Phase I study of liposomal irinotecan in patients with metastatic breast cancer: findings from the expansion phase.

PURPOSE: Metastatic breast cancer (mBC) remains incurable and is associated with low survival rates. This study assessed the efficacy and safety of liposomal irinotecan in heavily pretreated patients with mBC, with or without active brain metastases (BM). METHODS: Following the dose escalation phase and determination of recommended phase 2 dose, the expansion phase of this phase I, open-label, non-randomized study, assigned adult women to cohorts based on mBC subtype: cohort 1, hormone receptor +/human epidermal growth factor receptor 2-; cohort 2, triple-negative breast cancer; or cohort 3, any mBC subtype with active BM. Patients received liposomal irinotecan 50 or 70 mg/m2 free base every 2 weeks. Here, we report secondary outcomes including best overall response (BOR), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). RESULTS: For non-central nervous system (non-CNS) disease across all cohorts (intent-to-treat population, N = 29), the ORR was 34.5% (95% confidence interval: 17.94-54.33), with a BOR of partial response in 10 patients (34.5%), stable disease in five (17.2%), progressive disease in 10 (34.5%); four patients were unevaluable (13.8%). The ORR for the CNS cohort was 30.0% (95% confidence interval: 6.67-65.25) using modified Response Evaluation Criteria in Solid Tumors. Common grade 3 or higher TEAEs were diarrhea (27.6%), nausea (17.2%), fatigue (13.8%), asthenia (10.3%), and hypokalemia (10.3%). Serious treatment-related TEAEs were reported in six patients (20.7%). No treatment-related TEAEs resulted in death. CONCLUSIONS: Liposomal irinotecan monotherapy demonstrated antitumor activity in heavily pretreated patients with mBC, with or without BM. The observed safety profile was consistent with that in previous studies. CLINICAL TRIAL REGISTRATION: Trial registration ID NCT01770353.

Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review.

PURPOSE: Triple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. Although there have been advances in the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancers, targeted therapies for TNBC remain unavailable. In this narrative review, we summarize recent discoveries related to the underlying biology of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway in TNBC, examine clinical progress to date, and suggest rational future approaches for investigational therapies in TNBC. RESULTS: As with other subtypes of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are common in TNBC. Preclinical data support the notion that these aberrations predict TNBC inhibition by targeted agents. In a recently published phase 2 clinical trial, an AKT inhibitor (ipatasertib) improved outcomes in a subset of patients with metastatic TNBC when combined with paclitaxel in the first-line setting. In addition, new compounds with distinct specificity and potency targeting different PI3K/AKT/mTOR components and cognate molecules (e.g., mitogen-activated protein kinase) are being developed. These agents present a wide range of toxicity profiles and early efficacy signals, which must be considered prior to the advancement of new agents in later-phase clinical trials. CONCLUSIONS: The development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways.

A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale.

Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

Treatment of the Pregnant Patient with Breast Cancer.

Pregnancy-associated breast cancer is defined as invasive breast cancer diagnosed during gestation, within 1 year postpartum, or during lactation. Of particular interest is the treatment of invasive breast cancer during gestation; standard treatment protocols must take into account the health of the fetus. This article reviews the literature and emerging data regarding the treatment of pregnancy-associated breast cancer. Existing staging and treatment practices need slight modification in the setting of pregnancy. The timing of surgery and the administration of cytotoxic chemotherapy must take into account age of gestation, but these modalities are safe in pregnancy.

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

INTRODUCTION: Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. METHODS: Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. RESULTS: A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. CONCLUSIONS: Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov; identifier: NCT00963547.

Early-Stage Triple-Negative Breast Cancer Journey: Beginning, End, and Everything in Between.

Triple-negative breast cancer (TNBC) is a very heterogeneous and aggressive breast cancer subtype with a high risk of mortality, even if diagnosed early. The mainstay of early-stage breast cancer includes systemic chemotherapy and surgery, with or without radiation therapy. More recently, immunotherapy is approved to treat TNBC, but managing immune-rated adverse events while balancing efficacy is a challenge. The purpose of this review is to highlight the current treatment recommendations for early-stage TNBC and the management of immunotherapy toxicities.

Pretherapy Ferumoxytol-enhanced MRI to Predict Response to Liposomal Irinotecan in Metastatic Breast Cancer.

Purpose To investigate ferumoxytol (FMX)-enhanced MRI as a pretreatment predictor of response to liposomal irinotecan (nal-IRI) for thoracoabdominal and brain metastases in women with metastatic breast cancer (mBC). Materials and Methods In this phase 1 expansion trial (ClinicalTrials.gov identifier, NCT01770353; 27 participants), 49 thoracoabdominal (19 participants; mean age, 48 years ± 11 [SD]) and 19 brain (seven participants; mean age, 54 years ± 8) metastases were analyzed on MR images acquired before, 1-4 hours after, and 16-24 hours after FMX administration. In thoracoabdominal metastases, tumor transverse relaxation rate (R*2) was normalized to the mean R*2 in the spleen (rR*2), and the tumor histogram metric rR*2,N, representing the average of rR*2 in voxels above the nth percentile, was computed. In brain metastases, a novel compartmentation index was derived by applying the MRI signal equation to phantom-calibrated coregistered FMX-enhanced MRI brain scans acquired before, 1-4 hours after, and 16-24 hours after FMX administration. The fraction of voxels with an FMX compartmentation index greater than 1 was computed over the whole tumor (FCIGT1) and from voxels above the 90th percentile R*2 (FCIGT1 R*2,90). Results rR*2,90 computed from pretherapy MRI performed 16-24 hours after FMX administration, without reference to calibration phantoms, predicted response to nal-IRI in thoracoabdominal metastases (accuracy, 74%). rR*2,90 performance was robust to the inclusion of some peritumoral tissue within the tumor region of interest. FCIGT1 R*2,90 provided 79% accuracy on cross-validation in prediction of response in brain metastases. Conclusion This first in-human study focused on mBC suggests that FMX-enhanced MRI biologic markers can be useful for pretherapy prediction of response to nal-IRI in patients with mBC. Keywords: MRI Contrast Agent, MRI, Breast, Head/Neck, Tumor Response, Experimental Investigations, Brain/Brain Stem Clinical trial registration no. NCT01770353 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Daldrup-Link in this issue.

Fertility and reproductive considerations in premenopausal patients with breast cancer.

BACKGROUND: Approximately 10% of all new breast cancer diagnoses occur in young women. Although lacking medical comorbidities, these patients often have unique issues with regard to their reproductive health that merit special consideration. As breast cancer outcomes continue to improve, quality of life for patients and their families after breast cancer treatment has come to the forefront of cancer research, particularly in the growing field of oncofertility. METHODS: This article reviews the literature on the singular situations and controversies faced by premenopausal breast cancer patients. RESULTS: Data on amenorrhea and the effects of modern chemotherapeutic agents on amenorrhea are limited, although the role of tamoxifen in amenorrhea is more clearly defined as increasing the rate of amenorrhea across several studies. At the forefront of studies on fertility and premenopausal breast cancer patients are investigations on fertility preservation via ovarian protection and on assisted reproductive technologies. The use of gonadotropin-releasing hormone analogs for ovarian protection remains controversial and continues to be investigated. CONCLUSIONS: Early integration of assessment and counseling regarding fertility preservation is part of the multidisciplinary approach in the care of the premenopausal breast cancer patient and is key to optimizing both cancer treatment and fertility plans for the future. Because of the many ongoing biological, practical, and ethical controversies surrounding oncofertility, eligible patients should be strongly encouraged to participate in clinical trials and studies to further increase our knowledge in this growing field.

Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data.

Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2 negative) breast cancer accounts for over 70% of all breast cancers. There has been much advancement in the treatment of HR+/HER2 negative metastatic breast cancer (MBC), in particular the development of more tailored and targeted therapies. Recently, greater understanding of the role of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway in breast cancer has led to the development of PI3K inhibitors, which have proven to be effective in the treatment of HR+/HER2 negative MBC. In this review, we will discuss the role of the PI3K/AKT/mTOR pathway in breast cancer and therapies that have been developed to inhibit PI3K. We will discuss in detail the development of PI3K inhibitor alpelisib, indications for use in HR+/HER2 negative MBC, safety and tolerability and the future direction of this therapy in the treatment of breast cancer.

A randomized placebo-controlled trial of bupropion for Cancer-related fatigue: Study design and procedures.

BACKGROUND: Cancer-related fatigue is a significant problem and is associated with poor quality of life. Behavioral interventions include exercise and cognitive-behavioral therapy, which survivors may be unwilling or unable to adopt. Pharmacologic interventions (e.g., selective serotonin reuptake inhibitors) have been disappointing. One potential therapy is the antidepressant bupropion, a norepinephrine-dopamine reuptake inhibitor that targets both inflammation and the hypothalamic-pituitary-adrenal axis. The current study is intended to provide a rigorous test of the efficacy and tolerability of bupropion for cancer-related fatigue. METHODS: A randomized, double-blind, placebo-controlled trial will examine the effects of bupropion on cancer-related fatigue. The trial will be conducted nationwide through the University of Rochester Medical Center (URMC) National Cancer Institute Community Oncology Research Program (NCORP). Disease-free breast cancer survivors (n = 422) who completed chemotherapy and/or radiotherapy 12-60 months previously and report significant fatigue will be randomized 1:1 to receive bupropion (300 mg/day) or placebo. Outcomes will be assessed at baseline and the 12-week follow-up. The primary outcome, fatigue, will be measured with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F). Secondary outcomes include quality of life, depression, and drug tolerability. Exploratory outcomes include cognition and symptomatology. Potential biological mechanisms and genetic moderators of cancer-related fatigue will also be explored. DISCUSSION: This study is the first placebo-controlled trial to our knowledge to evaluate bupropion for cancer-related fatigue. Positive results could revolutionize the treatment of cancer-related fatigue, as bupropion is safe, inexpensive, widely-available, and may be more tolerable and acceptable for many patients than current, limited treatment options.

White blood cell count nadir following remission induction chemotherapy is predictive of outcome in older adults with acute myeloid leukemia.

Kinetics of white blood cell (WBC) elimination following induction chemotherapy for older adults with acute myeloid leukemia (AML) may serve as a surrogate for its effectiveness and safety by enabling real-time prognostication. We reviewed 122 older adults with AML treated at the Cleveland Clinic. Recursive partitioning analysis was used to identify optimal cut points in nadir WBC count and time to WBC nadir that correlate with survival. Multivariable analysis identified time to WBC nadir less than or equal to 10 days (HR 2.15, 95%CI 1.12 - 4.12, p = 0.02), low WBC nadir (less than 0.04 x 10(9)/l, HR 2.68, 95%CI 1.15 - 6.23, p = 0.02) and high WBC nadir (greater than 0.12 x 10(9)/l HR 1.5, 95%CI 0.96 - 2.37, p = 0.08), as predictors of worse outcomes. Time to WBC nadir predicts survival. The absolute WBC nadir value follows a J-curve, with lower value indicating a worse outcome.

Molecular Testing and the Pathologist's Role in Clinical Trials of Breast Cancer.

Molecular characterization of breast cancer is pivotal for identifying new molecular targets and determining the appropriate treatment choices. Advances in molecular profiling technology have given greater insight into this heterogeneous disease, over and above hormone receptor and human epidermal growth factor receptor 2 status. Agents targeting recently characterized molecular biomarkers are under clinical development; the success of these targeted agents is likely to depend on identifying the patient population most likely to benefit. Therefore, clinical trials of breast cancer often require prescreening for, or stratification by, relevant molecular markers or exploratory analyses of biomarkers that can predict or monitor the response to treatment. Consequently, the role of the pathologist has become increasingly important. The key considerations for pathologists include tissue availability, ownership of archival tissue, type of diagnostic/biomarker test required, method of sample processing, concordance between different tests and testing centers, and tumor heterogeneity. In the present review, we explore how pathology is used in current clinical trials of breast cancer and describe the various technologies available for molecular testing. Furthermore, the factors required for the successful application of pathology in clinical trials of breast cancer and the issues that can arise and how these can be circumvented are discussed.

A phase I study of indoximod in patients with advanced malignancies.

PURPOSE: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates. EXPERIMENTAL DESIGN: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. RESULTS: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 µM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels. CONCLUSIONS: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.

Beta-catenin expression patterns in matched pre- and post-neoadjuvant chemotherapy-resistant breast cancer.

BACKGROUND: ß-catenin is a critical component of the cadherin cell-to-cell adhesion pathway and a key participant in the Wnt signaling pathway. Activation of ß-catenin signaling in the Wnt pathway is a known contributor to tumor cancer progression and metastasis and may result in resistance to chemotherapeutic agents. The aim of this study is to evaluate the patterns of expression of ß-catenin in breast carcinoma cells before and after neoadjuvant chemotherapy. Discovery of the molecular mechanisms responsible for resistance to chemotherapy treatment could result in more effective therapy, and improve outcome and survival. DESIGN: Twenty-nine matched pre-treatment and post-neoadjuvant chemotherapy breast carcinomas were subjected to immunohistochemical study using anti-ß-catenin antibody. Normal staining was defined as crisp membrane staining in >90% tumor cells; aberrant expression was nuclear staining in >5% tumor cells. RESULTS: Of the 29 included cases, five cases of invasive lobular carcinoma lacked ß-catenin immunoreactivity pre- and post-treatment. Mildly reduced membranous staining was seen in two post-treatment samples. One case of triple-negative ductal carcinoma had reduced pre- and post-treatment staining. All other cases showed normal pre- and post-treatment ß-catenin expression. No aberrant staining was identified. CONCLUSION: In our study, there was no difference in the expression of ß-catenin in pre- and post-neoadjuvant chemotherapy specimens. These results do not suggest that ß-catenin plays a role in conferring neoadjuvant chemotherapy resistance.

Racial differences in acute toxicities of neoadjuvant or adjuvant chemotherapy in patients with early-stage breast cancer.

BACKGROUND: Racial disparities in breast cancer outcomes are attributed to differences in baseline tumour characteristics and biology, stage, age, ethnic background and socioeconomic factors. However, little is known about racial differences in treatment-related toxicities. We hypothesised that racial/ethnic differences result in differential tolerance to chemotherapy potentially, leading to compromised dose intensity/density of chemotherapy in patients with early-stage breast cancer. METHODS: Data were collected from patients treated at five international centers for early breast cancer with the same adjuvant/neoadjuvant chemotherapy (FEC 100: fluorouracil 500mg/m(2), epirubicin 100mg/m(2), and cyclophosphamide 500mg/m(2),every 21d for 3-6 cycles). Toxicities were assessed by first episode of ⩾grade 2 toxicity. RESULTS: Toxicities were compared according to four race/ethnicity groups (103 Caucasian, 30 African American, 164 Asian, and 34 Hispanic patients). Tumour characteristics across four race/ethnicity groups were similar. Asians had a significantly higher rate of grade 3 haematologic toxicity than Caucasians, African Americans or Hispanic women (32%, 16%, 10%, and 15%, respectively; p<0.05). In multivariate analysis, only lower BMI was associated with a higher incidence of ⩾grade 3 toxicities. However, no significant differences in chemotherapy dose intensity/density were shown across the four race/ethnicity groups. CONCLUSION: Racial differences in acute toxicity were noted in women with breast cancer who were treated with FEC 100 chemotherapy, suggesting that extrapolating toxicities from chemotherapy across ethnicities is not possible and emphasising the need to validate safety of chemotherapeutic regimens in patients of different ethnicities by enhancing the participation of minorities in clinical trials.