Hormone Receptor-positive Invasive Breast Cancer Research Articles

Comparative analysis of genomic tests for the prediction for late recurrence risk in hormone receptor–positive invasive breast cancer in a sample of Colombian patients.

e13092 Background: Approximately 70% of invasive breast cancers are hormone receptor-positive, requiring 5 years of endocrine therapy as the gold standard treatment. However, extended endocrine therapy (EET) may be needed, considering the late recurrence risk up to 15 years post-diagnosis. Different genomic tests predict the risk of recurrence. The 70-gene signature classifies patients as low or high risk during the first 5-years after diagnosis. The 12-gene test identifies high and low-risk patients for distant relapse up to 15 years, while a third test, based on 7-gene expression, assesses distant relapse risk up to 10 years. These tests assist clinicians in defining the need for EET. This study aims to compare the results of these genomic tests to determine late recurrence and distant relapse risks after 5 years, guiding EET indications. Methods: This is a retrospective descriptive transversal study involving 27 female patients diagnosed with hormone receptor-positive invasive breast cancer, treated in the same oncologic center in Colombia. All patients were first tested with the 70-gene genomic profile, with 15 patients undergoing the 12-gene test and 12 cases undergoing the 7-gene assay approximately 5 years later. Concordance between test results was assessed, and socio-demographic variables were descriptively analyzed. Results: The mean age was 54.4 years (SD=11.7). Invasive ductal carcinoma comprised 77.7% and invasive lobular carcinoma 22.22%. The 70-gene profile identified 21 cases (77.7%) as low-risk. Among those, 87.5% had a high-risk result with the 12-gene test, and 60% had a high-risk score with the 7-gene test. Conclusions: The findings support the utility observed in the sub-analysis of the NSABP-B42 study, showing that a low-risk result in the 70-genes signature, means high risk of late recurrence and the need for EET, emphasizing the importance of further evaluation and validation of genomic tests in predicting breast cancer recurrence risks. Larger sample sizes are necessary to confirm these results and establish their clinical relevance in oncology practice.

Completeness of endocrine therapy information in the Primary Care Prescription Database (PCPD) and secondary care treatment datasets: A national population-based cohort study using routine healthcare data

BackgroundEndocrine therapy (ET) is a widely used treatment for breast cancer. In the UK, use is typically initiated in secondary care, with subsequent treatment in primary care. Evaluating use of ET depends on data sources containing accurate and complete information. This study aimed to evaluate the completeness and consistency of ET recorded in primary and secondary care data (SCD) and determine the value of combining data sources in describing use of ET. MethodsThis cohort study included women (50 + years) diagnosed with hormone receptor-positive invasive breast cancer in England, April-2015 to December-2019. Concordance of ET recorded in SCD and the Primary Care Prescription Database (PCPD) was evaluated. Factors associated with recording of ET in each setting were assessed using statistical models. ResultsOverall 110,529 women were included. 94% had ET recorded in either SCD or PCPD. ET captured in SCD varied from 3% (in Systemic Anti-Cancer Therapy data) to 52% (in the Cancer Outcomes and Services Dataset; COSD). By contrast, 93% of patients had an ET prescription in PCPD. Among patients with ET recorded, this was not captured in COSD for 45%. Capture in COSD was lowest for younger women, those with no comorbidity/frailty, with lower stage or HER2-positive disease, or with other treatments recorded. Overall concordance between COSD and PCPD was 57%, but varied substantially across NHS trusts (lowest decile≤28%; highest decile≥86%). Among women with ET recorded in both settings, the earliest record was in COSD for 97%; 59% of initial ET prescriptions recorded in COSD were not captured in PCPD. Combining PCPD and COSD data enabled estimation of ET duration. ConclusionsPCPD is vital for understanding the use of ET within this population. Completeness of SCD could be improved by ensuring information on first ET prescription is recorded. PCPD (linked to SCD) is a valuable resource for examining patterns of care for patients with cancer, including treatment duration and adherence.

Association between nociplastic pain and premature endocrine therapy discontinuation in breast cancer patients.

At least 5years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and Chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. Six hundred eighty-one patients diagnosed between 2012 and 2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.

Early Institutional Experience of Ultra-Hypofractionated Breast Radiotherapy in a Large Academic Cancer Center

<h3>Purpose/Objective(s)</h3> Ultra-hypofractionated radiotherapy (U-HFRT) is non-inferior to moderate hypofractionation (M-HFRT) for local control following breast-conserving surgery for early-stage breast cancer and is safe in terms of normal tissue toxicity. Our objective was to evaluate early institutional experience of U-HFRT in a real-world setting at a large academic cancer center. <h3>Materials/Methods</h3> Stage 0-II breast cancer patients who received adjuvant whole breast irradiation (WBI) or partial breast irradiation (PBI) between May 2020 and March 2021 were compiled. Patients were divided into 2 cohorts: U-HFRT (26 Gy in 5 daily fractions) and M-HFRT (40.05 Gy in 15 fractions). Clinical and treatment characteristics were extracted from medical records and displayed using descriptive statistics. Physician-assessed skin toxicity was collected for patients treated with U-HFRT during RT and at follow-up visits using the RTOG radiation morbidity scale. Associations between toxicity and clinical/treatment characteristics were determined using mixed effects logistic regression, accounting for time. Comparisons between the U-HFRT and M-HFRT cohorts were performed using the Wilcoxon rank sum test (continuous) and Chi-square/Fisher's exact test (categorical). <h3>Results</h3> Median age at diagnosis for the entire cohort was 60.5 years: U-HFRT 66.2 years and M-HFRT 55.1 years (p<0.001). For the U-HFRT cohort, 70% had hormone-receptor positive invasive breast cancer (70% pT1c, 95% pN0) and 20% had DCIS. WBI/PBI was delivered to 385 patients, of which 188 (49%) received U-HFRT. For these patients, the majority (72%) received WBI, 28% PBI and a boost was used in 26%, compared to 96%, 4% and 47%, respectively, for those treated with M-HFRT (p<0.001). Grade 1 RTOG skin toxicity significantly improved over time for patients who received U-HFRT: 37% during RT, 57% within 90 days post-RT and 6% >1-year post-RT (p<0.001). Grade 2 toxicity was minimal (5% within 90 days post-RT) and there were no grade 3 toxicities. Age, RT volume (WBI vs. PBI) and chemotherapy were not associated with toxicity for U-HFRT; however, increased toxicity was observed for patients who received a boost (p<0.001). Factors associated with increased usage of U-HFRT were older age, use of PBI, no boost and no breast reconstruction (p<0.001). <h3>Conclusion</h3> U-HFRT was rapidly adopted at our institution for early-stage breast cancer and is associated with low rates of reported skin toxicity. The use of U-HFRT was greatest in patients with low-risk breast cancer, consistent with a conservative approach to implementation in a real-world setting.

Using Tailored Messages to Target Overuse of Low-Value Breast Cancer Care in Older Women

National recommendations allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 y/o with early-stage, hormone-receptor positive invasive breast cancer, but these therapies remain common. Previous work demonstrates an individual's maximizing-minimizing trait-an inherent preference for more or less medical care-may influence the preference for low-value care. We recruited an equal number of women ≥ 70 yrs who were maximizers, minimizers, or neutral based on a validated measure between September 2020 and November 2020. Participants were presented a hypothetical breast cancer diagnosis before randomization to one of three follow-up messages: maximizer-tailored, minimizer-tailored, or neutral. Tailored messaging aimed to redirect maximizers and minimizers toward declining SLNB and radiotherapy. The main outcome measure was predicted probability of choosing SLNB or radiotherapy. The final analytical sample (n=1600) was 515 maximizers (32%), 535 neutral (33%) and 550 (34%) minimizers. Higher maximizing tendency positively correlated with electing both SLNB and radiotherapy on logistic regression (P < 0.01). Any tailoring (maximizer- or minimizer-tailored) reduced preference for SLNB in maximizing and neutral women but had no effect in minimizing women. Tailoring had no impact on radiotherapy decision, except for an increased probability of minimizers electing radiotherapy when presented with maximizer-tailored messaging. Maximizing-minimizing tendencies are associated with treatment preferences among women facing a hypothetical breast cancer diagnosis. Targeted messaging may facilitate avoidance of low-value breast cancer care, particularly for SLNB.

A validated model to predict low recurrence risk distinguished by 21-gene recurrence score in hormone receptor-positive invasive breast cancer patients.

532 Background: In the prospective TAILORx and RxPONDER trials, the 21-gene Recurrence Score (RS) showed endocrine therapy alone was non-inferior to chemo-endocrine therapy in the analysis of invasive disease-free survival in postmenopausal hormone-receptor (HR)-positive breast cancer patients with RS &lt; = 25. They also indicated chemotherapy was associated with benefit for women 50 years or younger with RS 11 to 25. However, in Japan, the test is not conventionally available because of non-coverage by national insurance. We aimed to develop and validate a model to predict RS using clinicopathological factors that identify patients who would have low risk shown by testing the 21-gene RS and can avoid chemotherapy. Methods: Four hundred patients, including 187 N0/1 postmenopausal, and 213 N0 premenopausal women who underwent surgery and had the RS from St. Luke’s International Hospital, Tokyo, Japan, were included in derivation cohort. Derivation cohort was divided into 2 groups by RS 25; patients with RS of 0 to 25 (n = 321) and with RS over 26 (n = 79). Multivariate logistic regression analysis was performed using candidate factors for all patients and pre- or postmenopausal patients. The prediction model was validated using an external cohort of 70 patients from Showa University School of Medicine, Tokyo, Japan. Results: Nuclear grade (NG) (adjusted OR, 5.28, 95% CI, 2.47–11.30), high Progesterone receptor (PgR) expression (Allred score 7-8) (adjusted OR, 10.62, 95% CI, 5.34–21.13) and low Ki67 level ( &lt; = 20%) (adjusted OR, 5.29, 95% CI, 2.33-12.01) were significant independent predictors of RS of 0 to 25. With these factors could predict RS of 0 to 25 (AUC of 0.848, 95% CI, 0.803-0.893) with the highest probability of low-RS for 100%. The prediction model of the validation cohort had same discriminatory ability having an AUC of 0.812 (95% CI, 0.701-0.923). In postmenopausal patients, NG (adjusted OR, 4.81, 95% CI, 1.72–13.42), high PgR expression (adjusted OR, 10.62, 95% CI, 4.52–37.72), and low Ki67 level (adjusted OR, 4.94, 95%CI, 1.87-13.04) were significantly associated with RS of 0 to 25 in multivariate analysis. A regression model with these 4 factors could predict RS of 0 to 25 (AUC of 0.842, 95%CI, 0.782-0.902). In premenopausal patients, NG (adjusted OR, 8.76, 95% CI, 1.14–67.40), high PgR expression (adjusted OR, 3.22, 95% CI, 1.61–6.43), and low Ki67 level (adjusted OR, 2.87, 95% CI, 1.20–6.87) were significantly associated with RS of 0 to 10 in multivariate analysis. These factors could predict RS of 0 to 10 (AUC of 0.811, 95% CI, 0.731-0.891). However, the highest probability of low-RS provided this model for premenopausal women was 46.8%. Conclusions: Our validated model could provide useful information to distinguish low-RS especially for postmenopausal patients with high reproducibility. However, for premenopausal women, the 21-gene RS is warranted.

206P - Effect of denosumab on low bone mineral density in postmenopausal Japanese early breast cancer patients receiving aromatase nhibitors: 36-month results

BackgroundAromatase inhibitors (AI) are standard as postoperative adjuvant therapy for hormone positive postmenopausal breast cancer. In recent years, the administration period tends to be longer, and bone loss which is a side effect has become a serious problem. We have already reported the effect of denosumab up to 24 months on postmenopausal early breast cancer patients with low bone mineral density (BMD) receiving AIs as adjuvant hormonal therapy. BMD in the lumber spine was found to increase, and the combination of denosumab revealed useful for blocking bone mineral loss in Japanese women receiving AIs. MethodsStudy design: A non-randomized, prospective study at three institutions was conducted in Japan. Patients administered 60mg of denosumab subcutaneously every 6 months. The BMD of the lumbar spine and bilateral femoral neck was measured at baseline and at 6, 12, 18, 24, 30 and 36 months. The levels of serum tartrate-resistant acid phosphatase isoform 5b (TRAP5b), bone alkaline phosphatase (BAP), albumin-corrected serum calcium concentration was measured at baseline and 1, 6, 12, 18, 24, 30 and 36 months. Patients: Postmenopausal women with early-stage hormone receptor-positive invasive breast cancer who were scheduled to receive an AI as adjuvant hormonal therapy or receiving AI adjuvant therapy were included in the analysis. We also included those who had completed a chemotherapy regimen ≥ 4 weeks before entering the study and patients with low BMD (lumbar spine, right femoral neck, and left femoral neck BMD: -2.5< T-score <-1.0). Endpoints: The primary endpoint was the change in percentage of the BMD of the lumbar spine (L1–L4) from baseline to 12 months. ResultsA total of 103 patients were enrolled. Seventy-three patients completed the study. At 36 months, the BMD of the lumbar spine increased by 8.8%. The BMD of the right and left femoral neck increased by 4.4% and 2.7%, respectively. Symptomatic clinical fractures did not occur in patients receiving AI and denosumab. ConclusionsAt 36 months, as with the data to the previous 24 months, in combination of denosumab for Japanese women receiving adjuvant AI treatment, an increase in BMD was noted. Clinical trial identificationUMIN-CTR, UMIN 000016173. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureT. Taguchi: Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Daiichi Sankyo Co., Ltd.; Research grant / Funding (institution): Eisai Co. Ltd. All other authors have declared no conflicts of interest.

Abstract P1-06-02: Comparative survival analysis of multiparametric tests in the TEAM pathology study: What to do when molecular tests disagree?

Abstract Multiparametric assays for risk are increasingly used in the management of node-negative and node-positive hormone receptor-positive invasive breast cancer. Data from multiple sources suggests different tests may provide different risk estimates at the individual patient level1. Analysis from the TEAM pathology study (Bayani and Yao et al npjBreast Cancer, 2017) allows direct comparison of prognostic information from gene signatures in a clinical trial cohort of postmenopausal patients. Risk classifications using genes comprising the following multi-parametric tests: OncotypeDx® (Genomic Health Inc.)2,3, Prosigna™(NanoString Technologies, Inc.)4-6, Mammaprint® (Agendia Inc.)7,8 were performed. For the OncotypeDX-Like Recurrence Score (RS), RNA abundance was processed to fit the measurement range as described2,3, with classification into high, intermediate or low risk groups based the derived RS and modeled for DRFS. For the Prosigna-Like Risk of Recurrence Score (ROR), samples were processed as previously outlined9, then modelled against DRFS. For the MammaPrint-Like Risk Score, samples were processed by published methods8 and modelled for DRFS. Comparing OncotypeDx-Like with Prosigna-Like showed that 45% of cases were classified identically by both (3.3% low risk, 20.9% intermediate, 20.7% high). Of 3370 cases, 353 (10.5%) had scores differing by more than 1 classification (i.e. hi/low or low/high). Almost all (343) of these were cases classified high risk by OncotypeDX-Like RS/low risk by Prosigna-Like ROR (Table 1). Univariate Cox regression analysis, using low/low cases as a reference (relative risk of distant metastasis =1.0), suggested that cases called low risk by Prosigna-Like ROR/High risk by OncotypeDx-Like RS did not perform differently from cases called low risk by both tests (Table 2). However, all cases called intermediate by one test and high risk by another appeared to be high risk (Table 2). Comparisons between Prosigna-Like ROR and MammaPrint-Like scores showed similar concordance between low/low and high/high (52.5% of cases with concordant results). In Prosigna-Like ROR intermediate risk cases, MammaPrint-Like results divided cases between low and high risk, as predicted. Comparisons between these tests is challenging, and evidence on their discordance in risk stratification presents further dilemmas. Preliminary analysis of TEAM suggests a complex inter-relationship between test results in the same patient cohorts requiring careful evaluation. Table 1OncotypeDX-Like RSLowInt.HighTotalLow1126163431071Prosigna-Like RORInt.1677046151486High10106697813Total289142616553370 Table 2OncotypeDX-Like RSLowInt.HighLowRef1.26 (0.57-2.79)1.13 (0.49-2.62)Prosigna-Like RORInt.1.2 (0.47-3.05)2.22 (1.03-4.78)4.27 (2.01-9.08)High6.10 (1.58-23.6)4.15 (1.79-9.59)4.92 (2.32-10.42) Citation Format: Bartlett JMS, Bayani J, Kornaga E, Piper T, Mallon E, Yao CQ, Boutros PC, Hasenburg A, Kieback DG, Markopoulos C, Dirix L, Seynaeve C, Can de Velde CJH, Rea DW. Comparative survival analysis of multiparametric tests in the TEAM pathology study: What to do when molecular tests disagree? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-02.

67P - Prediction model of low risk recurrence distinguished by 21-gene recurrence score in hormone receptor-positive invasive breast cancer: A validation study

67P - Prediction model of low risk recurrence distinguished by 21-gene recurrence score in hormone receptor-positive invasive breast cancer: A validation study

Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database.

The Oncotype DX® Breast Recurrence Score™ (RS) assay is validated to predict breast cancer (BC) recurrence and adjuvant chemotherapy benefit in select patients with lymph node-positive (LN+), hormone receptor-positive (HR+), HER2-negative BC. We assessed 5-year BC-specific survival (BCSS) in LN+ patients with RS results in SEER databases. In this population-based study, BC cases in SEER registries (diagnosed 2004-2013) were linked to RS results from assays performed by Genomic Health (2004-2014). The primary analysis included only patients (diagnosed 2004-2012) with LN+ (including micrometastases), HR+ (per SEER), and HER2-negative (per RT-PCR) primary invasive BC (N=6768). BCSS, assessed by RS category and number of positive lymph nodes, was calculated using the actuarial method. The proportion of patients with RS results and LN+ disease (N=8782) increased over time between 2004 and 2013, and decreased with increasing lymph node involvement from micrometastases to ≥4 lymph nodes. Five-year BCSS outcomes for those with RS<18 ranged from 98.9% (95% CI 97.4-99.6) for those with micrometastases to 92.8% (95% CI 73.4-98.2) for those with ≥4 lymph nodes. Similar patterns were found for patients with RS 18-30 and RS≥31. RS group was strongly predictive of BCSS among patients with micrometastases or up to three positive lymph nodes (p<0.001). Overall, 5-year BCSS is excellent for patients with RS<18 and micrometastases, one or two positive lymph nodes, and worsens with additionally involved lymph nodes. Further analyses should account for treatment variables, and longitudinal updates will be important to better characterize utilization of Oncotype DX testing and long-term survival outcomes.

Abstract P2-05-36: Clinicopathological predictors for low risk recurrence distinguished by 21-gene recurrence score in estrogen receptor-positive invasive breast cancer patients

Abstract Background: The 21-gene Recurrence Score (RS) (Oncotype DX®; Genomic Health, Redwood City, CA) is the most valid and reliable multigene assay to predict prognosis or response to treatment in hormone receptor-positive invasive breast cancer patients. However, in Japan, the test is expensive (about 4,000 US dollars) and one of the problems is that about 30% of patients will be categorized as having moderate recurrence risk. If clinicopathologic factors can be used to predict patients with low recurrence, many patients can avoid postoperative chemotherapy without testing the RS. Such predictors shall have a substantial impact on medical economics too. The aim of this study was to determine significant clinicopathological predictors for low recurrence risk by RS in patients with estrogen receptor-positive primary breast cancer. Methods: Retrospective cross-sectional study was conducted in tertiary referral hospital in Tokyo, Japan. Two hundreds twenty patients with estrogen receptor-positive invasive breast cancer underwent surgery for breast cancer and tested for RS from November 2009 to March 2016. RS £18 was defined as low recurrence risk. The patients were divided into 2 groups, patients with low recurrence risk (n=143) and with a moderate/high recurrence risk (n=77). Age, menopausal status, histologic type (invasive ductal vs. lobular carcinoma), nuclear grade, progesterone receptor (PR) expression, Ki67 index, tumor size, lymph node status, and lymphovascular invasion were considered as candidate predictors. Student's t test or Wilcoxon-Rank Sum test and Fisher's exact test was used for continuous variables and proportion, respectively. Simple and multiple logistic regression model were used to determine significant predictors. Classification and regression tree analysis (CART) was also conducted. Results: Mean age (SD) of low and moderate/high recurrence patients was 53 years-old (9.4) and 55 years (10.2), respectively. Univariate analyses revealed that the invasive lobular carcinoma, the high PR expression, Ki67 &amp;lt; 24, and the absence of lymphovascular invasion were significantly associated with low recurrence risk. According to multiple logistic regression, The odds ratio (OR) [95%CI] of histological type (invasive lobular), high PR expression, Ki67 &amp;lt; 24, and the absence of lymphovascular invasion was 0.43 [0.08-1.8], 10 [5.4-23.6], 0.95 [0.93-0.97], and 0.57 [0.23-1.18], respectively. The area under the receiver operating characteristic curve was 0.83. CART showed that the probability of low recurrence risk was 79% if with high PR expression, and 92% if with high PR expression and Ki67 &amp;lt; 24. Conclusions: High PR expression and Ki67 &amp;lt; 24 were significant predictors for low recurrence risk by RS in estrogen receptor-positive invasive breast cancer patients. More than 90% of patients with high PR expression and Ki67 &amp;lt; 24 could be classified as low recurrence risk by RS. Citation Format: Tsuchida Y, Hayashi N, Omata F, Yamauchi H. Clinicopathological predictors for low risk recurrence distinguished by 21-gene recurrence score in estrogen receptor-positive invasive breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-36.

Breast cancer specific mortality in patients with early-stage hormone receptor–positive invasive breast cancer and oncotype DX recurrence score results in the SEER database.

176 Background: NCI’s SEER Program provides cancer incidence and survival statistics for ~28% of the US. New research models are needed to characterize the use and impact of genomic tests on patient outcomes. Genomic Health and SEER collaborated to electronically supplement SEER registries with Recurrence Score (RS) results, and have evaluated breast cancer specific mortality (BCSM) in early stage hormone receptor (HR)+ HER2- invasive breast cancer. Methods: Pts were eligible for pre-specified node negative (N-) disease analysis if HR+, HER2- (by RT-PCR), no prior malignancy, 40-85 years of age, and diagnosed between Jan 2004 (Oncotype DX available Jan 2004) and Dec 2011 (SEER survival analysis complete through 2012). BCSM was defined as previously described (Howlader et al, JNCI 2010). Additional analyses of BCSM were performed for pts with N+ disease. Results: Of 169,158 eligible N- pts, 38,568 (23%) had a RS, increasing from 2% in 2004 to 35% in 2011. Pts with RS had median age of 57yr, were 99.4% female, 84% white, 29% grade 1 &amp; 54% grade 2, 25% &lt; 1cm &amp; 53% 1-2cm. Median FU was 39mo. 8,239 pts had &gt; 5yrs follow-up. Among RS &lt; 18 (N = 21,023), RS 18-30 (N = 14,494) and RS ≥ 31 (N = 3,051) pts, chemotherapy use was reported in 7%, 34%, &amp; 69%, respectively, and 5yr N- BCSM was 0.4% (95% CI, 0.3-0.6), 1.4% (95% CI, 1.1-1.7) and 4.4% (95% CI,3.4-5.6), respectively. Multivariate showed that RS was significantly associated with BCSM after adjusting for age, grade, and tumor size (p &lt; 0.001), and when stratified by treatment (p &lt; 0.001). BCSM results in additional N- subgroups (e.g., socioeconomic), and in &gt; 60,000 N+ pts will be presented. Conclusions: 5yr survival outcomes are excellent in the over 21,000 N- pts with RS &lt; 18 disease. RS ≥ 31 disease is associated with greater 5yr mortality despite addition of chemotherapy. The large sample size of this population-based observational study provides important information on prospective outcomes in subsets of pts that are often underrepresented in randomized clinical trials.

The Value of Ki67 in Very Young Women with Hormone Receptor-Positive Breast Cancer: Retrospective Analysis of 9,321 Korean Women.

Young breast cancer patients have a poorer prognosis, especially when their tumors are hormone receptor positive. We analyzed the association between Ki67 and age and the impact of these factors on outcomes in hormone receptor-positive breast cancer. The records of 9,321 hormone receptor-positive invasive breast cancer patients from three large centers were retrospectively reviewed. Each institution separately assayed Ki67 level immunohistochemically. Univariate and multivariate analysis for recurrence-free survival (RFS) was performed on 4,738 patients from a single center. Ki67 level was inversely proportional to age in all three data sets and was significantly higher for younger patients (p < 0.001, 0.03, and <0.001, respectively). This correlation was seen only in the human epidermal growth factor receptor 2 (HER2)-negative population. Survival analysis showed that both very young age (<35 years) and high Ki67 level (≥10 %) were independent prognostic factors. Although young age was a worse prognostic indicator regardless of HER2 status, Ki67 index was associated with worse prognosis only in HER2-negative patients. When patients were stratified into those with low and high Ki67, young age remained a significant factor for RFS, with hazard ratios in these two Ki67 groups of 2.15 and 2.57, respectively (p < 0.001). Also, the young age/low Ki67 group had significantly poorer RFS than the older age/high Ki67 group (p < 0.001). Ki67 level was higher in younger patients. However, very young patients had a poorer prognosis regardless of Ki67 level. Unknown biologic factors other than high cell proliferation might play a role in the aggressiveness of hormone receptor-positive breast cancer in very young patients.

The value of progesterone receptor expression in predicting the Recurrence Score for hormone-receptor positive invasive breast cancer patients

OncotypeDX(®) (ODX) is a well-validated assay for breast cancer treatment planning. We explored whether the conventional pathological factors could pick up high risk patients without the help of the ODX. The ODX was performed on 139 hormone receptor-positive invasive breast cancers in a single Japanese institution. The recurrence risk was compared between the ODX and the St. Gallen Consensuses. The correlations were analyzed between the Recurrence Score (RS) measured by ODX and the pathological factors. In addition, we performed a follow-up survey and examined the association of the RS with the confirmed recurrence or death. The ODX classified 68 (49 %) as low RS, 52 (37 %) as intermediate RS, and 19 (14 %) as high RS cases. Correlations were noted between RS and progesterone receptor (PR) (r = -0.53), Ki-67 (r = 0.42), and nuclear grade (NG) (r = 0.41). None had a high RS with PR(3+) or NG1. Only one high RS patient had a Ki-67 (<20 %). The combinations of high RS with PR(0)/Ki-67 (≥20 %) and PR(1+)/Ki-67 (≥20 %) were 70 and 58 %, respectively. The combinations with high RS and PR(0)/NG3, PR(0)/NG2, and PR(1+)/NG3 were 83, 75, and 75 %, respectively. The median follow-up was 39.1 months (range 24.0-67.8). There were one low RS (1 %), four intermediate RS (8 %), and three high RS patients (16 %) who developed local or distant recurrence. Hormone receptor-positive invasive breast cancers are stratified with the combinations of PR/Ki-67 or PR/NG. Some of the high recurrence risk cases might be identified without the ODX.

Understanding discontinuation of oral adjuvant endocrine therapy by women with hormone receptor–positive invasive breast cancer nearly 4 years from diagnosis

The aim of this study was to investigate the extent of discontinuation of oral adjuvant endocrine therapy (OAET) in women nearly 4 years from the diagnosis of their first episode of invasive breast cancer and the reasons for such discontinuation. We used a large, prospective cohort study of women who had been diagnosed with their first episode of invasive breast cancer between 2004 and 2006, recruited through a state-based cancer registry. All participants completed an enrollment questionnaire (EQ) within 12 months of diagnosis and annual follow-up questionnaires (FQs) thereafter. The data in this report were obtained from the EQ and the first three FQs. A total of 1,370 women with hormone receptor-positive disease completed the EQ. At the completion of the third FQ nearly 4 years from diagnosis, 1,193 women remained in the study. Use of OAET peaked by 2 years postdiagnosis. At nearly 4 years from diagnosis, 18% of the 1,193 women remaining in the study were not taking OAET. Of these women, just more than half had ceased therapy mainly owing to a range of adverse effects, predominantly estrogen deficiency symptoms, but the remainder (8% of women remaining in the study) had never used OAET. Our study confirms that early discontinuation of OAET due to estrogen deficiency symptoms remains an important issue despite calls for strategies to address this problem. The number of women potentially suitable for OAET but not receiving it was almost as great as the number of those who have discontinued therapy.

Abstract P6-07-38: The Value of Progesterone Receptor in Predicting the Recurrence Score for Hormone-Receptor–Positive Invasive Breast Cancer Patients

Abstract Background: Molecular genomic profiling currently plays a major role in treatment decisions for breast cancer patients. The 21-gene signature (Oncotype DX® [ODX]) is one of the most well-validated assays. Herein we evaluated the associations between high Recurrence Score (RS) measured by the ODX and pathological factors. Methods: From October 2007 to October 2010, the ODX assay was performed for 139 hormone-receptor–positive invasive breast cancer patients at single institution. Correlations between the RS and the following pathological factors were analyzed: tumor size (T), lymph node metastasis (N), nuclear atypia (NA), mitotic counts (MC), nuclear grade (NG), lymphatic and vascular invasion (LI and VI), estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki-67. Expression of ER, PgR, HER2, and Ki-67 was examined by immunohistochemistry. The Ki-67 labeling index was automatically counted with an Ariol-SL50 instrument (APPLIED IMAGING). The other pathological factors were estimated under the supervision of one experienced pathologist. Spearman rank correlation coefficients were calculated for the analyses. When the r was &amp;gt;0.4 or &amp;lt;–0.4 for two factors, they were determined to be well correlated. Results: Of 139 patients, the ODX assay revealed 68 (49%) low RS cases, 52 (37%) intermediate RS cases, and 19 (14%) high RS cases. Moderate positive or negative correlations were noted between the RS and PgR (r = −0.53), the RS and Ki-67 (r = 0.42), and the RS and NG (r = 0.41). No patients had high RS with PgR (3+) or NG1. The rate of high RS with Ki-67 (&amp;lt;20%) was one patient (2%). The number of cases who did not show PgR (3+) or NG1 or Ki-67 (&amp;lt;20%) was only 34 (25%). Among high RS cases, the correlation between PgR (0) and NG3 was 83%, the correlation between PgR (0) and NG2 was 75%, and the correlation between PgR (1+) and NG3 was 75%. The rate of high RS with PgR (0) and Ki-67 (≥20%) was 70%, that of PgR (1+) and Ki-67 (≥20%) was 58%, and that of PgR (2+) and Ki-67 (≥20%) was 21%. Correlations with T, N, NA, MC, LI, VI, ER, and HER2 were smaller (r ranging from −0.33 to 0.38). Conclusion: This study demonstrated that PgR, NG, and Ki-67 tend to be strongly correlated with the RS. Judging from PgR (3+), NG1, and Ki-67 (≥20%), we could select the patients who were proposed to perform the ODX. Among these factors, the correlation with PgR was particularly robust. PgR expression is a known marker of a functional ER and represents ER activity. In addition, the absence of PgR may reflect hyperactive cross-talk between ER and growth factor signaling pathways. We consider that these mechanisms could enhance the value of PgR in predicting the RS. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-38.

The Discriminatory Value of CYP2D6 Genotyping in Predicting the Dextromethorphan/Dextrorphan Phenotype in Women with Breast Cancer

Background: The growth inhibitory effect of tamoxifen is used for the treatment of breast cancer. Tamoxifen efficacy is mediated by its biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoenzyme, to the active metabolite endoxifen. We investigated the relationship of CYP2D6 genotypes to the metabolism of dextromethorphan (DM), which is frequently used as a surrogate marker for the formation of endoxifen. Methods: The CYP2D6 genotype was determined by polymerase chain reaction (PCR) in previously untreated patients with hormone receptor-positive invasive breast cancer considered to receive antihormonal therapy. The DM/dextrorphan (DX) urinary excretion ratios were obtained in a subset of patients by high-pressure liquid chromatography (HPLC)-mediated urine analysis after intake of 25 mg DM. The relationships of genotype and corresponding phenotype were statistically analyzed for association. Results: From 151 patients predicted based on their genotype data for the ‘traditional’ CYP2D6 phenotype classes poor, intermediate, extensive and ultrarapid, 83 patients were examined for their DM/DX urinary ratios. The genotype-based poor metabolizer status correlated with the DM/DX ratios, whereas the intermediate, extensive and ultrarapid genotypes could not be distinguished based on their phenotype. Citalopram intake did not significantly influence the phenotype. Conclusions: The DM metabolism can be reliably used to assess the CYP2D6 enzyme activity. The correlation with the genotype can be incomplete and the metabolic ratios do not seem to be compromised by citalopram. DM phenotyping may provide a standardized tool to better assess the CYP2D6 metabolic capacity.

Commentary: Improving Breast Cancer Testing for Patients—The Secret Sauce Is Collaboration

Breast cancer treatment is becoming increasingly personalized, as more and more studies appear that define the molecular basis of treatment response. As many as two thirds of breast cancers are estrogen receptor (ER) and/or progesterone receptor (PgR) positive, with their growth influenced by activation of the ER pathway. The purpose of ER/PgR testing is to identify patients with breast cancer whose tumors express ER and/or PgR (hormone receptor positive) and who should therefore be considered candidates for treatment with endocrine therapies, which may include options like tamoxifen, an aromatase inhibitor, and/or suppression of ovarian function, as appropriate. These treatments can substantially improve survival in patients with hormone receptor–positive invasive breast cancer. Immunohistochemistry (IHC) is an established assay to determine the ER/PgR status of a tumor by measuring protein amounts of ER and PgR in breast cancer cells. However, up to 10% to 20% of IHC test results throughout the world may be inaccurate (false positive or false negative). This significant level of testing inaccuracy led ASCO and the College of American Pathologists (CAP) to convene an expert panel to address the causes of the inaccuracies and develop a guideline to improve testing performance. The guideline1 was published in June 2010 jointly by Journal of Clinical Oncology and Archives of Pathology and Laboratory Medicine, and a summary2 appears in this issue of Journal of Oncology Practice. The guideline builds on a previous successful collaboration between ASCO and CAP resulting in a guideline for HER2 testing in breast cancer. In both documents, the principal strategies for improving testing accuracy are specified: specimen handling, testing parameters, reporting requirements, and quality assurance (QA) programs. The guideline defines the threshold for a positive ER or PgR test; defines specimen handling requirements; and emphasizes appropriate use of QA practices, including laboratory proficiency testing and accreditation by agencies such as CAP that require adherence to guideline elements. For ER/PgR testing, the emphasis on specimen handling has been strengthened. Data have recently been published that illustrate the serious consequences of treatment delay as a result of fixation on testing accuracy. A recently published study3 from Intermountain Healthcare found that samples taken on weekends were much more likely to be ER negative than those taken during the week. Studies conducted in Asian countries by Nichols et al4 showed that breast cancer specimens in those countries were usually ER negative unless specimen handling issues were addressed. Laboratories are now required to record the time the tumor was removed, the time the tissue was placed in fixative, and the fixative duration. Remotely obtained specimens should be bisected and placed in fixative to be sure that the tumor is quickly exposed to fixative. Increased attention to simple measures such as the handling of tissue specimens, the uniform fixation of specimens, the standardization and validation of lab assays, rigorous reporting procedures, and greater access to treatment interventions has the potential to significantly improve breast cancer outcomes around the world. Collaboration among medical specialists is necessary to achieve the best patient outcomes. The ASCO/CAP Panel chose to specifically focus on IHC assays for ER/PgR testing based on its widespread use, its worldwide impact, and the large body of evidence available. In the future, the ASCO/CAP Panel may review new methods and predictive assays to identify patients most likely to benefit from endocrine therapies as new high-level data on validated assays and outcomes become available. In conjunction with the publishing of the guideline, ASCO and CAP have developed clinical tools and resources for oncologists and pathologists that summarize the findings and recommendations. These resources include a slide presentation on the ASCO Web site and the guideline summary in JOP. In addition, CAP has developed a Breast Predictive Factors Testing Certificate Program and associated Continuing Medical Education, which will also allow pathologists to gain special expertise in the development and implementation of these tests. Patients seeking additional information should visit MyBiopsy.org.

Adjuvant Endocrine Therapy in Hormone Receptor-Positive Postmenopausal Breast Cancer: Evolution of NCCN, ASCO, and St Gallen Recommendations

Endocrine therapy has a firm role in adjuvant treatment of women with hormone receptor-positive invasive breast cancer. Until recently, tamoxifen was the most commonly used adjuvant endocrine therapy in premenopausal and postmenopausal women. Several randomized clinical trials have studied the third-generation selective aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) as adjuvant endocrine therapy in postmenopausal women. These studies compared therapy with an AI alone versus tamoxifen alone; 2 to 3 years of tamoxifen followed by switching to an AI versus continuation of tamoxifen; or extended therapy with an AI after approximately 5 years of tamoxifen therapy. No statistically significant differences in overall survival were observed. A single trial using extended treatment with an adjuvant AI suggests a small, statistically significant survival advantage in women with axillary lymph node-positive disease while showing no statistically significant decrease in survival with the use of an AI. The toxicities of the AIs are generally acceptable, with fewer endometrial cancers, gynecologic complaints, and thromboembolic events, but more bone fractures and arthralgias compared with tamoxifen alone. Three widely disseminated treatment guidelines, the National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology, the American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors, and the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, now incorporate AIs in the adjuvant therapy of postmenopausal women with estrogen receptor-positive breast cancer.

Special issues related to breast cancer adjuvant therapy in older women

Increasing age remains the major risk factor for breast cancer and more than half of all breast cancers in North America and the European Union occur in women 65 years and older. Anticipated life expectancy, co-morbidity, and functional status must all be considered when offering systemic adjuvant treatment to older women. Tamoxifen significantly decreases the risk of recurrence and improves survival in all women with hormone receptor-positive invasive breast cancer, including women 70 years and older. More recently, aromatase inhibitors have been shown to be even more effective than tamoxifen in reducing breast cancer recurrence in postmenopausal women, and are an appropriate choice for initial endocrine therapy in older women. Adjuvant chemotherapy improves survival in postmenopausal women, but adds little to endocrine therapy in the majority of women with node-negative, hormone receptor-positive tumors. Chemotherapy should be considered for patients with high-risk node-negative, hormone receptor-negative tumors and those with node-positive tumors. Co-morbidity and its effect on survival should be factored into all chemotherapy decisions. Older women are frequently under-treated and are still under-represented in clinical trials; sometimes this represents good clinical judgment, but age bias alone can result in under-treatment and higher breast cancer-related mortality or state-of-the-art trials not being offered to older, but otherwise eligible, patients. Physician education and more clinical trials designed for older women are needed.