RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer.
OBJECTIVE
We sought to determine whether dysregulation of the retinoblastoma (RB) tumor suppressor pathway was associated with improved response to neoadjuvant chemotherapy in breast cancer.


METHODS
An RB-loss signature was used to analyze the association between pathway status and pathologic complete response in gene expression datasets encompassing three different neoadjuvant regimens. Parallel immunohistochemical analysis of the RB pathway was conducted on pretreatment biopsies to determine the association with pathologic response to neoadjuvant chemotherapy.


RESULTS
An RB-loss gene expression signature was associated with increased pathologic complete response in datasets from breast cancer patients treated with 5-fluorouracil/adriamycin/cytoxan (FAC; P < 0.001), T/FAC (P < 0.001), and Taxane/Adriaymcin (P < 0.001) neoadjuvant therapy encompassing approximately 1,000 patients. The association with improved response to neoadjuvant chemotherapy was true in both estrogen receptor (ER)-positive and ER-negative breast cancer. Elevated expression of p16ink4a is associated with the RB-loss signature (R = 0.493-0.5982), and correspondingly p16ink4a mRNA levels were strongly associated with pathologic complete response in the same datasets analyzed. In an independent cohort, immunohistochemical analyses of RB and p16ink4a revealed an association of RB loss (P = 0.0018) or elevated p16ink4a (P = 0.0253) with pathologic complete response. In addition, by Miller-Payne and clinicopathologic scoring analyses, RB-deficient tumors experienced an overall improved response to neoadjuvant chemotherapy.


CONCLUSIONS
Disruption of the RB pathway as measured by several independent methods was associated with improved response to neoadjuvant chemotherapy. The RB-pathway status was relevant for pathologic response in both ER-positive and ER-negative breast cancer with similar results observed with multiple chemotherapy regimens. Combined, these data indicate that RB status is associated with the response to neoadjuvant chemotherapy in breast cancer and could be used to inform treatment.
Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Agnieszka.Witkiewicz@jefferson.edu
Agnieszka K
AK
Witkiewicz
Adam
A
Ertel
Jeanne
J
McFalls
Matias E
ME
Valsecchi
Gordon
G
Schwartz
Erik S
ES
Knudsen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D016160:Retinoblastoma Protein / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein