Prospective longitudinal multi-omics study of palbociclib resistance in hormone receptor+/HER2- metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1013-1013
Author(s):  
Yeon Hee Park ◽  
Seock-Ah Im ◽  
Kyunghee Park ◽  
Ji Wen ◽  
Ahrum Min ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Metastatic Breast Cancer ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Significant Advance ◽  
Luminal A ◽  
Luminal B ◽  
Pre Treatment ◽  
Tumor Biopsies

1013 Background: The development of CDK4/6 inhibitors represents a significant advance in the treatment of metastatic breast cancer (MBC). To better understand the impact of treatment and drug resistance at the molecular level, we performed multi-omics profiling of matched pre-treatment, on-treatment, and post-progression tumor biopsies from patients treated with palbociclib combined with endocrine blockades (AIs and fulvestrant). The purpose of the study was to identify biomarkers of palbociclib resistance as well as to assess molecular changes during treatment, and those appearing at disease progression. Methods: Patients with Hormone Receptor positive (HR+)/HER2- MBC treated with palbociclib in combination with endocrine therapies were prospectively enrolled from July 2017 to June 2020. Of the 89 patients enrolled, we obtained tumor biopsies and matched blood samples, taken at pre-treatment, on-treatment (6 weeks or 12 weeks) and progressive disease (PD) from 71 patients (first line: 55, second line or later: 16 pts.) who had agreed to informed consent form. Tumor biopsies were profiled using whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-Seq). Results: Median follow-up duration was 20 (3-48) months and median age of the patients was 45 (range 30-71) years. The median progression free survival (PFS) of 71 patients was 15 (0.7-39.8) months. The Luminal B subtype is associated with shorter PFS compared to Luminal A (8.6 m vs 19.3 m, p=0.03, HR=1.96). The Luminal B subtype along with multiple cell cycle regulatory genes such as CCNE1 (8.3 m, p=0.015, HR=2.07), CCNE2 (8.5 m, p=8.5e-3, HR=2.2), CDK2 (8.45 m, p=0.05, HR=1.79) are associated with shorter PFS while estrogen response signatures (20.9 m, p=4.6e-3, HR=0.43) and PGR gene expression (20.2 m, p=6.2e-2, HR=0.56) are associated with more favorable prognosis. A Cox-regression multivariate model (p=5.17e-5, C-Index=0.72) was developed and revealed that PFS is independently associated with BRCA1/2 (HR=1.44; CI=[0.49, 4.29]), TP53 mutation statuses (HR=3.58; CI=[1.58, 8.13]), the HRD mutation signature (HR=1.40; CI=[1.09, 1.81]) and the proliferative index (HR=1.53; CI=[1.00, 2.34]), an expression signature of cell proliferation. Tumors classified as Luminal A at baseline frequently switched into Luminal B or Her2-enriched subtypes at PD, along with up-regulation of cell cycle markers and proliferation signatures. Further, tumor mutation burden (TMB) and HRD index, a DNA-based measure of genomic instability, significantly increased from baseline to PD in patients with TP53 and BRCA1/2 wild-type tumors. Conclusions: Our longitudinal multi-omics study identified prognostic biomarkers as well as post-treatment enrichment of HRD related genomic scars and frequent switching into molecular subtypes with aggressive and estrogen independence characteristics. Clinical trial information: NCT03401359 .

LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 534-534 ◽  
Author(s):  
Amita Patnaik ◽  
Lee S. Rosen ◽  
Sara M. Tolaney ◽  
Anthony W. Tolcher ◽  
Jonathan Wade Goldman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Metastatic Breast Cancer ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Cell Cycle Inhibitor ◽  
Hormone Receptor Positive

Correlate effects of local therapy for the primary tumor in metastatic breast cancer at diagnosis with molecular subtypes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11502-e11502
Author(s):  
Fatima Zahra Hijri ◽  
Samia Arifi ◽  
Sami Aziz Brahmi ◽  
Nezar Bouyahia ◽  
Zineb Benbrahim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Primary Tumor ◽  
Molecular Subtypes ◽  
Metastatic Breast ◽  
Local Therapy ◽  
Axillary Lymph ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B

e11502 Background: Few studies demonstrated that surgical resection of the primary tumor in patients with metastatic breast cancer at diagnosis is associated with significant improvement of survival. The aim of this study is to evaluate the correlation impact of local surgery in metastatic breast cancer at diagnosis with molecular subtypes. Methods: A retrospective study was conducted from 2007 to 2011 in our institution, of all stage IV breast cancer patients; who undergo breast surgery. Clinical , tumor characteristics, molecular subtypes, prognostic factors, therapeutic results data were analyzed. Results: We selected 59 cases. The mean age was 36 years (range: 22-44). 55 % women presented with locally advanced breast cancer with 13% T4 d . All patients underwent mastectomy except 4 who underwent conservative surgery .41 patients had axillary lymph node dissection. 63% were luminal A, 17% were luminal B, 7% were Her2-positive and 13% were basal-like . All patients received anthracycline based regimen and only 33% received taxanes. Loco regional radiotherapy (RT) was given to 6 women. Average follow-up was 13 months: - 20 patients represented partial response : 15 patients in luminal A , 3 patients in luminal B ,1 patients in basal-like and 1 patient in HER2-positive. - 11 patients (19%) were stable : 9 patients in luminal A and 2 patient in luminal B . -24 patients represented a progressive disease including 11 patients presented locoregional recurrence : 75 % in HER-positive, 40 % in basal-like, 50% in luminal B and 30% in luminal A (p=0.4). - 4 patients died in basal-like. The median local recurrence-free survival was 19 months and the median progression-free survival was 20 months. The local relapse is less observed in patients who: have a small tumor size (p = 0.003), had axillary lymph node dissection (p = 0.02) and loco regional radiotherapy (p = 0.03). The metastatic progression is less observed in patients with small tumor size (p = 0.01). Conclusions: Local Therapy of the primary tumor improves local control of disease, particularly in women with Small tumors. However, no significant correlation between impact of locale therapy and Molecular Subtypes was observed.

First results of a prospective registry in unresectable locally advanced or metastatic breast cancer patients: GEICAM/2014-03 (RegistEM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1077-1077
Author(s):  
Carlos Jara ◽  
Isabel Alvarez ◽  
Mireia Margeli Vila ◽  
Cesar Augusto Rodriguez ◽  
Purificacion Martinez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Advanced Disease ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Primary Breast Tumor ◽  
Luminal A ◽  
Luminal B ◽  
First Diagnosis

1077 Background: In Spain there is limited prospective data for unresectable locally advanced breast cancer (ULABC) or metastatic breast cancer (MBC) patients (pts) treated as per clinical practice. RegistEM study will provide epidemiological, pathological and clinical data, including treatments given for different disease stages. Understanding the real distribution of the different BC subtypes is the primary objective. Methods: This is a non-interventional cohort study enrolling approximately 1,400 pts with advanced disease diagnosed from January 2016 to December 2018, either after recurrence or as first diagnosis, in 38 Spanish sites. Biological samples (primary tumor, metastatic lesions, blood) are currently being collected. In this first analysis, we include 489 pts who met study criteria before October 31, 2017. All data are described in two subgroups: on the most recent tumor lesion or on the primary breast tumor. Results: At first diagnosis, 67.9%, 31.5% and 0.6% of pts had early BC (EBC), MBC and ULABC, respectively. In the total analysis population, median age at diagnosis of advanced disease was 59.6 years, most of pts were white (98.2%), female (99.4%) and postmenopausal (70%). Family history of BC and ovarian cancer was reported in 5.7% pts. In ~390 pts BC clinical subtypes distribution was luminal B(HER2-)-like (~55%), luminal B(HER2+)-like (~16%), luminal A-like or triple negative (TN) (~10% each) and HER2 enriched-like (~8%). Median time to recurrence (years) in EBC pts was: luminal A-like 5.8, luminal B(HER2-)-like 5.1, luminal B(HER2+)-like 3.9, HER2 enriched-like 2.7 and TN 1.7. Bone (59%), visceral (58%) and lymph node (27%) lesions were the most frequent metastatic locations. The two most frequent therapies in first line consisted in: endocrine therapy (ET) (47%) and ET+biological therapy (BT) (29%) for luminal A-like; ET (32%) and ET+BT (32%) for luminal B(HER2-)-like; chemotherapy (CT)+ET+BT (43%) and CT+BT (24%) for luminal B(HER2+)-like; CT+BT (68%) and CT (16%) for HER2 enriched-like; CT (59%) and CT+BT (34%) for TN. Conclusions: These first data confirm that luminal B (HER2-)-like subtype is the most predominant in MBC.

scholarly journals Role of Tumor Subtypes in Response to Neoadjuvant Chemotherapy in Non-metastatic Breast Cancer

2021 ◽  
Vol 24 (12) ◽  
pp. 881-886
Author(s):  
Negar Mashoori ◽  
Ramesh Omranipour ◽  
Abdolali Assarian
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Pathologic Complete Response ◽  
Metastatic Breast ◽  
Tumor Grade ◽  
Her2 Status ◽  
Luminal A ◽  
Luminal B ◽  
Female Patients

Background: Neoadjuvant chemotherapy (NAC) is an integral part of breast cancer treatment. Determination of the factors that can distinguish patients who will have best response to NAC is invaluable. In this study, we aimed to elucidate the factors influencing patient response to NAC. Methods: We retrospectively collected data of female patients with non-metastatic breast cancer that had received NAC followed by surgery, admitted to Imam Khomeini hospital between 2015–2019. We investigated the association between various tumor and patients’ characteristics with pathologic complete response (PCR). Results: Overall data of 205 female patients were collected. PCR was observed in 27.6% of cases. PCR rate in luminal A, luminal B, HER2 enriched, and TNB tumors was reported in 11.1%, 30.2%, 35.7%, and 36.4% of patients respectively (P=0.27). In patients with luminal B tumors, PCR was more prevalent in patients with positive HER2 only (P=0.006). In our study factors which was significantly associated with PCR were: tumor grade, progesterone receptor (PR) status, and HER2 status. In the multiple regression model, positive PR in the tumor lowered the odds of pathologic response 3.6 times (P=0.004). Conclusion: In our study, tumor grade, PR status, and HER2 status was associated with response to NAC. PCR was more prevalent in non-luminal tumors; however, PCR rate in luminal B patients-especially those with HER2 positive status- was slightly less than non-luminals.

Luminal Subtypes Predict Improved Survival Following Central Nervous System Metastasis in Patients With Surgically Managed Metastatic Breast Carcinoma

2014 ◽  
Vol 138 (2) ◽  
pp. 175-181 ◽  
Author(s):  
Andrea L. Wiens ◽  
Sarah E. Martin ◽  
Elizabeth C. Bertsch ◽  
Gail H. Vance ◽  
Ryan A. Stohler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Central Nervous System ◽  
Nervous System ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Metastatic Breast ◽  
Luminal A ◽  
Luminal B

Context.—Metastatic breast cancer to the central nervous system (CNS) is second only to lung cancer metastasis to the CNS in frequency. Patients with triple-negative primary breast cancer and those with human epidermal growth factor receptor 2 (HER2)–positive primary breast cancer are at an increased risk for metastasis. Very little is known about predictive or prognostic variables once patients develop CNS metastases. Currently, therapeutic options are limited, with surgery generally offered primarily to those with solitary lesions. Context.—To determine the influence of molecular subtypes of metastatic breast cancer on survival from the time of CNS metastasis and to aid in the prognostic stratification of these patients. Design.—We identified 59 cases of metastatic breast cancer to the CNS and analyzed them for various demographic and clinicopathologic parameters. Tumors were categorized into molecular subtypes using immunohistochemical methods: luminal A [estrogen receptor (ER)+/Ki67low], luminal B (ER+/Ki67 high), intrinsic HER2 (ER−/HER2+), and triple-negative. Survival after CNS metastasis for each group was plotted using a Kaplan-Meier curve, and multivariate analysis was performed. Results.—Patients with metastases from luminal tumors had a statistically significant survival advantage when compared with those of the triple-negative phenotype. Importantly, survival among patients with luminal A and luminal B tumors was not significantly different. Similarly, patient's age, histologic grade, and number of lesions did not contribute to determining outcomes. Conclusions.—Estrogen receptor positivity (ie, luminal phenotype) of tumors appears to determine outcomes after development of metastases. In contrast, proliferation rate had little or no effect on the long-term survival. Understanding the biology of metastases can help stratify patients into prognostically meaningful categories and tailor treatment regimens for individual patients.

scholarly journals Inflammatory Breast Cancer: Clinical Characteristics and Influence of Molecular Subtypes on Treatment Response

2021 ◽  
Vol 107 (1_suppl) ◽  
pp. 12-12
Author(s):  
D Aissaoui ◽  
M Bohli ◽  
R Ben Amor ◽  
J Yahyaoui ◽  
A Hamdoun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Response ◽  
Inflammatory Breast Cancer ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B ◽  
Significant Difference

Introduction: Inflammatory Breast Cancer (IBC) is a rare and very aggressive breast cancer with poor prognosis. The prevalence is different from a country to another. In Tunisia, it is about 5 to 7% of breast cancer. The aim of this study is to describe the epidemiological and histopathological features of patients with inflammatory breast cancer and to evaluate the treatment response according to the molecular subtypes. Methods: This retrospective review identified 31 patients with no metastatic IBC treated in our radiotherapy department between December 2019 and November 2020. IBC was confirmed using the clinical criteria. Baseline clinic-pathological and treatment information was retrieved from medical records. Statistical analysis was performed with IBM SPSS V.20. Results: Median age was 51.3 years [27-68]. 48% of tumors were grade 3. The average tumor size was 36mm [10-90]. The histological type was ductal carcinoma in 97%. Vascular invasion was noted in 24 patients (77%). Thirty patients were classified as stage IIIB and one patient was IIIC. 74% were hormone receptor positive and 45% were HER2 positive. Luminal B was the predominant subtype (52%) followed by Her2 positive (32%), Luminal A (23%), and triple negative (3%) All patients had chemotherapy: neoadjuvant for 26 patients (84%) and adjuvant for 5 patients (16%). Nine patients (29%) had tumor pathological complete response (pCR). Partial response was observed in 18 patients (58%). Lymph node pCR was noted in 16% of cases (n=5). Endocrine therapy and trastuzumab were given to 76% and 45% of patients, respectively. The influence of the molecular subtype was not statistically significant on the response to neoadjuvant treatment. The highest rate of pCR were 43% for Her2positive, then 27%, 21% and 9% for Luminal B, Luminal A and Triple negative, respectively (p=0.2). Conclusion: Our study showed a high percentage of hormone receptor and Her2+ (74% and 45% respectively) in IBC. Luminal B was the most frequent subtype. Anthracycline-based chemotherapy and trastuzumab improved the pCR rate: 44% for Her2positive. Triple negative showed poorer pCR than other breast cancer subtype without a significant difference. A larger study is warranted to confirm our findings.

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