Evolving standards of care and new challenges in the management of HER2-positive breast cancer.

The management of human epidermal growth factor receptor (HER2)-positive breast cancer (BC) has rapidly evolved over the last 20 years. Major advances have led to US Food and Drug Administration approval of 7 HER2-targeted therapies for the treatment of early-stage and/or advanced-stage disease. Although oncologic outcomes continue to improve, most patients with advanced HER2-positive BC ultimately die of their disease because of primary or acquired resistance to therapy, and patients with HER2-positive early BC who have residual invasive disease after preoperative systemic therapy are at a higher risk of distant recurrence and death. The concept of treatment de-escalation and escalation is increasingly important to optimally tailor therapy for patients with HER2-positive BC and is a major focus of the current review. Research efforts in this regard are discussed as well as updates regarding the evolving standard of care in the (neo)adjuvant and metastatic settings, including the use of novel combination therapies. The authors also briefly discuss ongoing challenges in the management of HER2-positive BC (eg, intrinsic vs acquired drug resistance, the identification of predictive biomarkers, the integration of imaging techniques to guide clinical practice), and the treatment of HER2-positive brain metastases. Research aimed at superseding these challenges will be imperative to ensure continued progress in the management of HER2-positive BC going forward.

Contemporary Axillary Surgical Management in Patients with Pathologically Node Positive Disease After Neoadjuvant Chemotherapy: A Survey of Members of the American Society of Breast Surgeons.

BACKGROUND: Axillary lymph node dissection (ALND) is increasingly omitted for breast cancer patients with pathologic nodal disease after neoadjuvant chemotherapy (NAC). This study aimed to understand when and why surgeons consider omitting ALND after NAC. METHODS: The American Society of Breast Surgeons membership was surveyed, and responses were tabulated. To identify patterns, multiple correspondence analyses followed by cluster analysis on coordinates provided by the former were performed. Chi-squared analyses determined whether cluster characteristics were significantly (P < 0.05) associated with omission of ALND. RESULTS: Of members, 328/2172 (15.1%) completed the survey. Most (60.7%) always offer sentinel lymph node surgery to cN1 patients who respond to NAC, and many (43.9%) sometimes omit ALND in the setting of residual nodal disease. Respondents less often consider omitting ALND with increasing volume of pathologic nodal disease after NAC and are less likely to omit ALND among patients with cN1 disease at presentation than cN0 (P < 0.05 across all volumes). Respondents cited radiation administration (74.1%) and belief that ALND would not improve locoregional (48.2%), distant recurrence or survival (47.6%) outcomes when axillary radiation is administered as reasons to omit ALND. The respondent group comprising male private practice surgeons, practicing ≥ 21 years, consider omitting ALND significantly more frequently. CONCLUSIONS: Surgeons sometimes consider ALND omission for patients with pathologic nodal disease after NAC but are more likely to do so in cN0 patients and patients with smaller volumes of nodal disease. These decisions are largely based on perceived lack of oncologic benefit despite absence of prospective data supporting this deescalation.

A Phase I Study of a Combination of Liposomal Irinotecan and Veliparib in Solid Tumors.

BACKGROUND: Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination. METHODS: A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles. RESULTS: Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose-limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1). CONCLUSION: The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733).

Clinical management of metastatic hormone receptor-positive, HER2-negative breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second-line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single-institution analysis to identify treatments and outcomes after progression on a CDK4/6i. METHODS: We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014 to February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020. RESULTS: Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression-free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6-34.9) vs 19.8 months (95% CI 15.7-29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single-agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months-NE), single-agent ET was 6.0 months (95% CI 3.3-14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months-NE). CONCLUSIONS: Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 (Cituxumumab) in Patients with HER2-Positive Advanced Breast Cancer Previously Treated with Trastuzumab and Chemotherapy: NCCTG N0733 (Alliance).

PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment. CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT00684983.

Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer.

This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.

Lay abstract In this research study (A011801; CompassHER2 RD), patients with early stage HER2-positive breast cancer who already received treatment with chemotherapy and anti-HER2 targeted therapies followed by surgery are mainly enrolled. If cancer is still present in the breast and/or lymph nodes at the time of surgery, there is a higher risk of a recurrence in the future, and enrollment on A011801 is an option. Usually, if there is tumor remaining after chemotherapy and anti-HER2 targeted therapies, the main treatment is the use of an FDA-approved intravenous drug called T-DM1. Additional treatment may also include radiotherapy and/or medications to block the activity of estrogen. The usual treatment approach reduces the likelihood of breast cancer recurring in the future. This study has been performed to answer the following question: Is the combination of T-DM1 and a newer drug tucatinib better than usual treatment with T-DM1 alone at preventing cancer from returning? Study participants will receive treatment with T-DM1 and placebo (a pill that looks like the study drug but contains no medication) or T-DM1 and tucatinib, for up to 14 cycles, unless their breast cancer returns or the side effects become too severe. Research bloods are taken on study along with standard blood work, and we also request a stored tumor sample from the original biopsy and from the breast cancer surgery for research purposes. Optional Quality of Life Questionnaires are also included in the trial. After the study, participants finish T-DM1 and placebo, or T-DM1 and tucatinib, and their doctor will continue to follow their condition with clinic visits every 6 months for 10 years and watch for side effects and for signs of breast cancer recurring. Clinical Trial Registration: NCT04457596 (ClinicalTrials.gov).

Clinico-pathologic features, treatment and outcomes of breast cancer during pregnancy or the post-partum period.

PURPOSE: Breast cancer during pregnancy (BC-P) or the first year post-partum (BC-PP) is rare and whether it differs from breast cancer (BC) in young women not associated with pregnancy is uncertain. METHODS: We queried our institutional database for BC-P and BC-PP cases and matched controls with BC not associated with pregnancy diagnosed between January 1, 1985 and December 31, 2013. We performed two parallel retrospective cohort studies evaluating clinico-pathologic features, treatment and outcomes for BC-P and BC-PP cases compared to their controls. RESULTS: In our population of 65 BC-P cases, 135 controls for BC-P cases, 75 BC-PP cases and 145 controls for BC-PP cases, high grade and estrogen receptor-negativity were more frequent in both case groups than their controls. Among those with stage I-III BC, patterns of local therapy were similar for both case groups and their controls, with the majority undergoing surgery and radiation. Over three-fourths of those with stage I-III BC received chemotherapy. BC-P cases tolerated chemotherapy well, with the majority receiving doxorubicin/cyclophosphamide every 3 weeks. On multivariate analyses of those with stage I-III BC, BC-P cases had non-significantly higher hazards of recurrence and death compared to their controls, while BC-PP cases had non-significantly lower hazards of recurrence and death compared to their controls. CONCLUSION: BC-P and BC-PP were associated with adverse clinic-pathologic features in our population. However, we did not observe inferior outcomes for BC-P or BC-PP compared to controls, likely due to receipt of aggressive multi-modality therapy.

Ten-Year Trends in Antiemetic Prescribing in Patients Receiving Highly Emetogenic Chemotherapy.

Purpose: Prevention of chemotherapy-induced nausea and vomiting is essential to preserve quality of life in patients with cancer receiving highly emetogenic chemotherapy (HEC). Recently, new drugs (eg, fosaprepitant, and the newer neurokinin-1 receptor antagonists [NK1RAs] rolapitant and netupitant) and updated antiemetic guidelines have emerged. However, trends in real-world antiemetic use are understudied. Methods: We identified patients treated with an initial dose of HEC (either cisplatin or doxorubicin/cyclophosphamide) from January 2006 to June 2016 using administrative claims data from a US commercial insurance database (OptumLabs). Antiemetic use was determined by identifying intravenous/oral/transdermal administration within ±1 day of the chemotherapy dose and/or prescription fill from 14 days before to 7 days after chemotherapy. We used descriptive statistics to present patient demographics, chemotherapy drugs administered, presence/absence of a central intravenous access device, and antiemetics used. Results: A total of 23,030 patients (67.3%) received doxorubicin/cyclophosphamide and 11,206 (32.7%) received cisplatin. Dexamethasone and 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) were consistently used by 85% to 95% of patients, consistent with guideline recommendations. NK1RAs were underused early on, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use increased precipitously starting in 2009, preceding a sharp decrease in aprepitant use beginning in 2011. Receipt of olanzapine, rolapitant, and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used by most patients receiving HEC, in accordance with guideline recommendations. NK1RA use was less adherent with guidelines.

Where Do We Stand on the Integration of PARP Inhibitors for the Treatment of Breast Cancer?

PURPOSE OF REVIEW: To provide an overview of the clinical development of poly(ADP-ribose) polymerase inhibitors (PARPi) in breast cancer to date and to review existing challenges and future research directions. RECENT FINDINGS: We summarize the clinical development of PARPi in breast cancer from bench to bedside, and discuss the results of recent phase 3 trials in patients with metastatic breast cancer (MBC) and germline mutations in BRCA1/2 (gBRCAm). We will also provide an update regarding mechanisms of action and resistance to PARPi, and review clinical trials of PARPi as monotherapy or in combination regimens. PARPi are a novel treatment approach in persons with gBRCA1/2m-associated MBC. Going forward, the clinical applicability of these compounds outside the gBRCAm setting will be studied in greater detail. The identification of accurate predictive biomarkers of response is a research priority.

Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer.

BACKGROUND: Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum-refractory and -resistant ovarian cancer. METHODS: In this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients received birinapant at 47 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Pharmacokinetics were obtained during cycle 1. Plasma, peripheral blood mononuclear cells (PBMCs), and percutaneous tumor biopsy samples were collected before cycle 1 and after 6 weeks. The primary endpoint was an objective response or progression-free survival lasting greater than 6 months in a mini-max design. RESULTS: Eleven patients received birinapant; after this, accrual was terminated for lack of a clinical benefit. Birinapant was well tolerated, with predominantly grade 2 adverse events and 1 case of grade 3 lymphopenia. Pretreatment biopsy samples and PBMCs were collected; paired posttreatment biopsy samples and PBMCs were collected from 7 and 10 patients, respectively. There was consistent downregulation of cellular inhibitor of apoptosis protein 1 in tumors (P = .016) and PBMCs (P < .01). Procaspase 3 also decreased in tumors (P = .031) and PBMCs (P < .01); cleaved caspase 3 colocalized with H2A histone family member X (γ-H2AX) in tumors after birinapant exposure. Peripheral T and B cells decreased significantly after treatment, but natural killer cells did not (P = .04, P = .05, and P = .43, respectively). CONCLUSIONS: Birinapant shows consistent target suppression in vivo without single-agent antitumor activity in this small population. Single-agent pharmacodynamics are necessary to understand the drug's mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials.

The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl.

Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist.

Pertuzumab and its accelerated approval: evolving treatment paradigms and new challenges in the management of HER2-positive breast cancer.

The addition of trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), to standard chemotherapy in patients with HER2-positive breast cancer has resulted in major improvements in breast cancer outcomes, including improved survival, in both the adjuvant and metastatic settings. However, some patients experience disease relapse despite adjuvant trastuzumab-containing therapy, and resistance to trastuzumab develops in the majority of patients in the metastatic setting. An understanding of the molecular mechanisms underlying trastuzumab resistance has aided the development of novel HER2-targeted therapies. In June 2012, the HER2 dimerization inhibitor pertuzumab was approved by the US Food and Drug Administration (FDA) for use with chemotherapy and trastuzumab in the first-line treatment of metastatic HER2-positive breast cancer. In September 2013, accelerated approval was granted for use of pertuzumab in the neoadjuvant setting, representing a landmark decision by the FDA. This article discusses the development of pertuzumab to date, with a particular focus on the accelerated approval decision. We highlight the need to identify reliable biomarkers of sensitivity and resistance to HER2-targeted therapy, which would make possible the individualization of treatment for patients with HER2-positive breast cancer.

Standard-of-Care Treatment for HER2+ Metastatic Breast Cancer and Emerging Therapeutic Options.

Prior to the advent of the HER2-targeted monoclonal antibody trastuzumab, HER2+ breast cancer (BC) was considered an aggressive disease with a poor prognosis. Over the past 25 years, innovations in molecular biology, pathology, and early therapeutics have transformed the treatment landscape. With the advent of multiple HER2-directed therapies, there have been immense improvements in oncological outcomes in both adjuvant and metastatic settings. Currently, 8 HER2-targeted therapies are approved by the Food and Drug Administration (FDA) for the treatment of early-stage and/or advanced/metastatic disease. Nonetheless, approximately 25% of patients develop recurrent disease or metastasis after HER2-targeted therapy and most patients with HER2+ metastatic breast cancer (MBC) die from their disease. Given the many mechanisms of resistance to HER2-directed therapy, there is a pressing need to further personalize care for patients with HER2+ MBC, by the identification of reliable predictive biomarkers, and the development of novel therapies and combination regimens to overcome therapeutic resistance. Of particular interest are established and novel antibody-drug conjugates, as well as other novel therapeutics and multifaceted approaches to harness the immune system (checkpoint inhibitors, bispecific antibodies, and vaccine therapy). Herein, we discuss standard-of-care treatment of HER2+ MBC, including the management of breast cancer brain metastases (BCBM). Furthermore, we highlight novel treatment approaches for HER2+ MBC, including endeavors to personalize therapy, and discuss ongoing controversies and challenges.

Sexual Dysfunction in Patients With Metastatic Breast Cancer.

BACKGROUND: Sexual well-being is a key determinant of quality of life. Sexual dysfunction in patients with metastatic breast cancer (MBC) is understudied. PATIENTS AND METHODS: Patients were eligible for this study if they participated in the Mayo Clinic Breast Disease Registry (MCBDR), had a diagnosis of de novo MBC, and responded to a question about sexual dysfunction at the baseline MCBDR survey. Participants reported their sexual dysfunction on a scale of 0 (no dysfunction) to 10 (severe dysfunction) at baseline and then annually for 4 years. Participants answered additional sexual symptom questions in years 2 and 4. Associations between patient attributes and the presence and severity of sexual dysfunction, changes in sexual dysfunction from baseline to subsequent surveys, and associations between specific sexual symptoms and severity of sexual dysfunction were assessed. RESULTS: One hundred three patients with de novo MBC answered the sexual dysfunction question at baseline. The prevalence of any sexual dysfunction (score of 1-10) was 56.3% at baseline (n = 103), 57.1 % at year 1 (n = 77), 80.4% at year 2 (n = 46), 65.8% at year 3 (n = 38), and 85% at year 4 (n = 20). Vaginal dryness was reported by approximately 49% and 39% of patients in years 2 and 4 respectively. Vaginal dryness was associated with higher severity of sexual dysfunction. CONCLUSIONS: Self-reported sexual dysfunction is frequent in women with de novo MBC. Vaginal dryness is a frequently reported treatable symptom associated with higher severity of sexual dysfunction. Clinicians should assess patients with MBC for sexual dysfunction and discuss potential treatment strategies.

OmicsFootPrint: a framework to integrate and interpret multi-omics data using circular images and deep neural networks.

The OmicsFootPrint framework addresses the need for advanced multi-omics data analysis methodologies by transforming data into intuitive two-dimensional circular images and facilitating the interpretation of complex diseases. Utilizing Deep Neural Networks and incorporating the SHapley Additive exPlanations (SHAP) algorithm, the framework enhances model interpretability. Tested with The Cancer Genome Atlas (TCGA) data, OmicsFootPrint effectively classified lung and breast cancer subtypes, achieving high Area Under Curve (AUC) scores - 0.98±0.02 for lung cancer subtype differentiation, 0.83±0.07 for breast cancer PAM50 subtypes, and successfully distinguishe between invasive lobular and ductal carcinomas in breast cancer, showcasing its robustness. It also demonstrated notable performance in predicting drug responses in cancer cell lines, with a median AUC of 0.74, surpassing existing algorithms. Furthermore, its effectiveness persists even with reduced training sample sizes. OmicsFootPrint marks an enhancement in multi-omics research, offering a novel, efficient, and interpretable approach that contributes to a deeper understanding of disease mechanisms.

Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early-stage breast cancer: A prospective trial.

BACKGROUND: We previously reported that postmenopausal women with ER+ breast cancer (BC) receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 (inadequate estrogen suppression [IES]) had a 3.0-fold increased risk of a BC event. The objective of this study was to determine if increasing anastrozole to 10 mg/day (ANA10) could result in adequate estrogen suppression (AES: E1 <1.3 pg/mL and/or E2 <0.5) among those with IES on ANA1. METHODS: Postmenopausal women with ER+ BC planning to receive adjuvant ANA1 were eligible. E1 and E2 were assessed pre- and post-8-10 weeks of ANA1. Those with IES were switched to 8-10 week cycles of ANA10 followed by letrozole 2.5 mg/day. E1 and E2 were assessed after each cycle. Anastrozole concentrations were measured post-ANA1 and post-ANA10. Primary analyses included patients who documented taking at least 80% of planned treatment (adherent cohort). RESULTS: 132 (84.6%) of 156 eligible patients were ANA1-adherent. IES occurred in 40 (30.3%) adherent patients. 25 (78.1%) of 32 patients who began ANA10 were adherent, and AES was achieved in 19 (76.0%; 90%CI: 58.1-89.0%) patients. Anastrozole concentrations post-ANA1 and post-ANA10 did not differ by estrogen suppression status among adherent patients. AES was maintained/attained in 21 (91.3%) of 23 letrozole-adherent patients. CONCLUSIONS: Approximately 30% of ANA1-adherent patients had IES. Among those who switched to ANA10 and were adherent, 76% had AES. Further studies are required to validate emerging data that ANA1 results in IES for some patients and to determine the clinical benefit of switching to ANA10 or an alternative AI.

Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer: The Phase 2 TBCRC041 Randomized Clinical Trial.

Importance: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown. Objective: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022. Interventions: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). Main Outcomes and Measures: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. Results: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). Conclusions and Relevance: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT02860000.

Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP.

PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.

Slow Uptake of an Effective Therapy: Patterns of Olanzapine Prescribing for Those Receiving Highly Emetogenic Chemotherapy.

PURPOSE: For the past 5 years, most major antiemesis guidelines have included olanzapine-containing regimens among the recommended options for prophylaxis with highly emetogenic chemotherapy (HEC). We analyzed the uptake of olanzapine in clinical practice and the changing composition of multidrug antiemetic regimens. METHODS: A retrospective analysis was performed using an OptumLabs deidentified database of medical and pharmacy claims, which was filtered for patients starting HEC in the interval of 2006 to Q2 of 2021. Descriptive statistics were used to analyze patient characteristics and year-by-year antiemetic prescribing patterns, coinciding with cycles 1 and 2 of chemotherapy. RESULTS: A total of 63,154 distinct patients were included. The median age was 58 years (range, 18-88). Breast (45.2%) and hematologic (20.8%) cancers were the most common diagnoses. In 2016, olanzapine was prescribed to 1.4% of patients with cycle 1 of HEC. Prescriptions increased modestly each year, and by 2021, 13.9% of patients received olanzapine with their first cycle of chemotherapy. An additional 5.7% of patients received olanzapine for breakthrough symptoms or enhanced prophylaxis during cycle 2. In 2021, more than three-quarters of patients were prescribed antiemetics in a guideline-concordant manner, with an olanzapine-containing quadruplet (12.2%), an NK1-receptor antagonist triplet (64.5%), or an olanzapine triplet (suppressed for small sample size). CONCLUSION: Despite inclusion in major antiemesis guidelines, there has been relatively slow uptake of olanzapine for prophylaxis with HEC. This finding highlights the challenges of disseminating information and keeping prescribing systems updated with the newest evidence in supportive oncology.