Receptor-positive HER2-negative Advanced Breast Cancer Research Articles

Current Management and Future Perspectives of Hormone Receptor–Positive HER2-Negative Advanced Breast Cancer

ObjectivesAn overview of the best therapeutic approaches for the management of hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer is provided, and emerging treatment advances are discussed. Key nursing considerations and the role of the nurse in the provision of optimal care are explored. Data SourcesData sources include peer-reviewed articles sourced in electronic databases. ConclusionWith a multitude of current and emerging treatments for the management of hormone receptor–positive, HER2-negative advanced breast cancer, patients with this subtype have improved overall survival. It is essential that specialist nurses holistically support patients; this will ensure treatment adherence, leading to enhanced longevity and quality of life. Implications for Nursing PracticeNurses play an important role in patient education and the early identification and management of treatment toxicities. Nurses also need to monitor and facilitate adherence by identifying barriers and implementing strategies to overcome them, ultimately improving patient outcomes.

Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program.

SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA-mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life datda of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8-52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95% CI = 1.1-2.1), >5 lines of prior treatments (HR = 1.4, 95% CI = 1.0-2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3-13.6). N = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. A multicenter, retrospective-prospective Italian study. We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

227P Peripheral blood lymphocyte counts predict clinical outcomes in patients with hormone receptor-positive HER2-negative advanced breast cancer treated with CDK4/6 inhibitors

The prognostic impact of Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i)-induced modulation of several peripheral blood cell counts (PBC) in patients (pts) with Hormone Receptor-positive (HR+), Human Epidermal growth factor Receptor 2-negative (HER2-) advanced breast cancer (aBC) has never been explored so far.

Treatment sequence for hormone receptor-positive HER2-negative advanced breast cancer: Results of a retrospective analysis of Russian patients diagnosed with aBC in 2014-2021.

e13032 Background: CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have dramatically changed therapeutic landscape of hormone receptor-positive HER2-negative advanced breast cancer (HR+ HER2- aBC). There are three iCDK4/6 in Russia, which are available and included into the clinical guidelines as a preferred first line treatment option beginning since 2018. The aim of this study was to assess evolution of treatment approaches to HR+ HER2- aBC and identify demographic and disease characteristics in correlation with available groups of therapy (chemotherapy, endocrine therapy ±mTOR inhibitors/ CDK4/6i). Methods: Аdult patients diagnosed with de novo or recurrent HR+ HER2- aBC in 2014-2021 identified in outpatient departments of Moscow state oncology hospitals were included into our non-interventional, descriptive, retrospective cohort study. Primary objective of this real-world study was to describe the rate of CDK4/6i usage in the first line setting. As a secondary objective, we describe patient and disease characteristics in iCDK4/6 group, as well as in the endocrine monotherapy and chemotherapy groups. Results: From the cohort of 1000 patients (full-set analysis population) 874 cases were selected, who received treatment since 2018. 45.9% (95% CI 42.6, 49.2) patients were treated with CDK4/6i in combination with endocrine therapy in the first-line setting. From them in the subgroups of patients with or without visceral metastases 50.5% (95% CI 45.5, 55.5) and 42.1% (95% CI 37.7, 46.5) were treated with CDK4/6i in the first line setting, respectively. Among 874 cases 78.0% (95% CI 75.3, 80.7) patients received endocrine therapy ± targeted therapy; in the subgroups of patients with or without visceral metastases 69.5% (95% CI 64.9, 74.1) and 84.9% (95% CI 81.7, 88.1) were treated with endocrine therapy ± targeted therapy in the first line setting, respectively. Conclusions: Endocrine therapy is a predominant therapeutic option in the first line setting for HR+ HER2- aBC. Clinical trial information: NCT04852081. [Table: see text]

Management of patients with hormone receptor-positive HER2-negative metastatic breast cancer: data of randomized trials and real-world evidence.

The Satellite Symposium of Novartis Pharma was held on January 28th,2022, within the framework of the RUSSCO Big Conference "Breast Cancer". It was dedicated to the diagnostics and treatment of patients with hormone receptor-positive HER2-negative advanced breast cancer (HR+/HER2- aBC). The information concerning two new observational studies was showed during the symposium: the retrospective analysis of the sequence of BC patients treatment in Moscow and the PROSPERITY study. The preliminary results of the data analysis concerning Moscow patients with breast cancer indicated the widespread practice of using endocrine therapy as an early-line treatment for HR+/HER2- aBC. Special attention was paid to new data concerning the use of Piqray (alpelisib) for the treatment of HR+/HER2- aBC with a PIK3CA mutation. The review of new results obtained in clinical trials and in clinical practice of the Loginov Moscow Clinical Research Center (Moscow) was made. The obtained data results indicate that alpelisib in combination with fulvestrant is effective after disease progression on CDK4/6 inhibitors, regardless of the duration of prior CDK4/6i therapy, as well as in patients who previously received fulvestrant. The duration of alpelisib treatment can be prolonged due to the competent approach to prevent and to control the adverse events.

Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial

PurposePI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC).MethodsCohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).ResultsOverall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%).ConclusionAdding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects.Trial registration NCT03337724.

The Effects of HER2 on CDK4/6 Activity in Breast Cancer

BackgroundCDK4/6 inhibitors have been used to treat hormone receptor-positive HER2-negative advanced breast cancer. Their benefit in HER2-positive breast cancer has not been determined yet. In this study, we investigated the effects of HER2 on CDK4/6 activity by assessing the level of downstream phosphorylated retinoblastoma protein (pRb) in HER2-positive breast cancer (HER2 positivity is defined by immunohistochemical study or FISH, regardless of ER status) to determine if these cases may be responsive to CDK4/6 inhibitors. Materials and MethodsOne hundred and thirty cases of breast biopsies with invasive carcinoma were collected, including 77 cases of HER2+ (39 cases of ER +PR±HER2+ and 38 cases of ER-PR-HER2+) and 53 cases of HER2- (ER-PR-HER2-) breast cancer. Immunohistochemical study of pRb was performed and the pRb level was assessed by H-score (intensity x percentage of positive cells). ResultsThe pRb H-score ranges from 3 to 270. The average H-scores for the ER-PR-HER2+, ER+PR±HER2+ and ER-PR-HER2- groups are 115.8 ± 75.8, 93.1 ± 68.6 and 63.1 ± 65.6, respectively. By comparison, HER2+ cases have significantly higher pRb levels than HER2- cases (P = .001). Among HER2+ cases, there was a trend of positive correlation between the HER2 gene copy number, and the pRb level although not statistically significant (r = 0.192, 95% CI, [-0.033, 0.399], P = .09). ConclusionIn breast cancer, HER2 positivity leads to significantly higher levels of CDK4/6 activity as reflexed by pRb. Breast cancer that is positive for HER2 may respond to CDK4/6 inhibitors and pRb may potentially be used as a biomarker to predict the responsiveness.

The efficacy and safety of palbociclib combined with endocrine therapy in patients with hormone receptor-positive HER2-negative advanced breast cancer: a multi-center retrospective analysis.

To explore the efficacy and safety of palbociclib combined with endocrine therapy (ET) in advanced breast cancer (ABC). We conducted a retrospective study involving patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) ABC who received palbociclib combined with ET in the first- to third-line at three centers in China between January 2018 and October 2020. A total of 151 patients were included in this study. The median age of the patients at palbociclib initiation was 56 years (range 30–86 years) with a median follow-up of 10.9 months (range 2.0–41.2 months). Among these patients, 88 patients received palbociclib combined with ET as first-line therapy, and achieved a median progression-free survival (mPFS) of 19.8 months and an objective response rate (ORR) of 40.9%, meanwhile, in the first-line setting, 62 patients received palbociclib at an initial dose of 125 mg, achieving a mPFS of 20.9 months and an ORR of 46.8%. There were 39 and 24 patients who received palbociclib combined with ET as second- and third-line therapy, the mPFS were 10.0 months and 6.1 months, respectively. The most common and serious adverse events (AEs) were leukopenia and neutropenia. A total of 64 patients (42.4%) underwent palbociclib dose reduction due to AEs. Palbociclib combined with ET is an effective therapeutic regimen for HR+/HER2− ABC, particularly in the first-line setting with palbociclib initial dose of 125 mg, and AEs were manageable.

The frequency and spectrum of PIK3CA mutations in patients with estrogen receptor-positive HER2-negative advanced breast cancer residing in various regions of Russia

Relevance. PIK3CA belongs to the top three most frequently mutated genes in breast cancer (BC), especially in estrogen receptor (ER) positive, HER2 negative BC subtype. With an approval of selective PI3K-alpha inhibitor, alpelisib, this alteration has become actionable in ER+HER2- tumors. The frequency and spectrum of PIK3CA alterations in various cohorts is affected by a number of factors, including the distribution of BC expression subtypes, histological types, patient age, and even ethnicity.&#x0D; Aim. Aim of the current study was to characterize the frequency and spectrum of PIK3CA alterations in Russian BC patients.&#x0D; Materials and methods. The analysis of PIK3CA exon 7, 9 and 20 mutations was performed in a cohort of Russian ER+HER2- BC patients by a combination of high-resolution melting analysis, allele-specific PCR, and digital droplet PCR.&#x0D; Results. PIK3CA lesions were identified in 62/206 (30%) patients. Noteworthy, 59/62 (95%) of the identified variants were represented by the three most common p.E542K, p.E545K, and p.H1047R substitutions. The analysis of clinical and morphological characteristics revealed the trends towards association of PIK3CA mutations with older age and more frequent metastatic lung involvement.&#x0D; Conclusion. The obtained data on the frequency and spectrum of PIK3CA somatic aberrations can be helpful when organizing molecular genetic testing of breast cancer patients and using PI3K inhibitors in Russian population.

Efficacy of Palbociclib and Endocrine Treatment in Heavily Pretreated Hormone Receptor-positive Her2-negative Advanced Breast Cancer: Retrospective Multicenter Trial

Efficacy of Palbociclib and Endocrine Treatment in Heavily Pretreated Hormone Receptor-positive Her2-negative Advanced Breast Cancer: Retrospective Multicenter Trial

Abstract P6-18-23: Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: The UK compassionate access program experience

Abstract Background Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Program (CAP) previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the CAP across ten institutions in the United Kingdom. Methods We retrospectively identified HR-positive HER2-negative ABC patients on the Palbociclib CAP between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, chi-squared method and Cox regression were used as appropriate. Results 118 patients identified had median age of 59 (32-82). 97 (82.20%) were postmenopausal and 109 (92.37%) had ECOG Performance Status 0-1. 96 (81.36%) had visceral involvement, 19 (16.10%) bony only and 15 (12.71%) visceral only disease. Patients received a median 5 (range 3-11) prior lines of treatment and 3 (range 0-8) prior chemotherapy lines. 105 patients (89.74%) developed neutropenia (grade ≥3 in 59 [56.19%]). 6 experienced febrile neutropenia (5.13%). 57 (48.72%) had a dose reduction, down to 100mg in 48 (41.03%) and 75mg in 9 (7.69%) due to hematologic toxicity in 46 (80.70%). Dose delays were in median 7 days long (range: 0-56). Palbociclib was discontinued due to disease progression in 97 (82.91%) and to toxicity in 5 (4.27%). Grade 3 neutropenia occurred in 45 patients (67.16%) who received ≥3 and in 22 (32.84%) who received &amp;lt;3 prior chemotherapies (p 0.351). Palbociclib produced clinical benefit rate (CBR) of 47.52% and overall response rate of 15.84% in 101 patients assessed. CBR was 45.45% with previous endocrine treatment (ET) progression-free survival (PFS) &amp;lt;6 months versus 49.12% if PFS ≥6 months (p 0.714). Overall, median PFS was 4.5 months (95% CI 3.7-5.9). The PFS seen in different subgroups showed no impact in relation to the number of lines of prior chemotherapy (&amp;lt;3 lines: 5.9 months [95% CI 3.7-11.0]; ≥3 lines: 4.3 months [95% CI 3.3-5.5], p 0.159), but was numerically greater in those who had previous benefit from ET (PFS ≥6 months: 5.9 months [95% CI 4.4-8.0]; &amp;lt;6 months: 3.7 months [95% CI 2.8-4.5], p. 0.055) or in those with bone only disease (bone only: 11.0 months [95% CI 2.3-not reached]; other sites involved: 4.4 months [95% CI 3.6-5.5], p 0.024). Median OS was 15.8 months (95% CI 13.3-18.7) for the whole cohort and it was greater in patients who derived longer PFS from prior ET (≥6 months: 18.1 months [95% CI 13.0-NR]; &amp;lt;6 months: 14.4 months [95% CI 7.7-18.3], p. 0.052). Conclusions To date, this is the most extensive analysis of Palbociclib outcomes in ≥4th-line setting. In this heavily pretreated population clinical benefit was confirmed particularly for endocrine-sensitive disease and predominantly involving the bones and in earlier lines of treatment. Grade ≥3 neutropenia rates were similar to PALOMA trials, but the higher incidence of febrile neutropenia need to be carefully considered. Citation Format: Battisti NML, Kingston B, King J, Denton A, Waters S, Sita-Lumsden A, Rehman F, Stavraka C, Kristeleit H, Sawyer E, Houghton D, Davidson N, Howell S, Choy J, Harper P, Roylance R, Fharat R, Mohammed K, Ring A, Johnston S. Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: The UK compassionate access program experience [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 P6-18-23.

Palbociclib and endocrine therapy in heavily pretreated hormone receptor-positive HER2-negative advanced breast cancer: the UK Compassionate Access Programme experience.

Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Programme previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the Programme across ten institutions in the United Kingdom. We retrospectively identified HR-positive HER2-negative ABC patients on the Programme between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, χ2 method and Cox regression were used. 118 patients identified had a median age of 59. 82.2% were postmenopausal and 92.4% performance status 0-1. 81.4% had visceral involvement and 6.8% bone-only disease after a median of 5 prior treatments and 3 prior chemotherapies. Clinical benefit rate was 47.5%, overall response rate 15.8%, median PFS 4.5 months and median OS 15.8 months. Longer progression-free survival on prior endocrine therapy was a predictor of longer PFS and OS. 89.7% developed neutropenia (grade ≥ 3 in 56.8%). 5.1% experienced febrile neutropenia. 48.3% had dose reductions and 3.4% discontinued Palbociclib following toxicity. No statistically significant difference in grade ≥ 3 neutropenia was observed according to metastatic sites nor previous treatments. This is the most extensive analysis of palbociclib in ≥ 4th-line setting. Clinical benefit was confirmed particularly for endocrine-sensitive, predominantly bony disease and in earlier lines of treatment. Safety was similar to PALOMA trials with higher febrile neutropenia rate.

Toxicity and efficacy of Palbociclib with endocrine therapy of physician’s choice in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: A single centre experience.

e13039Background: Palbociclib is approved in the UK in first line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Program (CAP) allowed patient...

Abstract P4-22-09: A phase 2 open label study of everolimus in combination with endocrine therapy in resistant hormone receptor-positive HER2-negative advanced breast cancer

Abstract Background: Therapies targeting estrogen receptor (ER) signaling are standard for patients (pts) with hormone receptor positive (HR+) (ER and/or progesterone receptor [PR] positive) metastatic breast cancer (MBC). Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been associated with endocrine therapy (ET) resistance. BOLERO-2 demonstrated that the addition of the mTOR inhibitor, everolimus (EVE), to exemestane doubled the PFS in HR+ HER2- MBC pts who previously progressed on nonsteroidal aromatase inhibitor therapy.The premise of this phase 2 trial in HR+ MBC is that the addition of EVE to the last ET on which the disease progressed may restore sensitivity to ET and extend the benefit of the anti-estrogen therapy. Methods: Pts ≥18 yrs with HR+, HER2- unresectable, locally recurrent, or MBC refractory to ET in either the adjuvant or advanced/metastatic setting. 0-1 chemotherapy (chemo) regimens for MBC were permitted. Post-/ pre-/peri-menopausal women were eligible with ovarian function suppression permitted. Additional eligibility requirements include: no prior mTOR inhibitor therapy, measurable or evaluable disease, ECOG ≤2, adequate bone marrow and organ function. EVE (10 mg PO daily) was administered on a 4-wk cycle in combination with the same dose and schedule of the last ET to which their disease became resistant. Disease assessments were performed every 2 cycles and treatment continued until disease progression or unacceptable toxicity. Blood samples and archival tumor were collected respectively for the VeriStrat Assay and for the Foundation One molecular profiling platform. Results: 48 pts were enrolled; data from 26 pts is presented. Median age 63.5 yrs (range, 36-81) with 46% ≥ 65 yrs. 14 (54%) pts had received chemo in the adjuvant setting, 9 pts (35%) received chemo for MBC, and 4 pts (15%) received chemo in both settings. All pts had at least 1 prior hormonal therapy; 9 pts received ≥ 3 hormonal agents. EVE was combined with tamoxifen (27%), AIs (61%), and fulvestrant (12%). Median time on treatment was 18.6 wks (range 1-48.9 weeks). 5 pts (19%) remain on treatment and 21 (81%) have discontinued therapy due to: disease progression - 17, toxicity -2, and other causes - 2. 23 pts were evaluable for response. 1 pt on fulvestrant plus EVE had a PR and 18 pts (78%) had SD as best response, with SD &amp;gt; 6 mos in 7 pts, for a clinical benefit rate (CR+PR+ SD ≥ 6 months) of 35%. With a median follow up of 11 mos (range 2-16 mos), the median PFS was 6.6 months (range 3.6-9.4); the median OS has not been reached. Treatment-related adverse events consisted mostly of stomatitis, rash and fatigue with few G3 events: stomatitis 3 pts, rash 2 pts, and 1 each of fatigue, edema, and neutropenia. G1 pneumonitis was present in 2 pts. There were no G4 events or treatment related deaths. Conclusions: In HR+ HER2- advanced/MBC patients who progressed on prior ET, the addition of EVE to the ET to which their disease became resistant, resulted in 1 PR and 7 pts with SD &amp;gt; 6 mos. The results of the full study population will be presented. Modulation of the mTOR/AKT/PI3K pathway with EVE may extend the benefit of ET, even after tumor progression on ET alone. Citation Format: Yardley DA, Blakely L, Hemphill B, Joseph M, Liggett W, Daniel B, Castrellon A, Shastry M, Finney L, DeBusk L, Hainsworth JD, Burris III HA. A phase 2 open label study of everolimus in combination with endocrine therapy in resistant hormone receptor-positive HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-09.

Abstract OT2-1-08: A phase II open label study of everolimus in combination with anti-estrogen therapy in hormone receptor-positive HER2-negative advanced breast cancer

Abstract Background: Hormone receptor positive (HR+) breast cancer, defined as estrogen receptor and/or progesterone receptor positive, accounts for 70% of invasive breast cancers. While most HR+ tumors initially respond to anti-estrogen therapy, resistance, linked to crosstalk between cell signaling and signal transduction pathways, subsequently develops in almost 100%. Preclinical data has shown that the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway is activated in long-term estrogen-deprived and aromatase inhibitor-resistant breast cancer cells. It is hypothesized that in this group of endocrine-resistant patients (pts), resistance to anti-estrogen therapy is driven by the PI3K/Akt/mTOR pathway and hence the inhibition of this pathway may reverse resistance. This study will evaluate the efficacy of adding everolimus (an inhibitor of mTOR) to anti-estrogen therapy in pts with HR+ metastatic breast cancer (MBC) who have progressed on anti-estrogen therapy. Study Objectives: This multi-center, open-label Phase II trial is designed to determine the efficacy (primary endpoint is PFS), safety and tolerability of everolimus in combination with anti-estrogen therapy in pts with HR+, HER2-negative MBC with disease progression on prior anti-estrogen therapy. An exploratory objective of this study is to evaluate the prognostic value of the VeriStrat assay in this population. VeriStrat testing has been used to predict treatment efficacy in clinical trials of non small cell lung cancer, head and neck squamous carcinoma, and MBC. Eligibility: Pts ≥18 years with HR+, HER2-negative breast cancer that is either unresectable, locally recurrent, or metastatic are eligible. Pts must have progressed on anti-estrogen therapy (recurrence while on/within 12 months of treatment for early stage breast cancer, or progressed while on/within 1 month of treatment for advanced/MBC), but anti-estrogen therapy is not required to be the last therapy prior to enrollment. No washout for anti-estrogen therapy is required, and ≤1 previous chemotherapy regimen is allowed. Post menopausal or pre-/ peri-menopausal women on tamoxifen are eligible and ovarian function suppression is permitted. Prior treatment with a mTOR inhibitor is not allowed. Additional eligibility requirements include: measurable or evaluable disease, ECOG ≤2, adequate bone marrow and organ function and an adequate lipid profile (fasting serum cholesterol ≤300 mg/dL or ≤7.75 mmol/L and fasting triglyceride ≤2.5 x ULN). Trial Design: Everolimus will be administered at a dose of 10 mg PO daily in combination with the FDA prescribed doses of the most recent anti-estrogen therapy on which the pt progressed. Treatment cycles will be 4 weeks, with response evaluations by CT scans every 2 cycles. Pts will be treated until disease progression or unacceptable toxicity occurs. With an alpha=0.5, a sample size of 42 will provide 80% power to detect improvement in median PFS. Blood samples for the VeriStrat assay will be collected at baseline, on Cycle 3 Day 1, at disease progression and at the first follow-up visit post disease progression. Archival tumor tissue samples will be collected for comprehensive genomic profiling. This trial has a total accrual goal of 46 pts. Citation Format: Denise A Yardley, Mythili Shastry, Laura M DeBusk, Howard A Burris III, John D Hainsworth. A phase II open label study of everolimus in combination with anti-estrogen therapy in hormone receptor-positive HER2-negative advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-08.

Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: observations from a phase III clinical trial

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of advanced renal cell carcinoma, pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma associated with tuberous sclerosis complex, renal angiomyolipoma and tuberous sclerosis complex, and, in combination with exemestane, for hormone receptor-positive HER2-negative advanced breast cancer after failure of treatment with letrozole or anastrozole. Results from the phase III BOLERO-2 trial demonstrated that everolimus in combination with exemestane provided significant clinical benefit to patients with advanced hormone receptor-positive breast cancer. Although everolimus is generally well tolerated, as with most therapies administered in an advanced cancer setting, drug-related adverse events (AEs) inevitably occur. Most common AEs observed in the everolimus studies include stomatitis, rash, infection, noninfectious pneumonitis, and hyperglycemia. Clinical awareness and early identification of such AEs by oncology nurses are essential to dosing (interruptions, reduction, and treatment discontinuation); quality of life; and, ultimately, patient outcomes. Because everolimus has already been shown to significantly improve clinical efficacy in patients with advanced breast cancer, a proactive approach to the practical management of AEs associated with this mTOR inhibitor as well as other most common AEs observed in this patient population has been reviewed and outlined here.

Endocrine Therapy for Postmenopausal Women with Hormone Receptor–Positive her2–Negative Advanced Breast Cancer after Progression or Recurrence on Nonsteroidal Aromatase Inhibitor Therapy: A Canadian Consensus Statement

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.