The 29.5 kb <i>APOBEC3B</i> Deletion Polymorphism Is Not Associated with Clinical Outcome of Breast Cancer

<div><p>Increased <i>APOBEC3B</i> mRNA levels are associated with a hypermutator phenotype and poor prognosis in ER-positive breast cancer patients. In addition, a 29.5 kb deletion polymorphism of <i>APOBEC3B</i>, resulting in an <i>APOBEC3A-B</i> hybrid transcript, has been associated with an increased breast cancer risk and the hypermutator phenotype. Here we evaluated whether the <i>APOBEC3B</i> deletion polymorphism also associates with clinical outcome of breast cancer. Copy number analysis was performed by quantitative PCR (qPCR) in primary tumors of 1,756 Dutch breast cancer patients. The <i>APOBEC3B</i> deletion was found in 187 patients of whom 16 carried a two-copy deletion and 171 carried a one-copy deletion. The prognostic value of the <i>APOBEC3B</i> deletion for the natural course of the disease was evaluated among 1,076 lymph-node negative (LNN) patients who did not receive adjuvant systemic treatment. No association was found between <i>APOBEC3B</i> copy number values and the length of metastasis-free survival (MFS; hazard ratio (HR) = 1.00, 95% confidence interval (CI) = 0.90–1.11, <i>P</i> = 0.96). Subgroup analysis by ER status also did not reveal an association between <i>APOBEC3B</i> copy number values and the length of MFS. The predictive value of the <i>APOBEC3B</i> deletion was assessed among 329 ER-positive breast cancer patients who received tamoxifen as the first-line therapy for recurrent disease and 226 breast cancer patients who received first-line chemotherapy for recurrent disease. No association between <i>APOBEC3B</i> copy number values and the overall response rate (ORR) to either tamoxifen (odds ratio (OR) = 0.88, 95% CI = 0.69–1.13, <i>P</i> = 0.31) or chemotherapy (OR = 0.97, 95% CI = 0.71–1.33, <i>P</i> = 0.87) was found. Thus, in contrast to <i>APOBEC3B</i> mRNA levels, the <i>APOBEC3B</i> deletion polymorphism has neither a prognostic nor a predictive value for breast cancer patients. Although a correlation exists between <i>APOBEC3B</i> copy number and mRNA expression, it is relatively weak. This suggests that other mechanisms exist that may affect and therefore determine the prognostic value of <i>APOBEC3B</i> mRNA levels.</p></div

Association of <i>APOBEC3B</i> copy number status with clinicopathological variables in 1,756 primary breast cancers.

<p>Association of <i>APOBEC3B</i> copy number status with clinicopathological variables in 1,756 primary breast cancers.</p

Kaplan-Meier survival analysis as a function of APOBEC3B copy number status.

<p>(A) In 1,604 patients of the lymph node negative (LNN) and lymph node positive (LNP) cohort combined. (B) In 1,076 LNN patients who did not receive any adjuvant systemic treatment. (C) In 769 ER-positive LNN patients who did not receive any adjuvant systemic treatment. (D) In 300 ER-negative LNN patients who did not receive any adjuvant systemic treatment. (E) In 329 ER-positive breast cancer patients who received first-line tamoxifen for recurrent disease. (F) In 226 breast cancer patients who received first-line chemotherapy for recurrent disease. (G) In 76 breast cancer patients who received first-line CMF-based chemotherapy for recurrent disease. (H) In 150 breast cancer patients who received first-line anthracycline based chemotherapy for recurrent disease. Differences between the survival curves were calculated with the 3-sample logrank test.</p

Univariate logistic regression analysis of the overall response rate in patients treated with first-line tamoxifen and in patients treated with first-line chemotherapy for recurrent disease.

<p>Univariate logistic regression analysis of the overall response rate in patients treated with first-line tamoxifen and in patients treated with first-line chemotherapy for recurrent disease.</p

Power as a function of the hazard ratio for <i>APOBEC3B</i> copy number in each of the analyzed subgroups.

<p>The dashed horizontal line crosses the curve of each subgroup at the minimal hazard ratio for which we had 80% power in our <i>APOBEC3B</i> copy number analyses.</p

Schematic overview of study cohort.

<p>In total, this retrospective study consists of 1,756 primary breast cancers from patients who underwent surgery between 1978 and 2001. Inclusion criteria are specified in the Materials and Methods section. In the adjuvant setting, there were 1,076 lymph node negative (LNN) patients who did not receive adjuvant systemic treatment and 528 lymph node positive (LNP) patients who received adjuvant systemic treatment for the analysis of MFS. In the advanced setting, a group of 329 hormone-naive patients with ER-positive breast cancer received first-line tamoxifen for recurrent disease. Of these, 145 patients came from the LNN patients group and 73 came from the LNP patients group. The remaining 111 patients in this group did not qualify for MFS analysis (<i>i</i>.<i>e</i>. 82 patients did not fulfill LNN or LNP study eligibility criteria and 29 patients already presented with metastasis at the time of diagnosis). Furthermore, a group of 226 patients received first-line chemotherapy for recurrent disease. Of these, 85 patients came from the LNN patients group and 100 came from the LNP patients group. The remaining 41 patients in this group did not qualify for MFS analysis (<i>i</i>.<i>e</i>. 27 patients did not fulfill LNN or LNP study eligibility criteria and 14 patients already presented with metastasis at the time of diagnosis).</p

Univariate Cox regression analysis to evaluate the association of calculated <i>APOBEC3B</i> copy number values with the length of MFS.

<p>Univariate Cox regression analysis to evaluate the association of calculated <i>APOBEC3B</i> copy number values with the length of MFS.</p