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1.  Relationship Between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple Negative Breast Cancer 
Purpose
To perform an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy.
Experimental design
RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative RT-PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests.
Results
GRB7 was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn’s adjusted p value=0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR 2.31, p=0.04 using the median as the split). The 5-year recurrence rates were 10.5% (95% confidence intervals [CI] 7.8%, 14.1%) in the low and 20.4% (95% CI 16.5%, 25.0%) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy.
Conclusions
GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered.
doi:10.1158/1078-0432.CCR-10-3357
PMCID: PMC3570203  PMID: 21933890
Breast cancer; GRB7 RNA expression; recurrence
2.  Relationship Between Topoisomerase 2A RNA Expression and Recurrence after Adjuvant Chemotherapy for Breast Cancer 
Clinical Cancer Research  2009;15(24):7693-7700.
Purpose
To perform an exploratory analysis of the relationship between gene expression and recurrence in operable hormone receptor (HR)-positive, HER2-normal breast cancer patients treated with adjuvant doxorubicin-containing chemotherapy.
Experimental Design
RNA was extracted from archived tumor samples derived from 378 patients with stage I–III HR-positive, HER2-normal breast cancer and analyzed by RT-PCR for a panel of 374 genes, including the 21 gene Recurrence Score (RS). Patients were randomized to receive adjuvant doxorubicin plus cyclophosphamide or docetaxel in trial E2197, with no difference in recurrence seen in the treatment arms. All available recurrent cases were selected plus a non-recurrent cohort. Cox proportional hazard models were used to identify relationships between gene expression and recurrence.
Results
TOP2A expression exhibited the strongest association with increased recurrence risk (p=0.01), and was significantly associated with recurrence (p=0.008) in a multivariate analysis adjusted for clinicopathological features. Elevated TOP2A expression above the median was associated with a 2.6-fold increase (95% confidence intervals [CI], 1.3, 5.2 p=0.008) in risk of recurrence if the RS was less than 18, and a 2.0-fold increase (95% CI, 1.2, 3.2, p=0.003) if there was an intermediate RS of 18–30.
Conclusions
In patients with HR-positive, HER2-normal breast cancer, a population known to have a low incidence of TOP2A gene alterations thought to be predictive of anthracycline benefit, there is a range of TOP2A RNA expression that is strongly associated with recurrence after adjuvant anthracyclines which provides information complementary to RS, indicating that it merits further evaluation as a prognostic and predictive marker.
doi:10.1158/1078-0432.CCR-09-1450
PMCID: PMC3396025  PMID: 19996222
Breast cancer; TOP2A RNA expression; recurrence
3.  Physician Survey of the Effect of the 21-Gene Recurrence Score Assay Results on Treatment Recommendations for Patients With Lymph Node–Positive, Estrogen Receptor–Positive Breast Cancer 
Journal of Oncology Practice  2011;7(2):94-99.
This physician survey looks at the effect of the 21-gene recurrence score assay results on adjuvant treatment recommendations for patients with lymph node–positive, estrogen receptor–positive breast cancer.
Purpose:
To survey the effect of the 21-gene recurrence score (RS) assay results on adjuvant treatment recommendations for patients with lymph node–positive (N+), estrogen receptor–positive (ER+) breast cancer.
Methods:
Medical oncologists who ordered the 21-gene RS assay were invited to complete a survey regarding their most recent patient with N+/ER+ breast cancer. We obtained responses from 160 (16%) of the 1,017 medical oncologists.
Results:
Most of the respondents were in community (71%) versus academic (25%) settings and had practiced for a median of 11 years. T1, T2, or T3 disease was reported in 62%, 35%, and 3% of patients, respectively. One, two, three, or ≥ 4 nodes were reported in 69%, 18%, 6%, and 3% of patients, respectively. Eighty-six percent of the oncologists made treatment recommendations before obtaining the RS; 51% changed their recommendations after receiving the RS. In 33%, treatment intensity decreased from chemotherapy plus hormonal therapy to hormonal therapy alone. In 9%, treatment intensity increased from hormonal therapy alone to chemotherapy plus hormonal therapy. In 8%, treatment recommendations changed in a way that did not fit the definition of either increased or decreased intensity.
Conclusion:
In this survey of physician practice, the RS result was used to guide adjuvant treatment decision making in N+/ER+ breast cancer more often in patients with tumors less than 5 cm in size and one to three positive lymph nodes than in patients with larger tumors and four or more positive nodes and yielded an overall reduction in recommendations for chemotherapy.
doi:10.1200/JOP.2010.000046
PMCID: PMC3051869  PMID: 21731516
4.  Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in a Randomized Trial of Chemotherapy for Postmenopausal, Node-Positive, Estrogen Receptor-Positive Breast Cancer 
The lancet oncology  2009;11(1):55-65.
SUMMARY
Background
The 21-gene Recurrence Score assay (RS) is prognostic for women with node-negative, estrogen receptor (ER)-positive breast cancer (BC) treated with tamoxifen. A low RS predicts little benefit of chemotherapy. For node-positive BC, we investigated whether RS was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher recurrence risks.
Methods
The phase III trial S8814 for postmenopausal women with node-positive, ER-positive BC showed that CAF chemotherapy prior to tamoxifen (CAF-T) added survival benefit to tamoxifen alone. Optional tumor banking yielded specimens for RS determination by RT-PCR. We evaluated the effect of RS on disease-free survival (DFS) by treatment group (tamoxifen versus CAF-T) using Cox regression adjusting for number of positive nodes.
Findings
There were 367 specimens (40% of parent trial) with sufficient RNA (tamoxifen, 148; CAF-T, 219). The RS was prognostic in the tamoxifen arm (p=0.006). There was no CAF benefit in the low RS group (logrank p=0.97; HR=1.02, 95% CI (0.54,1.93)), but major DFS improvement for the high RS subset (logrank p=.03; HR=0.59, 95% CI (0.35, 1.01)), adjusting for number of positive nodes. The RS-by-treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), though the cumulative benefit remained at 10 years. Results were similar for overall survival and BC-specific survival.
Interpretation
In this retrospective analysis, the RS is prognostic for tamoxifen-treated patients with positive nodes and predicts significant CAF benefit in tumors with a high RS. A low RS identifies women who may not benefit from anthracycline-based chemotherapy despite positive nodes.
doi:10.1016/S1470-2045(09)70314-6
PMCID: PMC3058239  PMID: 20005174
5.  Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene 
Clinical and Vaccine Immunology  2006;13(9):1010-1013.
Squalene is a naturally occurring oil which has been used in the development of vaccine adjuvants, such as the oil-in-water emulsion MF59. In past years, by use of noncontrolled and nonvalidated assays, a claim was made that antisqualene antibodies were detectable in the sera of individuals with the so-called Gulf War syndrome. Using a validated enzyme-linked immunosorbent assay for the quantitation of immunoglobulin G (IgG) and IgM antibodies against squalene, we demonstrated that antisqualene antibodies are frequently detectable at very low titers in the sera of subjects who were never immunized with vaccines containing squalene. More importantly, vaccination with a subunit influenza vaccine with the MF59 adjuvant neither induced antisqualene antibodies nor enhanced preexisting antisqualene antibody titers. In conclusion, antisqualene antibodies are not increased by immunization with vaccines with the MF59 adjuvant. These data extend the safety profile of the MF59 emulsion adjuvant.
doi:10.1128/CVI.00191-06
PMCID: PMC1563566  PMID: 16960112
6.  Phase I Evaluation of Intranasal Trivalent Inactivated Influenza Vaccine with Nontoxigenic Escherichia coli Enterotoxin and Novel Biovector as Mucosal Adjuvants, Using Adult Volunteers 
Journal of Virology  2006;80(10):4962-4970.
Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-μg doses of hemagglutinin from each virus strain with either 3, 10, or 30 μg of heat-labile Escherichia coli enterotoxin (LTK63) and 990 μg of a supramolecular biovector; one intranasally vaccinated group was given 7.5-μg doses of hemagglutinin with 30 μg of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 μg hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 μg LTK63 with the biovector, occurring in 7/15 (47%; P = 0.0103), 8/15 (53%; P = 0.0362), and 14/15 (93%; P = 0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 μg LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P = 0.0491) and B/Guandong (P = 0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated.
doi:10.1128/JVI.80.10.4962-4970.2006
PMCID: PMC1472052  PMID: 16641287

Results 1-6 (6)