Risk of recurrence and pregnancy outcomes in young women with breast cancer who do and do not undergo fertility preservation.

PURPOSE: To assess the impact of fertility preservation (FP) requiring ovarian stimulation on breast cancer outcomes and pregnancy after breast cancer. METHODS: Women aged ≤ 40 years diagnosed with stage I-III breast cancer between 2007 and 2018 and referred for FP consultation prior to systemic therapy were identified from a British Columbia fertility center database. The primary endpoint was invasive breast cancer-free survival (iBCFS) and secondary endpoints were overall survival (OS) and achievement of pregnancy. Survival and pregnancy endpoints were compared using Cox and logistic regression analyses, respectively, for patients who did and did not undergo FP. RESULTS: The study included 153 patients, with 71 (46%) in the FP group and 82 (54%) in the non-FP group. Patients who underwent FP were more likely to be ECOG 0 (99% vs. 88%, p = 0.011) and receive chemotherapy (93% vs. 67%, p < 0.001), but had similar ER positivity status to non-FP patients (70% vs. 79%, p = 0.21). Over a median follow-up of 4.1 years, there were no differences in iBCFS (HR 1.006, 95% CI 0.416-2.438, p = 0.988) or OS (HR 0.789, 95% CI 0.210-2.956, p = 0.725) between FP and non-FP groups. Patients who underwent FP had higher odds of conceiving at least once (OR 3.024, 95% CI 1.312-6.970, p = 0.008). CONCLUSION: At a median follow-up of 4.1 years, FP did not impact iBCFS or OS, supporting its safety in young women with breast cancer. In addition, patients who underwent FP were more likely to become pregnant after breast cancer, highlighting the value of pre-oncologic treatment FP in survivorship family planning.

Impact of TAILORx on chemotherapy prescribing and 21-gene recurrence score-guided treatment costs in a population-based cohort of patients with breast cancer.

BACKGROUND: The trial assigning individualized options for treatment (Rx) (TAILORx) confirmed the predictive value of the 21-gene recurrence score (RS) assay in hormone receptor (HR)-positive, HER2-negative, node-negative breast cancer and established thresholds for chemotherapy benefit in younger and older patients. Real-world chemotherapy use and RS-guided treatment costs in British Columbia post-TAILORx were examined. METHODS: The authors assembled 3 cohorts of HR-positive, HER2-negative, node-negative patients with breast cancer defined by diagnosis: before RS funding (cohort 1 [C1]: January 2013-December 2013), after introduction of public RS funding (cohort 2 [C2]: July 2015-June 2016), and after TAILORx results (cohort 3 [C3]: July 2018-June 2019). Chemotherapy use was compared between cohorts by age and RS. Budgetary impacts of RS testing on chemotherapy costs were evaluated pre- and post-TAILORx. RESULTS: Among the 2066 patients included, chemotherapy use declined by 19% after RS funding was introduced and by an additional 23% after TAILORx publication (P = .001). Reduction in chemotherapy use was significant for RS 11-20 tumors (C3 vs C2, P = .004). There was no significant change in chemotherapy use in patients >50 years old (C2:12% vs C3:10%, P = .22). RS testing was associated with higher cost savings post-TAILORx, except in patients 70 to 80 years old, where testing led to excess costs when adjusting for the low rate of RS-concordant chemotherapy prescribed. CONCLUSIONS: TAILORx has had population-based impacts on chemotherapy prescribing in intermediate RS tumors and patients ≤50 years old. The lower clinical use of RS and increased spending in patients 70-80 years old highlights the importance of careful selection of older candidates for high-cost genomic testing. LAY SUMMARY: The 21-gene recurrence score (RS) test helps predict whether patients with hormone-positive, HER2-negative, lymph node-negative breast cancer are likely to benefit from chemotherapy. The recent trial assigning individualized options for treatment (Rx) (TAILORx) found that patients with intermediate RS tumors did not benefit from chemotherapy. The authors assessed whether TAILORx results translated to real-world changes in chemotherapy prescribing patterns. In this study, chemotherapy use decreased by 23% after TAILORx, with the greatest reductions seen among intermediate RS tumors and younger patients. In contrast, RS testing had lower clinical value and increased treatment costs in elderly patients, which requires further study to ensure optimal care for this age group.

Breast Tangent Beam Energy, Surgical Bed-to-Skin Distance and Local Recurrence After Breast-Conserving Treatment.

PURPOSE: Higher energy (>6 MV) photons reduce dose inhomogeneity with breast tangent beams, thereby reducing late breast toxicity, but skin and superficial tissue sparing by higher energy beams raises concerns about local recurrence (LR) risk. This study aimed to determine whether beam energy and surgical bed-to-skin distance affect LR. METHODS AND MATERIALS: This population-based study included newly diagnosed invasive breast cancers without skin involvement (pT1-4a, any-N, M0) treated with breast-conserving surgery and adjuvant whole breast radiation therapy without bolus or beam spoilers. The primary endpoint was the cumulative incidence of LR (CILR). Multivariable analysis (MVA) included mean beam energy, age, T-stage, nodal status, overall stage, lymphovascular invasion (LVI), grade, margin status, extensive intraductal component (EIC), breast cancer subtype, hormone therapy, and chemotherapy. In a subgroup with contoured surgical beds, another MVA included surgical bed-to-skin distance. RESULTS: The cohort consisted of 10,083 women treated from 2002 to 2011: 327 with 4 MV, 6006 with 6 MV, 2083 with >6 to 10 MV, and 1667 with >10 MV tangents. The median follow-up time was 11.1 years. The 10-year CILR was 3.1% (95% confidence interval [CI], 1.6-5.4) with 4 MV, 2.8% (2.4-3.3) with 6 MV, 4.2% (3.4-5.3) with >6 to 10 MV, and 2.6% (1.9-3.5) with >10 MV. On MVA of the entire cohort, LR risk was increased with positive margins, LVI, EIC, and lack of hormone therapy, but was not associated with beam energy (hazard ratio [HR], 1.01; 95% CI, 0.96-1.05; P = .8). On MVA of 3359 patients with contoured surgical beds, LR risk was not associated with surgical bed-to-skin distance (HR, 1.00; 95% CI, 0.99-1.02; P = .8). CONCLUSIONS: Use of higher breast tangent beam energies is not associated with increased risk of LR, including in cases with surgical beds that are close to the skin.

The Effect of Bolus on Local Control for Patients Treated With Mastectomy and Radiation Therapy.

PURPOSE: Bolus use during postmastectomy radiation therapy doubles the risk of grade 2 and 3 skin toxicity. Despite its unknown benefit, bolus is often prescribed during postmastectomy radiation therapy for patients without skin involvement. METHODS AND MATERIALS: For women with breast cancer receiving photon 3-dimensional conformal radiation therapy, bolus was used routinely for chest walls but was omitted for breast reconstructions by about half of radiation oncologists from 2007 to 2011. Eligible patients had newly diagnosed invasive breast cancers without skin involvement (pT1-4a, any-N, M0) treated with adjuvant or neoadjuvant radiation therapy. For the bolus and no-bolus groups, we compared the cumulative incidence of local recurrence (LR) and locoregional recurrence (LRR) with distant recurrence and death as competing risks and breast cancer mortality (BCM). Multivariable analysis of LR and BCM included stage, subtype, lymphovascular invasion, grade, margin status, beam energy, bolus use, hormone therapy, chemotherapy, and reconstruction. RESULTS: Systemic therapy was used for 98% of the 1887 patients. The bolus group had 1569 patients and the no-bolus group had 318 patients. Bolus was used in 51% (281/550) of patients treated with reconstruction and 96% (1288/1337) of patients treated without reconstruction. The 10-year outcomes (95% confidence interval) in patients treated with and without bolus were, respectively: LR 1.9% (1.3-2.7) versus 0.9% (0.3-2.6), LRR 3.1% (2.3-4.0) versus 3.2% (1.6-5.5), and BCM 19.4% (17.3-21.6) versus 18.3% (13.9-23.2). On multivariable analysis, bolus use was not associated with better LR (hazard ratio = 1.4 [0.3-6.4]) or BCM (hazard ratio = 0.8 [0.5-1.2]). CONCLUSIONS: For patients treated with mastectomy, radiation therapy, and modern systemic therapy, the cumulative incidence of LR was low, with or without bolus. Because bolus use increases toxicity and does not reduce LR or BCM, it should no longer be used routinely for patients without skin involvement who receive systemic therapy.

Mammographic density parameters and breast cancer tumor characteristics among postmenopausal women.

PURPOSE: Mammographic density is an important breast cancer risk factor, although it is not clear whether the association differs across breast cancer tumor subtypes. We examined the association between indicators of mammographic density and breast cancer risk by tumor subtype among postmenopausal women by investigating heterogeneity across tumor characteristics. METHODS: Mammographic density measures were determined for 477 breast cancer cases and 588 controls, all postmenopausal, in Vancouver, British Columbia, using digitized screening mammograms and Cumulus software. Mammographic dense (DA), non-dense (NDA), and percent dense (PDA) areas were treated as continuous covariates and categorized into quartiles according to the distribution in controls. For cases only, tests for heterogeneity between tumor subtypes were assessed by multinomial logistic regression. Associations between mammographic density and breast cancer risk were modeled for each subtype separately through unconditional logistic regression. RESULTS: Heterogeneity was apparent for the association of PDA with tumor size (p-heterogeneity=0.04). Risk did not differ across the other assessed tumor characteristics (p-heterogeneity values >0.05). CONCLUSION: These findings do not provide strong evidence that mammographic density parameters differentially affect specific breast cancer tumor characteristics.

Mammographic non-dense area and breast cancer risk in postmenopausal women: a causal inference approach in a case-control study.

PURPOSE: The association between high mammographic density (MD) and elevated breast cancer risk is well established. However, the role of absolute non-dense area remains unclear. We estimated the effect of the mammographic non-dense area and other density parameters on the risk of breast cancer. METHODS: This study utilizes data from a population-based case-control study conducted in Greater Vancouver, British Columbia, with 477 female postmenopausal breast cancer cases and 588 female postmenopausal controls. MD measures were determined from digitized screening mammograms using computer-assisted software (Cumulus). Marginal odds ratios were estimated by inverse-probability weighting using a causal diagram for confounder selection. Akaike information criteria and receiver operating characteristic curves were used to assess the goodness of fit and predictive power of unconditional logistic models containing MD parameters. RESULTS: The risk of breast cancer is 60% lower for the highest quartile compared to the lowest quartile of mammographic non-dense area (marginal OR 0.40, 95% CI 0.26-0.61, p-trend < 0.001). The cancer risk almost doubles for the highest quartile compared to the lowest quartile of dense area (marginal OR 1.81, 95% CI 1.19-2.43, p-trend < 0.001). For the highest quartile of percent density, breast cancer risk was more than three times higher than for the lowest quartile (marginal OR 3.15, 95% CI 1.90-4.40, p-trend < 0.001). No difference was seen in predictive accuracy between models using percent density alone, dense area alone, or non-dense area plus dense area. CONCLUSIONS: In this study, non-dense area is an independent risk factor after adjustment for dense area and other covariates, inversely related with the risk of breast cancer. However, non-dense area does not improve prediction over that offered by percent density or dense area alone.

Lifetime moderate-to-vigorous physical activity and ER/PR/HER-defined post-menopausal breast cancer risk.

PURPOSE: To assess the relationship of moderate-to-vigorous physical activity (MVPA) in leisure-time, household, and occupational domains across the total lifetime and in four age periods with breast cancer risk, as defined by estrogen receptor (ER)/progesterone receptor (PR) status and ER/PR/human epidermal growth factor-2 (HER2) status, among post-menopausal women. METHODS: Data were from 692 women with incident breast cancer and 644 controls in the Canadian Breast Cancer Study, a case-control study of women aged 40-80 years in British Columbia and Ontario. Mean metabolic equivalent (MET)-hours/week for questionnaire-assessed leisure-time, household, and occupational MVPA were calculated for the total lifetime and four age periods (12-17, 18-34, 45-49, and ≥50 years). Odds ratios (ORs) for the relationships between domain-specific MVPA at each lifetime period and risks of ER/PR-defined and ER/PR/HER2-defined breast cancers were estimated using polytomous logistic regression. Trend tests for dose-response relationships were calculated for the ORs across increasing tertiles of mean MET-hours/week of MVPA. RESULTS: Total lifetime leisure-time MVPA was associated with reduced risk of ER-/PR- breast cancer in a dose-response fashion (p trend = 0.014). In contrast, total lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer (p trend < 0.001). When further stratified by HER2 status, the effect of leisure-time MVPA appeared confined to HER2- breast cancers, and the effect of household MVPA did not differ according to HER2 status. Similar trends were observed when stratified by age period. CONCLUSIONS: Lifetime leisure-time MVPA appeared to be associated with reduced risk of ER-/PR-/HER2- breast cancers and lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer, regardless of HER2 status.

Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed.

PURPOSE: We hypothesized different Overall Survival (OS) in metastatic breast cancer (MBC) after relapse vs de novo presentation. METHODS: We identified women in British Columbia with MBC diagnosed between 01/2001 and 12/2009. OS from MBC was calculated for relapsed vs de novo cohorts in 3 subgroups, based on hormone receptors (HR) and HER2 status. Age at MBC, disease-free interval (DFI), de novo vs relapsed, year of MBC diagnosis, and systemic treatment were entered into univariable and multivariable analyses. RESULTS: We identified 3645 pts with known HR of which 2796 had known HER2. Median follow-up was 91 months. Median OS was longer for de novo vs relapsed MBC: HR+/HER2- 34 versus 23 months (mos) (p < 0.0001), HR-/HER2- (TN) 11 versus 8 mos (p = 0.02), HER2+ 29 versus 15 mos (p < 0.0001). For TN disease, no variable independently discriminated a group with increased risk of death. For both the HR +/HER2- and the HER2 + groups, relapsed vs de novo status (HzR 1.4 [95% CI 1.2-1.5; p < 0.0001], and HzR 1.6 [95% CI 1.4-1.9; p < 0.0001], respectively) and age >50 (HzR 1.2 [95% CI 1.1-1.4; p = 0.001] and HzR 1.3 [95% CI 1.1-1.5; p = 0.01], respectively) were associated with increased risk of death on multivariable analysis. CONCLUSION: These data provide information that may guide discussions about prognosis between physicians and patients with MBC. In addition, it highlights the importance of stratifying for initial stage at diagnosis in future MBC therapeutic trials.

Polymorphisms of Insulin-Like Growth Factor 1 Pathway Genes and Breast Cancer Risk.

Genetic variants of insulin-like growth factor 1 (IGF1) pathway genes have been shown to be associated with breast density and IGF1 levels and, therefore, may also influence breast cancer risk via pro-survival signaling cascades. The aim of this study was to investigate associations between IGF1 pathway single nucleotide polymorphisms (SNPs) and breast cancer risk among European and East Asian women, and potential interactions with menopausal status and breast tumor subtype. Stratified analyses of 1,037 cases and 1,050 controls from a population-based case-control study were conducted to assess associations with breast cancer for 22 SNPs across 5 IGF1 pathway genes in European and East Asian women. Odds ratios were calculated using logistic regression in additive genetic models. Polytomous logistic regression was used to assess heterogeneity by breast tumor subtype. Two SNPs of the IGF1 gene (rs1019731 and rs12821878) were associated with breast cancer risk among European women. Four highly linked IGF1 SNPs (rs2288378, rs17727841, rs7136446, and rs7956547) were modified by menopausal status among East Asian women only and associated with postmenopausal breast cancers. The association between rs2288378 and breast cancer risk was also modified by breast tumor subtype among East Asian women. Several IGF1 polymorphisms were found to be associated with breast cancer risk and some of these associations were modified by menopausal status or breast tumor subtype. Such interactions should be considered when assessing the role of these variants in breast cancer etiology.

Genetic variation in vitamin D-related genes and risk of breast cancer among women of European and East Asian descent.

Studies of vitamin D-related genetic variants and breast cancer have been inconsistent. This study aimed to investigate associations of vitamin D-related polymorphisms and breast cancer risk among European and East Asian women and potential interactions with menopausal status and breast tumour subtypes. Data from a case-control study of breast cancer (1037 cases and 1050 controls) were used to assess relationships between 21 polymorphisms in two vitamin D-related genes (GC and VDR) and breast cancer risk. Odds ratios were calculated in stratified analyses of European and East Asian women, using logistic regression in an additive genetic model. An interaction term was used to explore modification by menopausal status. Polytomous regression was used to assess heterogeneity by breast tumour subtype. False discovery rate adjustments were conducted to account for multiple testing. No association was observed between GC or VDR polymorphisms and breast cancer risk. Modification of these relationships by menopausal status was observed for select polymorphisms in both Europeans (VDR rs4328262 and rs11168292) and East Asians (GC rs7041 and VDR rs11168287). Heterogeneity by tumour subtype was seen for three VDR polymorphisms (rs1544410, rs7967152 and rs2239186) among Europeans, in which associations with ER-/PR-/HER2+ tumours, but not with other subtypes, were observed. In conclusion, associations between vitamin D-related genetic variants and breast cancer were not observed overall, although the relationships between vitamin D pathway polymorphisms and breast cancer may be modified by menopausal status and breast tumour subtype.