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A Phase II Study of Neoadjuvant Gemcitabine Plus Doxorubicin Followed by Gemcitabine Plus Cisplatin in Breast Cancer

ABSTRACT: This phase II study examined the pathological complete response (pCR) rate and safety of two gemcitabine-based combinations administered sequentially in breast cancer. We also examined gene expression profiles from tumor biopsies to identify biomarkers predictive of response. Methods: Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg/m2 plus doxorubicin 60 mg/m2 (Gem+Dox), then 4 cycles of gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 (Gem+Cis), and surgery. To examine dynamic changes in molecular profiles after one dose of therapy, we used three alternate sequences during cycle 1 (Gem d1, 8; Dox d2; Gem d1, 8; Dox d1; or Gem d2, 8; Dox d1). Results: Of 65 women (median age 46) treated, 13 (24.5% of 53 patients with surgery) had a pCR and 22 (33.8%) had a complete clinical response. Patients who received Gem d1, 8 and Dox d2 in cycle 1 (20/65) reported more toxicities, with G3/4 neutropenic infection/febrile neutropenia (7/20) and vomiting (5/20) as the most common cycle 1 events. Four drug-related deaths occurred. 46/65 patients yielded successful pretreatment gene expression profiles. Ten-fold cross-validated supervised analyses identified gene expression patterns that predicted with >73% accuracy (1) clinical complete response after eight cycles, (2) overall clinical complete response, and (3) pCR. Conclusions: This neoadjuvant regimen showed strong activity. A subset of patients receiving Gem d1, 8 and Dox d2 experienced unacceptable toxicity, whereas patients on other sequences had more manageable safety profiles. The predictive gene expression patterns may provide a method for selecting patients most likely to benefit from gemcitabine-containing neoadjuvant therapy. Key words: breast cancer, chemotherapy, gemcitabine, , gene expression, microarrays, neoadjuvant therapy Keywords: Dose response

ORGANISM(S): Homo sapiens

PROVIDER: GSE8465 | GEO | 2008/01/12

SECONDARY ACCESSION(S): PRJNA101549

REPOSITORIES: GEO

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Project description:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate. The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.

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A Phase II Study of Neoadjuvant Gemcitabine Plus Doxorubicin Followed by Gemcitabine Plus Cisplatin in Breast Cancer

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