Assessment of Molecular Markers of Clinical Sensitivity to Single-Agent Taxane Therapy for Metastatic Breast Cancer

2002 ◽  
Vol 20 (9) ◽  
pp. 2319-2326 ◽  
Author(s):  
Catherine Van Poznak ◽  
Lee Tan ◽  
Katherine S. Panageas ◽  
Crispinita D. Arroyo ◽  
Clifford Hudis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Markers ◽  
Metastatic Breast Cancer ◽  
Estrogen Receptors ◽  
Clinical Response ◽  
Performance Status ◽  
Single Agent ◽  
Progesterone Receptors ◽  
Metastatic Breast ◽  
Taxane Chemotherapy

PURPOSE: The taxanes affect tubulin polymerization and interfere with mitotic transition. A checkpoint blockade at the G1-S boundary would be expected to promote taxane-induced apoptotic cell death through a mechanism that may involve p27. Other proposed determinants of clinical taxane sensitivity/resistance include p53, members of the epidermal growth factor receptor (EGFR) superfamily (eg, HER2, EGFR), and estrogen receptors and progesterone receptors. These molecular markers and their correlation with clinical taxane sensitivity are investigated in this retrospective clinicopathologic study. PATIENTS AND METHODS: We performed immunohistochemistry (IHC) for estrogen receptors, progesterone receptors, HER2, EGFR, p53, and p27 on 144 breast tumor specimens from patients treated for metastatic breast cancer on a series of clinical trials of single-agent taxane chemotherapy for correlation with clinical response (complete or partial response). Patient characteristics that could influence response (ie, performance status, extent of disease, and prior therapy) were also examined. RESULTS: In univariate analysis, Karnofsky performance status ≥ 90% and no prior history of anthracycline therapy correlated with a good clinical response to single-agent taxane (P = .003 and P = .041, respectively). None of the IHC variables tested were predictive of clinical response to taxane therapy, although p27 negativity showed a trend toward significance (P = .075). Concordance between the polyclonal antibody with HercepTest (DAKO, Carpinteria, CA) and the monoclonal antibody CB-11 (BioGenex, San Ramon, CA) was noted (kappa = 0.943); however, neither univariate nor multivariate analysis demonstrated an association between HER2 status and response to taxane chemotherapy. CONCLUSION: The IHC biomarkers studied were not predictive of response to single-agent taxane chemotherapy in patients with metastatic breast cancer. Identification of molecular correlates of taxane response remains an important goal.

Phosphorylated/Activated HER2 as a Marker of Clinical Resistance to Single Agent Taxane Chemotherapy for Metastatic Breast Cancer

2005 ◽  
Vol 23 (6) ◽  
pp. 483-487 ◽  
Author(s):  
Shanu Modi ◽  
Michael P. DiGiovanna ◽  
Zhao Lu ◽  
Chaya Moskowitz ◽  
Katherine S. Panageas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Agent ◽  
Metastatic Breast ◽  
Clinical Resistance ◽  
Taxane Chemotherapy

Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer

2013 ◽  
Vol 31 (23) ◽  
pp. 2870-2878 ◽  
Author(s):  
John P. Crown ◽  
Véronique Diéras ◽  
Elzbieta Staroslawska ◽  
Denise A. Yardley ◽  
Thomas Bachelot ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Performance Status ◽  
Single Agent ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Phase Iii Trial ◽  
Free Survival

Purpose Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC. Patients and Methods Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). Results A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. Conclusion The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.

Mitoxantrone as a Single Agent in Pretreated Metastatic Breast Cancer: Effects on T Lymphocyte Subsets and Their Relation to Clinical Response

1991 ◽  
Vol 77 (3) ◽  
pp. 227-231 ◽  
Author(s):  
Sandro Barni ◽  
Paolo Lissoni ◽  
Franco Paolorossi ◽  
Roberto Rescaldani ◽  
Sergio Crispino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Response ◽  
T Lymphocyte ◽  
Lymphocyte Subsets ◽  
Single Agent ◽  
Metastatic Breast ◽  
T Lymphocyte Subsets

Combination chemotherapy with gencitabine and cisplatin in anthracycline and taxane pretreated metastatic breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1108-1108 ◽  
Author(s):  
F. M. Peria ◽  
F. E. Zola ◽  
D. G. Tiezzi ◽  
H. H. Carrara ◽  
P. M. Philbert ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Combination Chemotherapy ◽  
Performance Status ◽  
Single Agent ◽  
Metastatic Breast ◽  
Hematological Toxicity ◽  
Eligibility Criteria ◽  
Metastatic Sites ◽  
The Right

1108 Background: Metastatic breast cancer (MBC) anthracycline (A) and taxane (T) resistant has a complicated management.Combination chemotherapy, even in 2nd line, may have advantages over single agent therapy. Gencitabine (G) - cisplatin (C) combinations have been used as synergistic salvage therapy in MBC and it’s another option for patients with important symptoms and aggressive visceral disseminated disease. Methods: This trial analyses the safety and efficacy of G-C in A-T pretreated MBC. Eligibility criteria include: confirmatory pathological analyses; measurable disease; adequate performance status, organ and hematological functions. It was not allowed patients with exclusive bone metastasis. They received IV G 750mg/m2 and C 30mg/m2, both d1 and d8 every three weeks for 6 cycles up to a maximum of 9 cycles. Response evaluation was performed every third cycle and in the end of treatment. Results: From February 2005 through December 2006, 31 patients have been evaluated for response and toxicity from G-C combination. For 20/31 patients this treatment was 2nd line palliative chemotherapy. 26/31 received at least 3 or more cycles (medium 4 cycles) and no one treatment was discontinued due to toxicity. The most frequent site of metastasis was lung (20/31), followed by hepatic in 13 patients, bone in 11, skin in 10, lymph nodes in 7, brain metastasis in 3 and pericardium in only one. Each patient had at least lung or hepatic metastasis and medium of 2 different metastatic sites. According to RECIST criteria, partial response were observed in 8/31, stable disease in 17/31 (55%) and progressive disease in 6 patients. 90% of cycles were given at full dose and at the right time. Hematological toxicity was modest with grade 2–3 (NCI-CTC) leucopenia in 58/140 cycles, grade 1–2 anemia in 40/140, grade 1–2 thrombocytopenia in 27/140 and was none febrile neutropenia. Non hematological toxicity: grade 2 fatigue in 4 patients and grade 2 nausea in 6/31. Following 22 months, global survival was at mean 4.8 months. Conclusions: Combination chemotherapy with gencitabine 750mg/m2 and cisplatin 30mg/m2 both d1 and d8 is feasible and effective in A-T pretreated MBC and demonstrated good tolerance with low intensity of collateral effects. No significant financial relationships to disclose.

Interim safety analysis of the randomized phase III PELICAN trial evaluating pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line therapy for metastatic breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1118-1118
Author(s):  
S. Al-Batran ◽  
S. Saupe ◽  
M. Schmidt ◽  
R. Kreienberg ◽  
B. Otremba ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Disease Progression ◽  
Performance Status ◽  
Single Agent ◽  
Metastatic Breast ◽  
Pegylated Liposomal Doxorubicin ◽  
Phase Iii ◽  
First Line ◽  
Grade 3

1118 Background: Treatment of metastatic breast cancer (MBC) focuses on relieving symptoms and extending life. Single-agent therapy is preferred in the first-line setting to reduce the risk of toxicity and maintain quality of life. The PELICAN trial was designed to evaluate efficacy and safety of first-line PLD vs capecitabine at standard approved dosages. Methods: PELICAN is an open-label, multinational, randomized, multicenter trial. MBC Patients (pts) were randomized to receive PLD (50 mg/m2 every 28 days) or capecitabine (1250 mg/m2 BID x 14 days every 21 days) until disease progression or unacceptable toxicity. The primary endpoint was to compare time to disease progression between treatment arms. Toxicity was evaluated continuously. Results: The study is still ongoing, but no longer recruiting. So far, 210 pts (PLD, 105; capecitabine, 105) were evaluated for safety, of whom 131 pts have already completed their treatment (83 for disease progression, 19 for toxicity, 5 died, 24 for other reasons). 90% of pts had ECOG performance status 1 or 2, and 79% were postmenopausal. Mean age was 61.5 years, and 34% received prior adjuvant anthracycline. Pts received a median of 4 cycles of PLD and a median of 5 cycles of capecitabine. Over 90% of pts in both groups experienced at least one adverse event (AE). Grade 3/4 AEs were reported in 99 patients (PLD, 44; capecitabine, 55). Hand foot syndrome (HFS) was the most common AE (grade 3: PLD 35%; capecitabine 19%), followed by diarrhea (grade 3/4: PLD, 0; capecitabine, 13%) and thromboembolic events (PLD, 0%; capecitabine, 9%). Other grade 3/4 AEs affected 1 week in 16%. Conclusions: Overall, first-line monotherapy with PLD or capecitabine at approved doses was maintainable for a median of about 4 months with manageable AEs. Interim safety results of the PELICAN trial show no unanticipated toxicity. Efficacy results will be available once all patients have completed their therapy. [Table: see text]

scholarly journals Olaparib in hormone receptor-positive, HER2-negative metastatic breast cancer with a somatic BRCA2 mutation

2021 ◽  
Vol 13 ◽  
pp. 175883592110069
Author(s):  
Lee S. Schwartzberg ◽  
Lesli A. Kiedrowski
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Response ◽  
Hormone Receptor ◽  
Brca2 Mutation ◽  
Locally Advanced ◽  
Susceptibility Gene ◽  
Metastatic Breast ◽  
Breast Cancer Susceptibility Gene ◽  
Hormone Receptor Positive

The oral poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib is approved for the treatment of patients with human epidermal growth factor 2-negative (HER2−) metastatic breast cancer (mBC) and a germline breast cancer susceptibility gene (BRCA) mutation who have been treated with chemotherapy. This case report describes a 63-year-old postmenopausal woman with somatic BRCA2-mutated mBC who responded to olaparib treatment following multiple prior lines of therapy. The patient presented in January 2012 with locally advanced, hormone receptor-positive (HR+), HER2− BC which, despite initial response to neoadjuvant chemotherapy, recurred as bone disease in February 2014, and subsequently skin (June 2016) and liver (October 2016) metastases. A comprehensive 592-gene next-generation sequencing panel (Caris Life Sciences), performed on a skin biopsy, detected a pathogenic frameshift mutation in BRCA2 (H3154fs, c.9460delC), which was not identified in a 28-gene hereditary cancer germline analysis (Myriad Genetics, Inc.), and was therefore considered to be a somatic mutation. In January 2017, cell-free DNA (cfDNA) analysis (Guardant Health, Inc.) confirmed the BRCA2 H3154fs mutation in plasma. After several lines of chemotherapy and endocrine therapy, deriving clinical benefit from eribulin and capecitabine, the disease progressed by October 2017, and olaparib (300 mg orally twice daily) was initiated in January 2018. By April 2018, the liver lesions had shrunk by 80% and a >90% response in multiple skin lesions was noted. Clinical response was maintained for 8 months, followed by progression in the skin in September 2018. Biopsy of recurrent lesions revealed a novel BRCA2 mutation, E3152del (c.9455_9457delAGG), predicted to restore the open reading frame and presumably the mechanism of resistance to olaparib. Further likely resistance mutations were noted in subsequent cfDNA analyses. This case demonstrated a clinical response with olaparib as a later-line therapy for HR+, HER2− mBC with a somatic BRCA2 mutation.

scholarly journals Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens

2009 ◽  
Vol 20 (6) ◽  
pp. 1026-1031 ◽  
Author(s):  
K.L. Blackwell ◽  
M.D. Pegram ◽  
E. Tan-Chiu ◽  
L.S. Schwartzberg ◽  
M.C. Arbushites ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Agent ◽  
Metastatic Breast ◽  
Second Line

Development of a breast cancer-specific prognostic tool using CancerLinQ Discovery.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 275-275
Author(s):  
Emily Miller Ray ◽  
Xinyi Zhang ◽  
Lisette Dunham ◽  
Xianming Tan ◽  
Jennifer Elston Lafata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
Metastatic Breast Cancer ◽  
High Risk ◽  
Performance Status ◽  
Vital Signs ◽  
Metastatic Breast ◽  
Clinical Use ◽  
Final Model ◽  
Prognostic Tool

275 Background: Oncologists often struggle to know which patients are near end of life to enable a timely transition to supportive care. We developed a breast cancer-specific prognostic tool, using electronic health record data from CancerLinQ Discovery (CLQD), to help identify patients at high risk of near-term death. We created multiple candidate models with varying thresholds for defining high risk that will be considered for future clinical use. Methods: We included patients with breast cancer diagnosed between 1/1/2000 to 6/1/2020 who had at least one encounter with vital signs and evidence of metastatic breast cancer (MBC). All encounters from 1/1/2000 to 7/5/2020 were included. We used multiple imputation (MI) to impute missing numeric variables and treated missing values as a new level for categorical variables. We sampled one encounter per patient and oversampled within 30 days of death, so that the event rate (death within 30 days of encounter) was about 10%. We randomly divided these patients into training (70%) and test datasets (30%). We evaluated candidate predictors of the event using logistic regression with forward variable selection. Candidate predictors included age, vital signs, laboratory values, performance status, pain score, time since chemotherapy, and ER/PR/HER2 receptor status, and change from baseline and change rate of numeric variables. We obtained a single final model by combining resulted logistic regression model from 10 MI training sets. We evaluated this final model on the MI test sets. We varied the alert threshold (i.e., high-risk proportion) from 5% to 40%. Results: We identified 9,270 patients, representing 586,801 encounters. Significant predictors of mortality were: increased age, decreased age at diagnosis, negative change in body mass index, low albumin, high ALP, high AST, high WBC, low sodium, high creatinine, worse performance status, low pulse oximetry, increased age with increased creatinine, high pain score with no opiates, increased pulse rate, unknown/missing PR, opiate use in past 3 months, and prior chemotherapy in past 1 year but not past 30 days. Candidate models had prediction accuracy of 70-89% and positive predictive value of 31-77%. Conclusions: Demographic and clinical variables can be used to predict risk of death within 30 days of a clinical encounter for patients with MBC. Next steps include selection of a preferred model for clinical use, balancing performance characteristics and acceptability, followed by implementation and evaluation of the prognostic tool in the clinic. Candidate models, varying by threshold or percentage of patients assumed to be at high risk, for the outcome of death within 30 days among patients with metastatic breast cancer.[Table: see text]

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