Bosutinib in Combination With the Aromatase Inhibitor Letrozole: A Phase II Trial in Postmenopausal Women Evaluating First‐Line Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor‐Positive/HER2‐Negative Breast Cancer

Background.

Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2− BC.

Methods.

Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy.

Results.

Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy’s law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2.

Conclusion.

The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.     

A Pilot Study of Estradiol Followed by Exemestane for Reversing Endocrine Resistance in Postmenopausal Women With Hormone Receptor‐Positive Metastatic Breast Cancer

Background.

Endocrine resistance is a frequent complication, and strategies to reverse it are a high research priority for metastatic breast cancer (MBC) that is hormone receptor positive. Preclinical data suggest re-exposure to estrogen induces tumor regression in tamoxifen-resistant tumors. We conducted a pilot study to determine whether short-term estradiol exposure would reverse endocrine resistance and resensitize tumors

Methods.

Postmenopausal women with estrogen receptor-positive MBC whose disease had progressed after receiving at least one prior endocrine therapy were eligible for the study. Patients were initially treated with 6 mg/day estradiol, and those who had not progressed after 3 months were then switched to exemestane.

Results.

Thirteen patients were evaluable for toxicity and response. No grade 3 or 4 toxicities were observed. Of the 13 patients who initiated estradiol therapy, 6 patients (46%) had not experienced disease progression at month 3 and were switched to exemestane. On exemestane, disease progression was documented in five patients, with one having stable disease as best response. Median progression-free survival for all patients was 4.8 months (range: 0.6–9.5 months).

Conclusion.

Treatment with an estrogen prior to resuming antiestrogen treatments was not effective at reversing hormone resistance; however, low-dose estradiol treatment had measurable clinical activity with minimal toxicity and should be considered as a therapeutic option for hormone-refractory MBC.     

Phase II Trial of Fulvestrant With Metronomic Capecitabine for Postmenopausal Women With Hormone Receptor-Positive,HER2-Negative Metastatic Breast Cancer

BackgroundIn this phase II study, we explored efficacy and toxicity of combined endocrine and low-dose metronomic chemotherapy therapy consisting of fulvestrant and capecitabine in estrogen and/or progesterone receptor-positive, HER2-negative MBC.Patients and MethodsPatients with ≤ 1 previous hormonal treatment in the metastatic setting received an injection fulvestrant loading dose 500 mg on day 1, 250 mg on days 15 and 29 followed by 250 mg every 28 days along with continuous oral capecitabine in divided doses. The total fixed daily dose of capecitabine was either 1500 mg or 2000 mg, depending on the patient’s weight (< 80 kg vs. ≥ 80 kg). Primary end points were PFS and TTP. Toxicity was assessed by continuous evaluations of treatment-emergent adverse events (AEs) and changes from baseline in laboratory values.ResultsForty-one women, with a mean age of 64.5 years, were enrolled. Patients completed a median of 11 monthly treatment cycles. Median PFS was 14.98 months (95% confidence interval [CI], 7.26-upper limit [UL] not estimated) and median TTP was 26.94 months (95% CI, 7.26-UL not estimated). Median overall survival was 28.65 months (95% CI, 23.95-UL not estimated). Treatment was well tolerated with < 10% Grade 3 palmar-plantar erythrodysesthesia. Overall, the most frequent AEs were palmar-plantar erythrodysesthesia, fatigue, and nausea.ConclusionFulvestrant with metronomic capecitabine demonstrates substantial activity in hormone receptor-positive MBC and is well tolerated. Combined chemoendocrine approaches should be further explored considering the low toxicity of the combination with meaningful TTP.     

First‐Line Treatment Patterns and Clinical Outcomes in Patients With HER2‐Positive and Hormone Receptor‐Positive Metastatic Breast Cancer From registHER

Background.

Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting.

Methods.

registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors.

Results.

HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89).

Conclusions.

These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.     

Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive,HER2-Negative Metastatic Breast Cancer

BackgroundInternational guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported.Materials and MethodsKARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2.ResultsData from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2.ConclusionThe ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.     

Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer

Background

Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2^? metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial.

Phase II Trial of Weekly Nanoparticle Albumin-Bound Paclitaxel With Carboplatin and Trastuzumab as First-line Therapy for Women With HER2-Overexpressing Metastatic Breast Cancer

PurposeThis multicenter phase II trial evaluated the efficacy and safety of weekly nanoparticle albumin-bound paclitaxel with carboplatin and weekly trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer (MBC).Patients and MethodsWe treated 32 patients who had measurable MBC that was HER2-positive defined by an immunohistochemical staining score of 3+ or gene amplification by fluorescence in situ hybridization, required for those with an IHC of 2+. Patients were treated with albumin-bound paclitaxel 100 mg/m² and carboplatin at area under the curve (AUC) = 2 on days 1, 8, and 15 of a 28-day cycle. Trastuzumab was administered at 2 mg/kg weekly after a loading dose of 4 mg/kg. Because of hypersensitivity reactions occurring during carboplatin infusion numbers 6–8 in 4 of the first 13 patients with this premedication-free regimen, the protocol was amended for carboplatin and dosed at AUC = 6 day 1 each 28-day cycle, in lieu of introducing steroid prophylaxis. Patients were treated with 6 cycles and allowed to continue with all 3 drugs or trastuzumab alone if free of progression and unacceptable toxicity after 6 cycles.ResultsThe overall response rate (ORR) was 62.5% (95% CI, 45.7%–79.3%) with 3 confirmed complete responders (CRs; 9%) and 17 confirmed partial responses (PRs; 53%). An additional 6 patients (19%) had stable disease (SD) for greater than 16 weeks for a clinical benefit rate (ORR + SD > 16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%).ConclusionWeekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent.     

Fulvestrant 500 mg Versus Exemestane in Postmenopausal Women With Metastatic Breast Cancer Resistant to Adjuvant Nonsteroidal Aromatase Inhibitors in Clinical Practice: A Multicenter Retrospective Study

BackgroundFulvestrant 500 mg and exemestane are widely used agents in first-line therapy for metastatic breast cancer (MBC) of estrogen receptor (ER)-positive (ER⁺) postmenopausal MBC after failure of adjuvant nonsteroidal aromatase inhibitor (NSAI) treatment. Although fulvestrant 250 mg had similar efficacy compared with exemestane (Evaluation of Faslodex versus Exemestane Clinical Trial study) and fulvestrant 500 mg was superior to fulvestrant 250 mg (Comparison of FASLODEX In Recurrent or Metastatic Breast Cancer study), no direct comparison between fulvestrant 500 mg and exemestane has been conducted. The aim of this study was to compare the efficacy and safety of fulvestrant 500 mg and exemestane in daily practice.Patients and MethodsWe retrospectively evaluated the medical records of all patients with ER⁺ HER2⁻ MBC who received fulvestrant 500 mg or exemestane 25 mg as first-line therapy for MBC from 2015 to 2017 in 4 institutions. A total of 120 patients were available for analysis. Both agents accounted for 50% (60) patients.ResultsThe median progression-free survival (PFS) of the fulvestrant group was significantly longer than that in the exemestane group (6.2 months [95% confidence interval (CI), 5.0-7.4] versus 4.8 months [95% CI, 3.0-6.7], P = .024). In subgroup analysis, for patients with visceral metastasis or primary endocrine resistance, no significant difference considering PFS was observed in the 2 groups (P = .563 and .769). No significant difference of Grade 3/4 adverse events was observed in the 2 groups (3 patients, 5% versus 2 patients, 3.3%; P = .648).ConclusionFulvestrant 500 mg showed better efficacy than exemestane in first-line therapy for MBC of ER⁺ postmenopausal women after failure of adjuvant NSAI treatment. For patients with visceral metastasis or primary endocrine resistance, both treatments showed poor outcomes, indicating a need for further alternatives (targeted therapy or chemotherapy). Both agents were well tolerated in terms of toxicities.     

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer

BackgroundThe purpose of this study was to investigate whether combining pembrolizumab with palliative radiation therapy (RT) improves outcomes in patients with hormone receptor-positive (HR⁺) metastatic breast cancer (MBC).Patients and MethodsEligible patients had HR⁺/human epidermal growth factor receptor 2-negative MBC; were candidates for RT to ≥ 1 bone, soft tissue, or lymph node lesion; and had ≥ 1 lesion outside the RT field. Patients received 200 mg pembrolizumab intravenously 2 to 7 days prior to RT and on day 1 of repeating 21-day cycles. RT was delivered to a previously unirradiated area in 5 treatments each of 4 Gy. The primary endpoint was objective response rate. The study used a 2-stage design: 8 women were enrolled into the first stage, and if at least 1 of 8 patients experienced an objective response, 19 more would be enrolled. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory endpoints included association of overall response rate with programmed death-ligand 1 status and tumor-infiltrating lymphocytes.ResultsEight patients were enrolled in stage 1. The median age was 59 years, and the median prior lines of chemotherapy for metastatic disease was 2. There were no objective responses, and the study was closed to further accrual. The median progression-free survival was 1.4 months (95% confidence interval, 0.4-2.1 months), and the median overall survival was 2.9 months (95% confidence interval, 0.9-3.6 months). All-cause adverse events occurred in 87.5% of patients, including just 1 grade 3 event (elevation of aspartate aminotransferase).ConclusionsRT combined with pembrolizumab did not produce an objective response in patients with heavily pre-treated HR⁺ MBC. Future studies should consider alternative radiation dosing and fractionation in patients with less heavily pre-treated HR⁺ MBC.     

Real-World Outcomes of Everolimus and Exemestane for the Treatment of Metastatic Hormone Receptor-Positive Breast Cancer in Patients Previously Treated With CDK4/6 Inhibitors

PurposeEverolimus with exemestane (EVE+EXE) was FDA-approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) based on BOLERO-2. However, none of those patients received prior CDK4/6 inhibitors. The purpose of this study is to evaluate the efficacy of EVE+EXE in mHRBC after CDK4/6 inhibitors.MethodsA retrospective review of patients ≥18 years old with mHRBC treated with EVE+EXE, for ≥30 days, at our institution from January 1, 2012, to April 1, 2020 was conducted. Primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival and safety.Results192 patients were included in the study (n = 79, prior CDK4/6 inhibitor use; n = 113, no prior CDK4/6 inhibitor use). Baseline patient characteristics were similar between groups. Greater number of prior therapies before EVE+EXE use increased risk of disease progression (P = .017). Patients with prior CDK4/6 inhibitor use had a lower median PFS of 3.8 months (95% CI: 3.4-4.7) vs. 5.4 months (95% CI: 3.9-6.2) for patients without prior CDK4/6 inhibitor use, with a HR for progression of 1.46 (95% CI: 1.08 to 1.97, P = .013). Overall survival between groups was not significantly different.ConclusionPatients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not, without differences in overall survival. Although PFS is expected to decrease with subsequent lines of therapy, it is reasonable to use EVE+EXE after CDK4/6 inhibitors in selected patients, recognizing that additional benefit is modest.     

Triple‐Negative Breast Cancers: Associations Between Imaging and Pathological Findings for Triple‐Negative Tumors Compared With Hormone Receptor‐Positive/Human Epidermal Growth Factor Receptor‐2‐Negative Breast Cancers

Purpose.

Triple-negative (TN) breast cancers have high malignancy potential and are often characterized by early systemic relapse. Early detection is vital, but there are few comprehensive imaging reports. Here we describe mammography, ultrasound, and magnetic resonance imaging (MRI) findings of TN breast cancers, investigate the specific features of this subtype, and compare the characteristics of TN breast cancers with those of hormone receptor (HR)-positive/human epidermal growth factor receptor (HER)-2-negative breast cancers.

Materials and Methods.

From July 2009 to June 2011, mammography and ultrasound findings of 210 patients with pathologically confirmed TN (n = 105) and HR-positive/HER-2-negative breast cancers (n = 105) were retrospectively reviewed from our institutional database. Ultrasound vascularity was notified in 88 cases and elasticity scores were notified in 49 cases overall. Thirty-five patients underwent MRI (22 TN and 13 HR-positive/HER-2-negative). Mammograms, ultrasound, and MRI were reviewed according to the Breast Imaging-Reporting and Data System (BI-RADS) lexicon and classification.

Results.

TN breast cancers were more likely to show round, oval, or lobulated masses with indistinct margins on mammography than HR-positive/HER-2-negative breast cancers. On ultrasound, TN tumors were more likely than HR-positive/HER-2-negative breast cancers to show circumscribed or microlobulated margins and no posterior acoustic features or posterior enhancement-positive. On MRI, TN cancers exhibited suspicious aspects more often than HR-positive/HER-2-negative cancers, often with rim enhancement-positiveHER-2 (84.6% of masses were classified BI-RADS 5).

Conclusion.

This study is the first to describe findings on mammography, ultrasound, and MRI for TN breast cancers with a matched HR-positive/HER-2-negative control group. Several distinctive morphological features of these aggressive tumors are identified that can be used for earlier diagnosis and treatment, and ultimately to improve outcomes.     

A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

BackgroundTherapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR⁺) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR⁺/HER2⁻ MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR⁺/HER2⁻ MBC.Patients and MethodsPatients with HR⁺ MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%).ResultsForty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures.ConclusionAfter progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR⁺/HER2⁻ MBC.     

Lapatinib plus Letrozole as First‐Line Therapy for HER‐2+ Hormone Receptor–Positive Metastatic Breast Cancer

Objective.

To evaluate the efficacy and tolerability of letrozole plus lapatinib versus letrozole plus placebo in women with hormone receptor (HR)⁺ human epidermal growth factor receptor (HER)-2⁺ tumors receiving first-line therapy for metastatic breast cancer (MBC).

Patients and Methods.

Postmenopausal women (n = 1,286) with HR⁺ MBC were randomized to daily oral treatment with letrozole (2.5 mg) plus lapatinib (1,500 mg) versus letrozole (2.5 mg) plus placebo. Of the 1,286 patients enrolled in the phase III study, 219 had HER-2⁺ tumors. The primary endpoint was progression-free survival (PFS) in HER-2⁺ patients.

Results.

Results in the HR⁺ HER-2⁺ population (n = 219) are presented. The addition of lapatinib to letrozole resulted in a significantly lower risk for disease progression than with letrozole alone (hazard ratio, 0.71; 95% confidence interval, 0.53–0.96). The PFS time was 8.2 months, versus 3.0 months. The objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) were also significantly greater in lapatinib-treated women. The most common adverse events in the lapatinib group were diarrhea (68%) and rash (46%), primarily grade 1 and 2.

Conclusions.

The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2.