycle of neratinib will include a dose escalation and antidiarrheal prophylaxis. The primary objective of this study will be the pre-operative endocrine prognostic index (PEPI) score, which will be compared to a historical PEPI-0 rate for patients with HR+ breast cancer treated with neoadjuvant ET. Secondary objectives will include pCR, residual cancer burden, and rates of breast conserving surgery. Correlative studies will include biomarkers of tumor cell cycle arrest, apoptosis, HER2 pathway activation, and gene expression on the pre- and on-treatment (4 week) biopsy from the lead-in phase to document molecular synergy between neratinib and ET. Patient-derived organoids from the 4-week biopsies will be established and subjected to single-cell RNA, ATAC seq, and DNA sequencing to study tumor evolution and elucidate epigenetic programs and somatic alterations that allow breast cancer survival despite continuous HER2-directed therapy. This is a first-in-kind, mechanism-based, molecularly targeted combination of a HER2 TKI and ET in HER2-mutant ILC. We posit results from this study may generate a clear signal of clinical activity leading to a randomized phase III trial aimed at incorporating HER2-directed therapies as a treatment for operable, early stage ILC. This signal may also suggest for the first time the added value of NGS in patients with newly diagnosed HR+ breast cancer. Clinical trial information: NCT05919108 .

Escalation of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer: to whom, when and why?

This review presents the evolution of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer, describes late relapse phenomenon, provides clinical rationale for escalation of treatment, analyzes the key stages of the metastatic cascade, and provides a scientific rationale for the introduction of CDK4/6 inhibitors into adjuvant treatment regimens. The main results of two large randomized studies of therapy including abemaciclib (MonarchE) and ribociclib (NATALEE) in patients with early stages of hormone-dependent HER2-negative breast cancer are presented; the oncological results of escalation of treatment and the safety of therapy are assessed.

Abstract PO2-01-05: Neoadjuvant pyrotinib plus trastuzumab, and chemoterapy in patients with HER2-positive early breast cancer: a real-world study

Abstract Background Pyrotinib is a new oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets human epidermal growth factor receptor 1 (HER1), HER2, and HER4. Previous studies have confirmed it combined with capecitabine is safe and well-tolerated in advanced breast cancer. And also PHEDRA trial had demonstrated the efficacy and safety of pyrotinib combined with trastuzumab and docetaxel neoadjuvant therapy early HER2-positive breast cancer. However, the efficacy of pyrotinib plus trastuzumab-based in real-world neoadjuvant therapy for early breast cancer is unknown. Purpose The present study aimed to explore the efficacy of pyrotinib-based in neoadjuvant therapy for early breast cancer in real-world. Method This is investigator-initiated phase 2 real-world study recruited eligible patients, aged 18–70 years with invasive carcinoma, cT2-3N0-3M0 stage, HER2-positive breast cancer. The patients received 400 mg pyrotinib orally once per day for 21 days and trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance dose) plus different standard chemotherapy, including six 21-day cycles of docetaxel (75 mg/m2) plus carboplatin (6 mg/mL/min), or four cycles of epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) and four cycles paclitaxel (80 mg/m2). The primary endpoint was to calculate the number of patients who achieved a pathological complete response (pCR, ypT0/is, ypN0). (ChiCTR2100052892). Result The results of the 23 patients were reported, The pCR of 12 (52.2%) patients, who reached the threshold for the design, was noted. The study is ongoing. The most frequent grade 3 to 4 adverse events were diarrhea (35.6%), which all the patients received primary prevention of diarrhea, leukopenia (44.8%), and anaemia (23.7%). However, no treatment-related deaths were recorded. Conclusion Previous studies have shown the efficacy and safety of pyrotinib plus trastuzumab and docetaxel in neoadjuvant therapy of HER2-positive early breast cancer. The current trial suggests that pyrotinib plus trastuzumab-based standard chemotherapy in real-world has promising efficacy and manageable toxicity in patients with HER2-positive early breast cancer in a neoadjuvant setting, the trial is ongoing, we will enroll more patients. Citation Format: Jun Zhou, Rui Wang. Neoadjuvant pyrotinib plus trastuzumab, and chemoterapy in patients with HER2-positive early breast cancer: a real-world study [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 PO2-01-05.

Abstract PO1-23-02: Magnetic seeds used for the detection of target lymph nodes after neoadjuvant therapy for early breast cancer – a subgroup analysis of the prospective AXSANA (EUBREAST-03) trial

Abstract Background: Surgical strategies for axillary staging in patients with early breast cancer who convert from clinical lymph node positivity (cN+) to a clinically negative lymph node status (ycN0) after neoadjuvant therapy (NAT) vary between breast cancer centers and countries. The international prospective multicenter-cohort study AXSANA (EUBREAST-03) aims to comparatively evaluate long-term outcomes of different surgical staging procedures such as axillary lymph node dissection, sentinel lymph node biopsy (SLNB), target lymph node biopsy (TLNB) and targeted axillary dissection (TAD). A secondary study aim is the comparison of different localization techniques for the target lymph node (TLN), one of which is the use of magnetic seeds. Here we report on the largest so far studied prospective cohort using this technique. Methods: We prospectively examined the retrieval rate of magnetic seeds and the identification rate of a TLN in cN+ patients who underwent NAT and were scheduled for TAD. Magnetic seeds were inserted under ultrasound guidance before the start of NAT. The detection rate of TLN and its associations with residual axillary tumor burden as well as with techniques used for detection of SLN were analyzed. Results: Of the 169 patients with magnetic seed marking of the TLN prior to NAT who were included in the AXSANA study, 135 (79.9%) had undergone final surgery at the time of analysis. 13 patients had 2 magnetic seeds implanted, 122 only 1 seed. In 133 (98.5%) patients the magnetic seeds were successfully identified and removed. No additional procedures or imaging were performed in the two cases with seeds still in situ. In 131 out of 135 patients (97.0%) the TLN was identified and resected, in 4 cases no TLN could be identified although in two of those a dislocated magnetic seed was removed. 85 patients converted from cN+ to ycN0 and a TAD was planned. In 84 of these cases (98.8%) the TLN could be detected during TAD. Eight patients (9.4%) had residual tumor only in the TLN, 15 (17.6%) had residual tumor in TLN and SLN and seven (8.2%) only in the SLN. In 71 (84.2%) cases the TLN was also a SLN. Techniques used for the detection of SLN were Tc99 alone (41.2%), blue dye alone (3.5%), both tracers combined (7.1%), indocyanine green (1.2%) and magnetic tracers (36.5%). Because of the high detection rate of 98.5% for all TLN and 98.8% during TAD a formal analysis of confounding parameters was not performed. Conclusion: To our knowledge this is the largest prospective series of patients using magnetic seeds for the marking of involved lymph nodes prior to NAT. The retrieval rate of the seed and the detection rate for the TLN after NAT is excellent. Magnetic seeds are a reliable tool for the marking of involved lymph nodes before NAT. Citation Format: Hans-Christian Kolberg, Steffi Hartmann, Maggie Banys-Paluchowski, Elmar Stickeler, Jana de Boniface, Oreste Davide Gentilini, Sarah Fröhlich, Marc Thill, Michael P. Lux, Guldeniz Karadeniz Cakmak, Isabel Rubio, Michalis Kontos, Rosa Di Micco, Dawid Murawa, Thorsten Kühn. Magnetic seeds used for the detection of target lymph nodes after neoadjuvant therapy for early breast cancer – a subgroup analysis of the prospective AXSANA (EUBREAST-03) 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 PO1-23-02.

Abstract PO3-11-12: A Pragmatic Randomized Trial Comparing Morning versus Evening Dosing of Endocrine Therapy for Early Breast Cancer: Final Results (REaCT-CHRONO Study)

Abstract Background. Interventions to improve tolerability and adherence to endocrine therapy (ET) are critical to the global improvement of breast cancer (BC) survivorship. The optimal time of day to take ET in terms of quality of life, side effects and adherence is unknown. This study compared a morning dose versus an evening dose of ET in patients with early-stage BC (EBC). Methods. In this pragmatic, open-label, multicenter trial, patients with hormone receptor-positive (HR+) EBC were randomized (1:1) to receive either a morning dose (within 1 hour of the patient wake up time) or an evening dose of ET (within 1 hour of patient bedtime). The primary endpoint was endocrine toxicity/tolerability measured by the change in total Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) score from baseline (commencement of ET) to 12 weeks. The secondary endpoints included: ET toxicity/tolerability and quality of life (FACT-ES and FACT-B) from baseline to 4, 8, 12 and 52 weeks, non-persistence or non-adherence, and patient timing preference. Results. Between June 2021 and March 2022, 245 eligible patients were randomized, 122 to morning (122/245, 49.8%) and 123 to evening (123/245, 50.2%) dosing. Mean age was 61 [standard deviation (sd) 11.9], 181 patients (73.9%) were postmenopausal, 188 (76.7%) received tamoxifen, 58 (23.7%) received an aromatase inhibitor and 22 (9%) received luteinizing hormone-releasing hormone. The mean changes in the FACT-ES score from baseline to 12 weeks following the beginning of ET were -2.0 (sd=14.3) vs -5.4 (sd=16.8) in the morning vs evening arms respectively (Wilcoxon two-sample rank sum test p-value=0.22). Also, the proportion of patients with a clinically important increase (Fisher’s exact test p-value=0.54 0.89) or decrease (p-value= 0.89) in FACT-ES Scores was not statistically different between the arms. At 52 weeks, the mean changes in the FACT-ES score from baseline were -2.5 (sd=18.8) vs -4.8 (sd=15.5) in the morning vs evening arms respectively (p-value=0.23). There was no statistical difference in FACT-ES and FACT-B scores over the 52 weeks of the study. At 12 weeks, 94.5% (69/79) vs 98.7% (78/79) were still taking the ET (p-value=0.2), whereas at 52 weeks, 92.1% (58/63) vs 85.4% (41/48) were still taking ET (p-value=0.36), in the morning vs evening arms respectively. Also, 13.7% (10/73) vs 7.6% (6/79) and 3.2% (2/62) vs 12.5% (6/48) interrupted their ET at least once, in the morning vs evening arms, at 12 and 52 weeks respectively. At week 52, 57.9% (62/107) in the morning arm vs 13.5% (14/104) in the evening arm strongly preferred an ET morning dose, whereas 7.5% (8/107) vs 42.3% (44/104) strongly preferred an ET evening dose. No significant preference changes were observed in dose timing from baseline to week 52 (p-value=0.081). Conclusions. These results suggest no significant difference in quality of life or adherence if ET is taken in the morning or in the evening. Patients should be reassured that they can take ET at their preferred time. Clinical Trial Registration: NCT04864405 Table 1. Mean changes between FACT scores at 12 weeks and 52 weeks from baseline for patients receiving ET morning vs evening dose. A positive value indicates the FACT score increased over time. FACT ES: Endocrine Subscale; FACT B: breast Citation Format: Marie-France Savard, Mohammed Ibrahim, Gregory Pond, Deanna Saunders, Lisa Vandermeer, Lesley Fallowfield, Terry Ng, Arif Awan, Sandeep Sehdev, Ana-Alicia Beltran-Bless, Mark Clemons. A Pragmatic Randomized Trial Comparing Morning versus Evening Dosing of Endocrine Therapy for Early Breast Cancer: Final Results (REaCT-CHRONO Study) [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 PO3-11-12.

Abstract PO4-20-03: HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13)

Abstract Background: In estrogen receptor (ER)-positive human epidermal growth factor receptor2 (HER2)-negative early breast cancer (EBC) patients, NCCN treatment guideline recommend 21-gene tests for decision of adjuvant chemotherapy if tumor size is over 0.5cm or node positive disease. In addition, GenesWellTM BCT is a prognostic assay that predict the risk of recurrence in patients with ER-positive HER2-negative and nodal stage 0-1 EBC. According to gene tests, EBC patients with high recurrence risk would have help from adjuvant chemotherapy to increase the rate of disease free survival but toxicities of chemotherapy are not negligible. Therefore, the effort for escaping adjuvant chemotherapy has been performed and currently CDK4/6 inhibitor would be considered as the substitute for cytotoxic chemotherapy in ER-positive HER2-negative EBC patients. Methods: HIPEx trial is a multi-center, phase II clinical trial to determine the efficacy of adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative EBC with high recurrence score according to GenesWellTM BCT (NCT04247633). Eligible patients are women who received curative surgery and diagnosed as ER-positive, HER2-negative and pathologic stage T1b-T2 and/or N0-1. Clinical recurrence risk is high according to the modified Adjuvant! Online guideline and GenesWellTM BCT score is 4 or more which being genomic high risk. Other criteria include ECOG performance status ≤1, adequate organ functions and availability of an archival surgical specimens. Patients receive palbociclib 125mg once daily for 21 days of 28-day cycle plus tamoxifen or aromatase inhibitor (anastrozole, letrozole or exemestane) once daily for every day. Palbociclib would be taken for two years and endocrine therapy for five years or more. If adjuvant radiotherapy is required, palbociclib should be taken two weeks after the end date of radiotherapy. If patients are premenopausal status, GnRH agonist is allowed. Primary endpoint is 3-year event free survival (EFS) rate of high clinical and genetic risk ER-positive EBC. Secondary endpoints include 3-year overall survival, quality of life, safety and tolerability of palbociclib with endocrine therapy as an adjuvant setting, exploratory analysis of predictive and prognostic biomarkers and the performance of GenesWellTM BCT for 3-year EFS rate. In total, 578 patients would be enrolled in this trial. Based on the previous results of GenesWell™ BCT in Korea, the 3-year EFS rate for the past control group (chemotherapy followed by endocrine therapy) is 87.0% and the treatment group in this clinical trial is assumed to be 90.5%.(hazard ratio for EFS = 0.717). Null hypothesis is the 3year-EFS rate in patients received adjuvant palbociclib and endocrine therapy is not less than that of the past control group. Alternative hypothesis is the 3year-EFS rate of this trial is less than that of the past control group (one-sided). Significance level is 0.025, power is 0.80. Considering 10% drop out rate, 4-years of accrual patient enrollment and 3-years of follow up period, 578 patients were required in this clinical trial. Citation Format: Ji-Yeon Kim, Sung Hoon Sim, Jieun Lee, In Hae Park, Kyong Hwa Park, Seock-Ah Im, Jee Hung Kim, Kyoung Eun Lee, Jeong Eon Lee, Jai Min Ryu, Young Kee Shin, Yeon Hee Park. HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13) [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 PO4-20-03.

Abstract PO2-02-13: A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC)

Abstract Background: Extracellular matrix (ECM) stiffness in the tumor microenvironment is associated with aggressive features that lead to adverse clinical outcomes, including metastasis. Mechanical conditioning (MC) is the phenomenon whereby cancer cells that have grown in a fibrotic-like stiff ECM acquire aggressive features which can be maintained after metastasis in distant sites (Cell Rep.; 35:109293). MeCo Score is a gene expression signature that measures the response to ECM stiffness in early tumors which is associated with subsequent metastasis. We sought to study whether MeCo Score is associated with pathologic complete response (pCR) in early HER2negBC, and whether anti-fibrotic treatment with nintedanib (a multikinase VEGFR1-3, FGFR1-3 and PDGFRA/B inhibitor approved for idiopathic lung fibrosis) is able to mitigate the impact of MC. Methods: Baseline tumor samples from patients (N=130) from a randomized phase II clinical trial (Clin Cancer Res 23: 1432-42) in early HER2negBC trial comparing weekly paclitaxel monotherapy (85 mg/m2 x 12 courses; N=65; Arm A) versus the same treatment plus nintedanib (150 mg p.o. bid, continuous schedule; Arm B) were analyzed by RNAseq. MeCo Score was computed as previous described (Cell Rep.; 35:109293), and intrinsic PAM50 subtypes were determined using the R package genefu. Clinical, demographic and pathologic variables were gathered for all patients; pCR was graded according to the Residual Cancer Burden (RCB) score, RCB=0. Regression models were built using the variables RCB, T, N, G, age, intrinsic subtype, Ki67, MeCo Score and treatment arm. Bi-variate correlations were analyzed with the Pearson coefficient. All statistic tests were two-sided. Results: MeCo Score was successfully determined in 76 women (50% from each arm); the average score was 0.34 (range: 0.052 – 0.617). Of them, 48.6% were Luminal A, 34.2% Luminal B, 14.5% Basal-like, and 2.7% Normal according to PAM50. Median age was 49 y.o. (range: 30.6 – 79.2); tumor size distribution was T1:3.0%; T2:68.2%; T3:24.3%; T4: 4.5%; 47% of the patients were N0, 47% were N1 and 6% were N2. Most patients (85%) were ER and/or PR positive; 15% were “triple-negative”. Histological grade distribution was G1/G2/G3: 15%/62%/23%. The average Ki67 was 28.7% (range: 1%-98%). pCR was 10.8% and 4.5% in arms A and B. The average MeCo Score by intrinsic subtype was 0.26 (LumA); 0.43 (LumB) and 0.38 (Basal), LumB vs LumA P< 0.001; LumB vs Basal: P=0.037. We did not find correlation between MeCo Score and G, T, N, age or Ki67, neither in the Luminal subgroup or the whole cohort. In Arm A, patients with high MeCo Score (i.e., above median) had a 0% pCR rate compared to 10.5% pCR rate for those with low MeCo Score (P=0.035); however, in the nintedanib arm (Arm B) no differences were found: 10.5% versus 11.1% pCR rate in high versus low MeCo Score (P=0.4). Conclusions: Among early HER2negBC, Luminal B cases display the highest MeCo Scores. MeCo Score was independent of all classic prognostic variables. High MeCo Score is associated with lack of pCR to neoadjuvant paclitaxel monotherapy, but concurrent administration of the anti-fibrotic agent nintedanib rescues this association. Citation Format: Miguel Quintela-Fandino, Adam Watson, Adam Grant, Gus Mouneimne, Maria J. Bueno, Silvana Mouron. A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC) [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 PO2-02-13.

Abstract PO5-18-09: Anthracycline-free neoadjuvant therapy with nab-paclitaxel and carboplatin in non-luminal breast cancer: a single-arm phase II trial

Abstract Background Anthracycline and taxane-based chemotherapy are the corner stone of neoadjuvant therapy in early breast cancer. Anthracycline-free regimens have been addressed widely because of cardiac toxicity especially in HER2-positive breast cancer when combining trastuzumab and pertuzumab. Aim of this trial was to assess the efficacy and safety of nab-paclitaxel combined with carboplatin in the neoadjuvant therapy of non-luminal breast cancer. Methods The Neopath trial was a prospective, single-arm phase II trial conducted in Comprehensive Breast Health Center, Ruijin Hospital between April 2019 and October 2021. Patients who had cT2-4NanyM0 or cTanyN1-3M0 triple negative breast cancer (TNBC) or HER2-positive breast cancer were enrolled. Patients were treated with neoadjuvant nab-paclitaxel (100 mg/m2) and carboplatin (area under the curve 2) on days 1, 8, and 15, for four 4-week cycles. Concurrent trastuzumab at 2 mg/kg (loading dose 4 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) were given in patients with HER2-positive tumors. Surgery was performed after 4-6 cycles of neoadjuvant therapy. Trastuzumab and pertuzumab after surgery was continued every 3 weeks for a total duration of 1 year. The primary endpoint was pathological complete response (pCR) rate, defined as no invasive tumor in breast and axillary lymph nodes (ypT0/Tis N0) after neoadjuvant therapy. Secondary endpoints were pCR rate in predefined subgroups, pCR (ypT0 N0), objective response rate (ORR); event-free survival (EFS), breast conservation rate and toxicity. Results A total of 106 patients were enrolled in the study and 99 of them proceeded to surgery. The pCR (ypT0/is N0) rate was 41.41% in total, 33.78% in TNBC and 64.00% in HER2-positive breast cancer. Proportion of patients achieving pCR (ypT0 N0) was 38.38% in total, 31.08% in TNBC and 60.00% in HER2-positive tumors. In the ITT population, 93 patients were event-free at a median follow-up of 24 months, while 5 in TNBC group and 1 in HER2-positive group had relapse or distant metastasis. EFS in patients achieving pCR was higher than patients without pCR (HR=7.328, 95%CI=1.453-36.96, p=0.0158). ORR was 72.49% in total, 67.12% in TNBC and 88.00% in HER2-positive breast cancer. Total breast conservation rate was 10.1% and 12.2% in TNBC, 4.0% in HER2-positive subgroup. The most frequent grade 3 or higher adverse events were neutropenia (57%), vomiting (11%) and thrombocytopenia (8%). Conclusion Neoadjuvant anthracycline-free regimen of nab-paclitaxel combined with carboplatin in non-luminal breast cancer was an effective and well-tolerated regimen. Citation Format: Deyue Liu, Li Zhu, Jiayi Wu, Wei Wang, Shuning Ding. Anthracycline-free neoadjuvant therapy with nab-paclitaxel and carboplatin in non-luminal breast cancer: a single-arm phase II 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 PO5-18-09.

Abstract PO1-12-02: Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients

Abstract Denosumab (Dmab), an inhibitor of osteoclast activity and proliferation is approved for treatment of women on aromatase inhibitor (AI) therapy for early breast cancer (60 mg Q 6-months) and metastatic disease (120 mg Q 4-weeks) to protect against bone loss and prevention of skeletal-related events (SREs). 60 mg given twice a year has shown fracture reduction, especially in women on aromatase inhibitor therapy, and recent data supports benefits in disease free survival, bone-metastasis free-survival and overall survival with Dmab in early breast cancer. It appears superior in reduction of SREs versus zoledronic acid (ZA) in established skeletal metastatic disease; thus, a preferred choice in the oncology setting. In the osteoporosis setting, withdrawal of Dmab therapy leads to a “rebound” increase of bone resorption, rapid bone loss and potential vertebral fractures. Increased risk of spontaneous and multiple vertebral fractures has been seen in this patient population. To prevent this, after discontinuation of Dmab, the addition of another anti-resorptive such as ZA is initiated. Dmab withdrawal events are uncommonly reported in patients with metastatic skeletal disease due to generally poor prognosis. Dmab given as 120 mg/month in this setting may need to be curtailed for a variety of indications including hypocalcemia, major dental procedures, osteonecrosis of the jaw or atypical femoral fracture. In the oncologic setting, it is unclear if discontinuation of Dmab will lead to rebound bone resorption or increased incidence of fractures. We describe the case is of a 32-year-old woman with a history of T2N3M1, oligometastatic breast cancer (solitary bone metastases at L1, biopsy-proven) that was ER/PR/HER2 positive. She was treated with neoadjuvant trastuzumab, pertuzumab, taxotere and carboplatin followed by bilateral mastectomy, and radiation to chest wall and L1. She received total estrogen blockade initially with GnRH-agonist and exemestane and ultimately bilateral salpingo-oophorectomy plus exemestane. She continues pertuzumab and trastuzumab (80 treatments to date) for the past 5 years and denosumab 120 mg/month for 14 treatments and then every 3 months, 20 total treatments. Development of hip pain (regular runner) and concern for atypical fracture vs metastatic disease led to bone scan and PET/CT. Metastatic disease was ruled out and stress reaction was diagnosed. Dmab therapy was discontinued with monitoring of her metabolic bone turnover. 1 year after her last Dmab injection, bone turnover markers began to increase and ultimately demonstrated a very significant “rebound phenomenon.” Subsequently, a single dose of 120 mg denosumab decreased bone markers to previously low levels which remain low on routine monitoring, table below. In future, ZA will be initiated and continued on a yearly basis. Dmab has replaced ZA in managing bone health in breast cancer patients. Many oncologists use this without the assistance of bone health endocrinologists, who are an integral part of our cancer center. Bone modifying agents are often discontinued without consideration of the negative impact this may have. As this is a major survivorship issue, we document this case with literature review, to raise awareness for oncologists prescribing these medications. Citation Format: Susan Tannenbaum, Alvaro Alvarez Soto, Pamela Taxel. Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients [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 PO1-12-02.

Abstract PO5-19-01: The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer

Abstract Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information. Pathological complete response (pCR) following neoSACT, particularly in patients with earlier clinical TNM stage at diagnosis, identifies a population with excellent survival outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to absolute clinical benefit. Aims >HER2-RADiCAL seeks to reduce the treatment burden and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less systemic therapy with minimal/no loss of efficacy. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort/threshold-crossing design study embedded within a real-world data-driven clinical pathway model. Patients with ER-positive or negative HER2+ EBC with cT1N1 or cT2N0-1 stage at diagnosis are eligible after completion of standard of care neoSACT and locally determined pCR (ypT0/Tis ypN0). Patients with pathological features consistent with previous malignant involvement in >4 nodes are not eligible. Adjuvant trastuzumab +/- pertuzumab may have continued prior to study entry provided no more than 9 cycles of trastuzumab are received. After registration all participants receive a total of 9 cycles of trastuzumab including those administered prior to study entry. Participants receive no further pertuzumab and no adjuvant chemotherapy. Adjuvant endocrine therapy and radiotherapy are given as per standard of care. Central pathology review of pCR status will be conducted in a subset of cases. A Study Within a Trial (SWAT) will explore identification of factors influencing patient decision-making for participation in studies of response-adapted treatment. Statistical methods The primary endpoint is relapse-free interval. Recruitment of 720 participants over 3.5 years will provide 90% power to exclude an event rate >6.5% at 3 years (expected event rate ≤4%). Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, overall survival, treatment pathway adherence and cost-effectiveness. An interventional cohort is preferred to a randomised non-inferiority trial based on the known event rate in this population which is sufficiently low such that any deviation from this expected event rate would indicate failure of the reduced therapy strategy. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway derived from anonymised data for all patients treated for HER2+ EBC within the UK NHS. Patient and public involvement Our PPI partners continue to shape this research, holding key roles as trial management group members, overseeing progress of the study, contributing to protocol amendment development, and design and implementation of the SWAT. Current status The first patient was enrolled in December 2021. At 10th July 2023, 25 research sites have opened with 39 participants recruited. Site opening continues with a minimum target of 40. Responding to continued use of anthracycline-based regimens in UK practice, eligibility criteria have recently been extended to permit entry of patients who have received anthracycline-containing neoSACT. For further information contact her2radical-icrctsu@icr.ac.uk. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Laura Moretti, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Cliona Kirwan, Ciara O'Brien, Duncan Wheatley, Jennifer Glendenning, Mairead MacKenzie, Hilary Stobart, Claire Snowdon, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer [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 PO5-19-01.