Characterizing demographics, clinical, and genomic characteristics for U.S. patients with HR+, HER2- metastatic breast cancer following progression on a CDK4 and 6 inhibitor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1015-1015
Author(s):  
Fabrice Andre ◽  
Amit Aggarwal ◽  
Xi Rao ◽  
Yongmei Chen ◽  
Julie Kay Beyrer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
De Novo ◽  
Treatment Options ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Categorical Variables ◽  
Continuous Variables

1015 Background: Cyclin-dependent kinases 4 and 6 inhibitors (CDK4 & 6i) have advanced the therapeutic landscape for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, there is an unmet need for treatment strategies following progression on CDK4 & 6i +/- endocrine therapy (ET). The objective of this analysis is to aid in the development of post-progression treatment by characterizing genomic profiles of tumor biopsies after progression on a CDK4 & 6i +/- ET. Methods: This is a retrospective study comparing two cohorts of US patients (pts) diagnosed with HR+, HER2- MBC since January 2011. One cohort underwent biopsy following progression on a CDK4 & 6i +/- ET (Cohortpost) while the second cohort underwent biopsy with no evidence of CDK4 & 6i treatment (Cohortpre). Tumor tissue was analyzed using the next generation sequencing Tempus xT assay that analyses 595 cancer-related genes. Of 595 molecularly profiled pts, 369 had sufficient medical record data to be eligible for this analysis. Patient characteristics at metastatic diagnosis and CDK4 & 6i initiation were described. For genomic profile comparison, Mann-Whitney U-test was used for continuous variables such as tumor mutation burden (TMB) with significance at P < 0.05; Chi-square or Fishers' exact test was used as appropriate for categorical variables including mutation frequency, with significance at false discovery rate (FDR) < 0.2. Results: Of 369 pts, 177 (48%) were in Cohortpre and 192 (52%) were in Cohortpost. Overall, the mean age at the time of MBC diagnosis was 59 and 55 years, respectively; 47% and 66% of patients had evidence of prior chemotherapy or ET; and 30% and 25% had de novo stage IV MBC. The most common biopsy site was liver, occurring in 38% of pts overall (Cohortpre, 23%; Cohortpost, 52.6%). The xT assay results indicated that pts in Cohortpost had significantly higher TMB compared to patients in Cohortpre (median 2.92 vs 1.67, P < 0.0001). A subset of patients with liver mets across both cohorts (n = 141) showed a similar, but nonsignificant trend (median 2.92 vs 2.08, P = 0.0565). Additionally, pts in Cohortpost had a higher ESR1 alteration frequency compared to Cohortpre (mutations: 32.29% vs 9.60%, FDR < 0.0001; fusions: 7% vs 3%, P = 0.1420). No significant differences were noted in TP53, CCNE1, CCND1, RB1, CDK4, and CDK6 between cohorts. Conclusions: These findings describe clinical characteristics and specific genomic alterations noted after progression on CDK4 & 6i +/- ET. Further analyses will evaluate timing of resistance, mutational and transcriptomic signatures. This may aid in understanding mechanisms of progression associated with CDK4 & 6i +/- ET, ultimately contributing to development of treatment options post progression.

scholarly journals De novo Stage IV Luminal Breast Cancer: Yes or No for Local Treatment? Serial Cases and Review

2021 ◽  
Vol 9 (B) ◽  
pp. 1-5
Author(s):  
Marija Karakolevska-Ilova ◽  
Elena Simeonovska Joveva ◽  
Aleksandar Serafimov
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Bone Metastasis ◽  
Retrospective Studies ◽  
De Novo ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Additional Surgery ◽  
Stage Iv Breast Cancer

BACKGROUND: Primary stage IV breast cancer accounts about of 3–5% of newly diagnosed breast cancer cases. The management of this patient subset mostly comprises systemic therapy, with additional surgery or radiotherapy to control locoregional symptoms. Some of the retrospective studies showed the benefit of locoregional treatment as the first treatment of choice for overall survival (OS), but the efficacy of primary site surgery remains controversial for OS in prospective, controlled trials. AIM: We aimed to presents series of cases with primary metastatic breast cancer with diffuse bone metastasis. MATERIALS AND METHODS: This study was serial of cases with primary metastatic breast cancer with diffuse bone metastasis and a review of the literature. All of the cases were treated with upfront surgical resection of the primary in the breast. RESULTS: During the follow-up period of 36 months, all of our patients were still alive. CONCLUSION: Retrospective studies about resection of primary tumor as the first treatment of choice are with conflicting results, which may be related to randomization bias, including different biological types of breast cancer, different metastatic sites, and patients with different menopausal status. On the other hand, prospective studies did not show any powerful results that would lead the treatment in de novo stage IV breast cancer because of few limitations such a short follow-up period (between 23 and 40 months), younger patients, ER-positive/HER2 negative tumors, and type of chemotherapy given or not upfront. The effect of upfront surgery in newly metastatic breast cancer patients is still challenging, so there is a need to identify the exact cohort of patients who could benefit from surgery.

Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response.

1995 ◽  
Vol 13 (5) ◽  
pp. 1152-1159 ◽  
Author(s):  
A D Seidman ◽  
B S Reichman ◽  
J P Crown ◽  
T J Yao ◽  
V Currie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
De Novo ◽  
Objective Response ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Stage Iv ◽  
High Dose ◽  
Significant Activity ◽  
Two Phase

PURPOSE Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

scholarly journals Change in Survival in Metastatic Breast Cancer with Treatment Advances: Meta-Analysis and Systematic Review

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Jennifer L Caswell-Jin ◽  
Sylvia K Plevritis ◽  
Lu Tian ◽  
Christopher J Cadham ◽  
Cong Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Median Survival ◽  
De Novo ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Sensitivity Analyses ◽  
Er Positive ◽  
Meta Regression ◽  
Over Time

Abstract Background Metastatic breast cancer (MBC) treatment has changed substantially over time, but we do not know whether survival post-metastasis has improved at the population level. Methods We searched for studies of MBC patients that reported survival after metastasis in at least two time periods between 1970 and the present. We used meta-regression models to test for survival improvement over time in four disease groups: recurrent, recurrent estrogen (ER)-positive, recurrent ER-negative, and de novo stage IV. We performed sensitivity analyses based on bias in some studies that could lead earlier cohorts to include more aggressive cancers. Results There were 15 studies of recurrent MBC (N = 18 678 patients; 3073 ER-positive and 1239 ER-negative); meta-regression showed no survival improvement among patients recurring between 1980 and 1990, but median survival increased from 21 (95% confidence interval [CI] = 18 to 25) months to 38 (95% CI = 31 to 47) months from 1990 to 2010. For ER-positive MBC patients, median survival increased during 1990–2010 from 32 (95% CI = 23 to 43) to 57 (95% CI = 37 to 87) months, and for ER-negative MBC patients from 14 (95% CI = 11 to 19) to 33 (95% CI = 21 to 51) months. Among eight studies (N = 35 831) of de novo stage IV MBC, median survival increased during 1990–2010 from 20 (95% CI = 16 to 24) to 31 (95% CI = 24 to 39) months. Results did not change in sensitivity analyses. Conclusion By bridging studies over time, we demonstrated improvements in survival for recurrent and de novo stage IV MBC overall and across ER-defined subtypes since 1990. These results can inform patient-doctor discussions about MBC prognosis and therapy.

scholarly journals Hotspot ESR1 mutations are multimodal and contextual drivers of breast cancer metastasis

2021 ◽  
Author(s):  
Zheqi Li ◽  
Yang Wu ◽  
Megan E. Yates ◽  
Nilgun Tasdemir ◽  
Amir Bahreini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Metastasis ◽  
De Novo ◽  
Endocrine Resistance ◽  
Treatment Strategies ◽  
Metastatic Breast ◽  
Estrogen Receptor Α ◽  
Breast Cancer Metastasis ◽  
Cell Models

AbstractConstitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancer. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant, but not local recurrences. In concordance with transcriptomic profiling of ESR1 mutant tumors, genome-edited Y537S and D538G cell models have a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally confers enhanced cell-cell contacts while decreased cell-ECM adhesion. Context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as vulnerability. Mutant ESR1 exhibits non-canonical regulation of several metastatic pathways including secondary transactivation and de novo FOXA1-driven chromatin remodeling. Collectively, our data supports evidence for ESR1 mutation-driven metastases and provides insight for future preclinical therapeutic strategies.SignificanceContext and allele-dependent transcriptome and cistrome reprogramming in genome-edited ESR1 mutation cell models elicit diverse metastatic phenotypes, including but not limited to alterations in cell adhesion and migration. The gain-of-function mutations can be pharmacologically targeted, and thus may be key components of novel therapeutic treatment strategies for ER-mutant metastatic breast cancer.

scholarly journals Expression of Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) / Noxa correlates with survival in primary and metastatic human breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Metastatic Breast Cancer ◽  
Survival Rate ◽  
Treatment Options ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Stage Iv Breast Cancer

Women diagnosed with stage I breast cancer have a 99% 5-year survival rate while women diagnosed with stage IV metastatic breast cancer that has spread beyond the breast are presented with a 27% 5-year survival rate (1). There are limited treatment options available for women diagnosed with metastatic breast cancer. Understanding how gene expression differs in patients that are longer survivors of breast cancer can facilitate target discovery for novel therapeutics. In this study we compared the transcriptomes of primary tumors from patients with breast cancer based on survival at 24 months and identified phorbol-12-myristate-13-acetate-induced protein 1 (2), PMAIP1, also known as Noxa (3) as among the most differentially expressed genes the tumors of women that survived past 24 months versus those that expired before 24 months. Transcriptome comparison using an independent dataset, this from the metastatic tissues of patients with stage IV breast cancer again identified PMAIP1/Noxa as differentially expressed based on survival at 24 months (4). In both cases, PMAIP1 was expressed at significantly higher levels in the tumors of survivors. PMAIP1 is member of the BCL-2 family of proteins that regulate apoptosis, a type of cell death (5, 6). These data demonstrate that PMAIP1 expression is positively correlated with survival and together with the molecular function of PMAIP1 suggest that increased PMAIP1 expression in the tumors of patients with enhanced survival of metastatic breast cancer might function to promote cell death of tumor cells. Modulation of PMAIP1 expression may be a relevant therapeutic strategy in patients with breast cancer.

A real-world evidence study of CDK4/6 inhibitor treatment patterns and outcomes in metastatic breast cancer by gBRCA mutation status.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1563-1563
Author(s):  
Kimmie McLaurin ◽  
Tapashi Dalvi ◽  
Jenna M Collins ◽  
Beth L Nordstrom ◽  
Susan McCutcheon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Real World ◽  
Treatment Options ◽  
Unmet Need ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Treatment Patterns ◽  
Cox Models ◽  
Line Of Therapy

1563 Background: Limited data exist on the real-world treatment patterns and effectiveness of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors in the germline BRCA (g BRCA) mutated breast cancer population. Methods: Adults with human epidermal growth factor receptor 2 negative (HER2-), hormone receptor positive (HR+) metastatic breast cancer (mBC) treated with a CDK4/6 inhibitor from 01Jan2013–31Jan2018 were retrospectively selected from the Flatiron Health Oncology electronic medical record database. Patients with known g BRCA status were classified as having g BRCA mutated (g BRCAm) or wild type (g BRCAwt) disease. Time to first subsequent therapy or death (TFST) and overall survival (OS) were calculated from start of the earliest line of therapy with a CDK4/6 inhibitor. Kaplan-Meier (KM) medians were estimated, and TFST and OS compared between g BRCA groups with Cox models stratified by line of therapy and adjusting for demographic and clinical characteristics that modified hazard ratios (HRs) for g BRCA status by > 10%. Results: Of 2968 HER2- HR+ patients with mBC receiving a CDK4/6 inhibitor, g BRCA status was known for 859 (28.9%). Patients with g BRCAm and g BRCAwt received letrozole plus palbociclib (42.4 and 39.8%, respectively), fulvestrant plus palbociclib (32.9 and 30.7%), or other CDK4/6 regimens (24.7 and 29.5%) across all lines. The g BRCAm group had a non-significant, shorter TFST than g BRCAwt (stratified HR 1.24; 95% CI 0.96–1.59). OS was significantly shorter in g BRCAm than g BRCAwt patients (stratified HR 1.50; 95% CI 1.06–2.14). Conclusions: The results of this real-world study suggest that treatment outcomes with CDK4/6 inhibitors may be poorer in patients with g BRCAm compared with g BRCAwt disease. These findings indicate a higher unmet need among patients with g BRCAm, potentially requiring alternative treatment options. [Table: see text]

scholarly journals Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B)

Breast Cancer ◽  
2021 ◽  
Author(s):  
Takamichi Yokoe ◽  
Sasagu Kurozumi ◽  
Kazuki Nozawa ◽  
Yukinori Ozaki ◽  
Tetsuyo Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cohort Study ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Real World ◽  
Treatment Strategies ◽  
Metastatic Breast ◽  
Trastuzumab Emtansine ◽  
Breast Cancer Patients ◽  
Her2 Positive

Abstract Background Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer. Methods In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1–28.0], DCR = 66.6% (95% CI 60.8–72.0), median PFS = 6.1 months (95% CI 5.3–6.7), median TTF = 5.1 months (95% CI 4.4–5.6), and median OS = 23.7 months (95% CI 20.7–27.4). Conclusion The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.

Sign in / Sign up

Export Citation Format

Share Document