38 research outputs found
Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer
No full textWilliam J Gradishar Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Abstract: Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed. Keywords: community oncologists, hormone receptor-positive advanced breast cancer, endocrine resistanc
SOPHIA : A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer
No full textAbstract
Background: Despite significant advances in targeted therapy, HER2+ metastatic breast cancer (MBC) remains incurable. Ideal treatment includes pertuzumab and trastuzumab in combination with a taxane in the first line setting, followed by ado-trastuzumab emtansine on progression. Optimal treatment regimens in the third and greater line of therapy are not defined, but continued anti-HER2 therapy is recommended. Margetuximab is a Fc-modified monoclonal antibody to HER2 that recognizes the same epitope on HER2 as does trastuzumab, with similar affinity. Margetuximab demonstrates increased affinity to the activating CD16A Fc-receptor found on NK cells and macrophages and decreased affinity to the inhibitory CD32B receptor compared to trastuzumab. In vitro studies showed enhanced antibody dependent cell-mediated cytotoxicity compared to trastuzumab. In a Phase 1 dose escalation and expansion trial, margetuximab showed single agent clinical activity against HER2+ tumors in patients previously treated with trastuzumab and other anti-HER2 agents. Methods: SOPHIA is a randomized, prospective study testing the hypothesis that margetuximab plus chemotherapy (CTX) is more effective than trastuzumab plus CTX in patients previously treated for HER2+ MBC. Sequential primary endpoints are centrally assessed progression free survival (PFS) and overall survival (OS). The study size of 530 patients is determined to have 80% power to detect a hazard ratio for OS of 0.75. Secondary endpoints are investigator assessed PFS and centrally assessed overall response rate. Eligibility includes prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine; no more than 3 prior lines of therapy in the metastatic setting; prior demonstration of HER2+ status at a local reference laboratory; and absence of active brain metastases. Eligible patients are randomized 1:1 to receive CTX (physician's choice: capecitabine, eribulin, gemcitabine or vinorelbine) plus either margetuximab or trastuzumab until disease progression or toxicity. Antibody may be continued after stopping CTX in patients with responding or stable disease. Progress to date: The trial was initiated July 2015 and is ongoing in the US and Europe with planned expansion to Korea and Israel. ClinicalTrials.gov Identifier NCT02492711; Eudract 2015-000380-13.
Citation Format: Rugo HS, Pegram MD, Gradishar WJ, Cortes J, Curigliano G, Hong S, Wigginton JM, Lechleider RJ, Cardoso F. SOPHIA: A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic 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 OT1-02-07.</jats:p
Abstract PD4-05: Patterns of genomic alterations in ER-positive advanced breast cancer patients treated with CDK4/6 inhibitors
No full textAbstract
Background:Cyclin D kinase inhibitors (CDK-is) have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer (MBC) when combined with aromatase inhibition or estrogen receptor (ER) antagonism. Despite the benefit of this approach, clinical resistance develops sometimes early in the treatment without any response to endocrine therapy (primary endocrine resistance) or after initial response (secondary resistance) in all patients in the metastatic setting and the molecular basis for this resistance are still largely unknown. We evaluated the pattern of genomic alterations in circulating cell-free tumor DNA (ctDNA) analysis of metastatic breast cancer patients with ER-positive tumors treated with palbociclib combined with either letrozole or fulvestrant and progressing during therapy.
Methods: We conducted a retrospective study of patients with ER-positive MBC who had longitudinal assessment of their disease by ctDNA analysis. The plasma-based assay was performed utilizing Guardant360 (Guardant Health, CA), a digital NGS technology to sequence a panel of &gt; 50 cancer genes. After tabulating number of genomic alterations detected for every patient at baseline and after CDK-i therapy, analysis was performed to identify molecular profile changes in the entire population and in individuals with early progression of disease (&lt;6 months).
Results: We analyzed data of 15 ER-positive MBC patients: 8 patients received fulvestrant/palbociclib and 7 received letrozol/palpociclib. The most common mutations before CDK-i therapy were: PIK3CA (16%), TP53 (16%), ESR1 (13%), KIT (9%), EGFR (3%), APC (3%), ERBB2 (3%), MYC (3%), PTEN (3%), RB1 (3%). After therapy with CDK-i the pattern of mutations showed stable and persistent incidence of PIK3CA, TP53 and ESR1. However, new mutations where identified: FGFR1 (6%), IDH (2%), BRCA1 (2%), BRCA2 (2%), CCNE (2%), CCND1 (2%), RAF (2%), AR (2%), ALK(2%). Also, the pattern of gene amplifications presented an increased rate of MYC and FGFR1 amp. Patients with progression of disease before 6 months of CDK-i therapy presented baseline higher number and variation of mutations compared to patients with disease controlled beyond 6 months of therapy.
Conclusion: Longitudinal assessment with ctDNA analysis suggest that a genomic alteration landscape consisting of persistent detection of driver and acquired mutations along with emergent new abnormalities in regulatory genes could potentially be related to primary or secondary resistance to CDK-Is in ER+ MBC patients. Future investigation of these alterations should be conducted.
Citation Format: Cruz MR, Limentani K, Taxter T, Santa-Maria CA, Behdad A, Gradishar WJ, Nagy RJ, Cristofanilli M. Patterns of genomic alterations in ER-positive advanced breast cancer patients treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-05.</jats:p
Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer
No full textHikmat Abdel-RazeqDepartment of Internal Medicine, King Hussein Cancer Center, Amman, JordanI read with great interest the review written elegantly by Gradishar addressing the challenges that community oncologists face in treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer in your journal.1As the author correctly stated, resistance to endocrine therapy in women with hormone receptor-positive disease is very frequent and almost inevitable.Understanding the multiple known mechanisms for endocrine resistance has helped physicians and researchers target these pathways.2 Many of the recently introduced drugs, such as the mTOR inhibitor everolimus3 and the cyclin-dependent kinase (CDK 4/6) inhibitor palbociclib,4 are in clinical practice and have been already incorporated in international guidelines.5View original paper by Gradishar
Abstract P5-03-11: Possible role for cancer stem cells: results from a pilot neoadjuvant trial of HER-2 positive breast cancer patients treated with a combination of (Nab)-paclitaxel and lapatinib.
No full textAbstract OT3-01-01: A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer
No full textAbstract
Background
A hallmark of cancer is its ability to evade the immune system, however, it can be harnessed to detect and destroy cancer cells through inhibition of immune checkpoints such as CTLA-4 and PD-L1. This strategy has complementary and non-redundant mechanisms resulting in immune activation and antitumor synergy; progression free survival benefit has already been demonstrated in melanoma. A critical barrier in developing immunotherapies, however, is the identification of predictive biomarkers of response to therapy. Immunopharmacogenomic biomarkers, such as mutational burden, neoantigen profiles, and T cell receptor sequencing will elucidate the molecular interface between cancer and immune system, and may predict those most likely to benefit.
Methods
A single arm Phase II study was designed to determine the efficacy of PD-L1 and CTLA-4 inhibition and effects on immunopharmacogenomic dynamics in patients with metastatic breast cancer. The primary endpoint of this proposal is to investigate the response rate of the PD-L1 inhibitor, durvalumab, and the CTLA-4 inhibitor, tremelimumab, in metastatic breast cancer; secondary endpoints will examine the T cell receptor repertoire clonality, tumor mutational burden and neoantigen profiles. A total of 30 patients will be enrolled and treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks for 18 doses to complete 1 year of therapy with the option to renew therapy for an additional year; biopsies and blood at baseline and 2 months will be collected to assess immunopharmacogenomic biomarkers. Patients are eligible if they have triple negative or ER-positive breast cancer and have progressed on at least one line of chemotherapy and standard endocrine therapy if applicable. This is the first study to investigate immunopharmacogenomic biomarkers of response to dual checkpoint blockade in patients with metastatic breast cancer.
Citation Format: Santa-Maria CA, Jain S, Flaum L, Park J-H, Kato T, Gross L, Uthe R, Tellez C, Stein R, Rademaker A, Gradishar WJ, Nakamura Y, Giles FJ, Cristofanilli M. A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic 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 OT3-01-01.</jats:p
Abstract P2-02-21: The utility and correlation of circulating tumor cells (CTCs) and cell-free circulating tumor DNA (ctDNA) based on HER2 positivity
No full textAbstract
Background:
CTCs are well-established prognostic and predictive biomarkers for metastatic breast cancer (MBC) and other solid tumors. ctDNA is emerging as a quantitative blood-based biomarker for monitoring genomic alterations and disease progression. We evaluated the clinical utility and correlation of these liquid biopsy molecular tools in a cohort of MBC patients.
Methods:
CTC samples were obtained from an ongoing, prospective study of blood based prognostic biomarkers for breast cancer patients. At this time, 71 patients and 98 total samples have been collected. CTC enumeration was performed using the CellSearchTM platform (Menarini, IT). Within this cohort, MBC patients who had ctDNA testing were identified. ctDNA testing was performed using Guardant360TM (Guardant Health, CA), a digital next-generation sequencing technology. Two groups were analyzed: (1) HER2-negative patients with CTC ≥ 5 in 7.5 ml of blood (2) HER2-positive patients who had been treated with HER2 targeted therapy.
Results:
22 samples (N=16 patients) were found with CTC ≥ 5 (range 8-904) and concurrent ctDNA testing (median timeframe between collection 0 days, range 0-42 days). There was a significant association between number of CTCs and the total number of genomic alterations detected in ctDNA (paired two sample t-test, p=0.012). In addition, CTC enumeration was significantly correlated with somatic alteration burden of the dominant clone (paired two sample t-test, p=0.023). The most common alterations detected in the blood were TP53 (55% of patients, 18 total mutations), PIK3CA (41% of patients, 15 total mutations), and ESR1 (32% of patients, 14 total mutations). For patients with HER2 positivity receiving HER2-targeted therapies (N=16 samples from 11 patients), only 18.8% of samples had detectable CTCs (all less than 5) as compared to 75.0% of samples with detectable ctDNA alterations. In N=12 samples with detectable ctDNA mutations, mean number of genomic alterations was 4.4 with mean somatic mutation burden of 2.95%.
CTCs detectedctDNA detectedCTC ≥ 5Mean number of ctDNA alterations+Mean somatic alteration burden+HER2- (only cases with CTC ≥ 5)100% (22/22)100% (22/22)100%6.716.1%HER2+ (all cases)18.8% (3/16)75.0% (12/16)0%4.42.95%+excludes ctDNA samples without detected genomic alterations
Conclusions:
In HER2-negative MBC patients, CTC enumeration was significantly correlated with the number of ctDNA genomic alterations and somatic alteration burden, indicating the potential for ctDNA as a prognostic, quantitative biomarker of tumor burden. In patients with HER2 positivity, ctDNA may be a more sensitive liquid biopsy tool given the rarity of detecting CTCs detection in this population using the CellSearchTM system. In HER2-positive patients, consideration of size-dependent selection of CTCs using filtration of cells that have undergone epithelial-mesenchymal transition may improve detection in this subgroup.
Citation Format: Davis AA, Zhang Y, Behdad A, Taxter T, Strickland K, Santa-Maria C, Flaum L, Cruz MR, Platanias LC, Gradishar WJ, Cristofanilli M. The utility and correlation of circulating tumor cells (CTCs) and cell-free circulating tumor DNA (ctDNA) based on HER2 positivity [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-21.</jats:p
OT3-01-09: Phase 3 Trial Comparing Capecitabine in Combination with SorafenIb or Placebo for Treatment of Locally Advanced or Metastatic HER2−Negative Breast Cancer (RESILIENCE).
No full textAbstract PD1-02: Circulating tumor DNA (ctDNA): A <i>real-time</i> application of precision medicine to the management of metastatic breast cancer (MBC)
No full textAbstract
Background: Molecular diagnostic, in particular next-generation sequencing (NGS) technologies, improved the detection of actionable mutations (muts) in MBC at baseline and recurrence. We evaluated the ability of ctDNA to detect molecular abnormalities, monitor disease progression and predict outcome.
Methods: We conducted a retrospective study of 91 patients (pts) with locally advanced and MBC, who had longitudinal assessment of their disease by ctDNA analysis. The plasma-based assay was performed utilizing Guardant360 (Guardant Health, CA), a digital NGS technology to sequence a panel of &gt; 50 cancer genes. After tabulating number of muts and quantification of overall ctDNA detected for every patient at baseline, a receiver operating characteristic (ROC) analysis was performed to identify the best cut-offs that separated the pts who had a disease progression from those who hadn't, and the patients who died from those still alive. The overall survival (OS) analysis has been performed using Kaplan-Meier curves.
Results: 84 pts (92%) had stage IV cancer. 63% cases were ER+, 27% HER2+, 29% TNBC. 277 blood samples were collected and 84% had muts. 65% of the pts had serial samples. The average number of alterations detected in each sample was 3 (0-27) and the average ctDNA fraction detected was 4.5% (0-88.2%). The most common alterations were: TP53 (52%), PIK3CA (40%), ERBB2 (20%), NOTCH1 (15.5%), APC (14%), MET (13%). 16 pts (19%) were initiated on a targeted therapy based on ctDNA test results. At the time of analysis 36 pts (39.6%) were dead, 55 (60.4%) were currently alive. PFS was 5.2 months (ms) and OS was 21.5 ms. A statistically significant difference in PFS and OS by log rank test was found between % ctDNA at baseline &lt; 0.5 versus ≥ 0.5 (p = 0.003 and p = 0.012, respectively) and number of muts at baseline &lt; 2 versus ≥ 2 (p = 0.059 borderline and p = 0.0015). Moreover, a statistically significant association by Fisher's exact test was found between the number of alterations and the % ctDNA detected in the baseline sample (% of pts with muts ≥ 2 was 19% when % ctDNA &lt; 0.5%, versus 85% when % ctDNA ≥ 0.5%; p &lt; 0.0001).
PFS (ms) p = 0.059 (log rank test)Muts &lt; 2 (n = 32)Muts ≥ 2 (n = 58)658%40%1230%13%1821%6%24--PFS(ms) p = 0.003 (log rank test)% ctDNA &lt; 0.5(n = 27)% ctDNA ≥ 0.5(n = 60)665%39%1241%10%1823%6%24--
OS(ms) p = 0.002 (log rank test)Muts &lt; 2(n = 32)Muts ≥ 2(n = 57)697%66%1288%51%1888%42%24-29%OS(ms) p = 0.012 (log rank test)% ctDNA &lt; 0.5(n = 27)% ctDNA ≥ 0.5(n = 59)696%69%1290%55%1885%48%24-35%
Conclusions: ctDNA liquid biopsy provides a real-time, quantitative NGS-based assessment of MBC which is useful for treatment planning, disease monitoring and prognostic evaluation. Future prospective studies should consider the use of ctDNA for molecular and prognostic stratification.
Citation Format: Rossi G, Austin LK, Nagy RJ, Rademaker AW, Gradishar WJ, Santa-Maria CA, Curry-Edwards RL, Jain S, Flaum LE, Lima Barros Costa R, Zagonel V, Platanias LC, Giles FJ, Talasaz A, Cristofanilli M. Circulating tumor DNA (ctDNA): A real-time application of precision medicine to the management of metastatic breast cancer (MBC) [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 PD1-02.</jats:p
Abstract P1-05-06: Estrogen receptor 1 (<i>ESR1</i>) mutations in circulating tumor DNA (ctDNA): A guide to the management of advanced breast cancer (ABC)
No full textAbstract
Background: Estrogen receptor (ER)-α is expressed in about 70% of breast cancers and drugs that target the receptor function, selective estrogen receptor modulators (SERM) and aromatase inhibitors (AIs) represent the standard of care for patients (pts) with ER+ breast cancer. Nevertheless, prolonged exposure to endocrine therapy may result in acquired resistance and subsequent progression of disease. Recent evidence showed that activating mutations (muts) in the ligand-binding domain of ER-α occur in approximately 20% of pts exposed to endocrine therapies and those genomic abnormalities may represent the driver of endocrine resistance. In this context, ctDNA provides a non-invasive source for real-time next generation sequencing (NGS) studies, in order to understand the biology of ABC and guide and monitor treatment.
Methods: We conducted a retrospective review of 91 pts with ABC, including 57 pts with ER+ tumor, who had longitudinal assessment of their disease by ctDNA analysis. At the time of baseline sampling, 50/57 pts had stage IV cancer. The total number of blood samples collected was 184. 38 (67%) pts had serial samples. The average number of samples for each pt was 3 (range 1-7). The plasma-based assay was performed utilizing Guardant360 (Guardant Health, CA), a digital NGS technology to sequence a panel of &gt; 50 cancer genes.
Results: Among the ER+ subgroup (57 pts), we identified 11 pts (19%) harboring ESR1 muts in ctDNA. All 11 pts had metastatic disease: 2 (18%) had bone metastases, 2 (18%) had visceral metastases, 7 (64%) had both sites of disease. The median age was 55 years (range 33-73). 5 pts had inflammatory breast cancer. The most common ESR1 muts were: Y537S (6/11, 55%), D538G (4/11, 36%) and Y537N (3/11, 27%). 7 pts carried polyclonal muts. At the time of testing, 10 pts had already failed at least 1 line of endocrine therapy (average 2, range 1-5), including 6 pts that had received a fulvestrant-containing regimen, 8 pts ≥ 1 line of AIs. After the mut detection, 5 pt were on endocrine therapy and 4 pts were started on/continued chemotherapy. ESR1 muts disappeared in 2 pts (fulvestrant-palbociclib and chemotherapy respectively) who achieved stable disease as best response. Three pts continued to harbour muts and then progressed (one died). 2 pts had tissue NGS and ESR1 mut was not identified. Progression free survival and overall survival were 8 months (ms) and 21.5 ms in ESR1+ subpopulation versus 6.2 ms and 22.2 ms in the ESR1- pts (p = 0.78 and p = 0.97, respectively). At the time of analysis 5 pts were dead, 6 were currently alive.
ESR1+ (n. pts) ESR1- (n. pts) Pts (total n.)1146 Previous chemotherapies11 (100%)31 (67%) Previous fulvestrant-containing regimens6 (54%)20 (43%) Previous AIs ± targeted therapy8 (73%)27 (59%)
Conclusions: We observed that ESR1 muts, a known driver of endocrine resistance, occurs at a high frequency in heavily pre-treated estrogen receptor positive ABC. Blood-based diagnostics can be used to identify ESR1 muts sometimes not detected by tissue-based sequencing of the metastatic lesions indicating tumor heterogeneity and allowing dynamic monitoring of ABC.
Citation Format: Rossi G, Lima Barros Costa R, Nagy RJ, Rademaker AW, Gradishar WJ, Santa-Maria CA, Curry-Edwards RL, Jain S, Flaum LE, Zagonel V, Platanias LC, Giles FJ, Talasaz A, Cristofanilli M. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA): A guide to the management of advanced breast cancer (ABC) [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 P1-05-06.</jats:p
