Caroline A. Lohrisch

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

PurposeWe hypothesized different Overall Survival (OS) in metastatic breast cancer (MBC) after relapse vs de novo presentation.MethodsWe 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.ResultsWe identified 3645 pts with known HR of which 2796 had known HER2. Median follow-up was 91xa0months. Median OS was longer for de novo vs relapsed MBC: HR+/HER2- 34 versus 23xa0months (mos) (pxa0<xa00.0001), HR−/HER2- (TN) 11 versus 8 mos (pxa0=xa00.02), HER2+xa029 versus 15 mos (pxa0<xa00.0001). For TN disease, no variable independently discriminated a group with increased risk of death. For both the HRxa0+/HER2- and the HER2xa0+xa0groups, relapsed vs de novo status (HzR 1.4 [95% CI 1.2–1.5; pxa0<xa00.0001], and HzR 1.6 [95% CI 1.4–1.9; pxa0<xa00.0001], respectively) and agexa0>50 (HzR 1.2 [95% CI 1.1–1.4; pxa0=xa00.001] and HzR 1.3 [95% CI 1.1–1.5; pxa0=xa00.01], respectively) were associated with increased risk of death on multivariable analysis.ConclusionThese 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.

Using proliferative markers and Oncotype DX in therapeutic decision-making for breast cancer: the B.C. experience.

BACKGROUNDnProliferative scoring of breast tumours can guide treatment recommendations, particularly for estrogen receptor (er)-positive, her2-negative, T1-2, N0 disease. Our objectives were to □ estimate the proportion of such patients for whom proliferative indices [mitotic count (mc), Ki-67 immunostain, and Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.) recurrence score (rs)] were obtained.□ compare the indices preferred by oncologists with the indices available to them.□ correlate Nottingham grade (ng) and its subcomponents with Oncotype dx.□ assess interobserver variation.nnnMETHODSnAll of the er-positive, her2-negative, T1-2, N0 breast cancers diagnosed from 2007 to 2011 (n = 5110) were linked to a dataset of all provincial breast cancers with a rs. A 5% random sample of the 5110 cancers was reviewed to estimate the proportion that had a mc, Ki-67 index, and rs. Correlation coefficients were calculated for the rs with ng subcomponent scores. Interobserver variation in histologic grading between outside and central review pathology reports was assessed using a weighted kappa test.nnnRESULTSnDuring 2007-2011, most cancers were histologically graded and assigned a mc; few had a Ki-67 index or rs. The ng and mc were significantly positively correlated with rs. The level of agreement in histologic scoring between outside and central pathology reports was good or very good. Very few cases with a low mc had a high rs (1.8%).nnnCONCLUSIONSnPatients with low ng and mc scores are unlikely to have a high rs, and thus are less likely to benefit from chemotherapy. In the context of limited resources, that finding can guide clinicians about when a rs adds the most value.

Risk of Recurrence or Contralateral Breast Cancer More than 5 Years After Diagnosis of Hormone Receptor-Positive Early-Stage Breast Cancer

BACKGROUNDnThree large studies have shown a survival benefit from 10 years of adjuvant hormone therapy (AHT). We evaluated the risk of an event 5 years after the initial breast cancer (BC) diagnosis and identified the prognostic factors to assist clinicians considering extended AHT.nnnPATIENTS AND METHODSnPatients newly referred to the BC Cancer Agency with stage I to III estrogen receptor-positive BC diagnosed from 1989 to 2004 who had undergone AHT were identified by the BC Cancer Agencys Breast Cancer Outcomes Unit. Cases with recurrence, death, or contralateral BC occurring within the first 5 years were excluded. The 10-year event-free survival (EFS) and 95% confidence intervals (CIs) were calculated using the Kaplan-Meier method. This provided estimates of recurrence risk after the fifth year following the diagnosis. The histopathologic and age variables were examined for prognostic value by univariate analysis.nnnRESULTSnWithin our cohort, 6615 women were postmenopausal and 1886 were premenopausal at the BC diagnosis. The median follow-up period was 11 years. The 10-year EFS for women agedxa0< 50 years with stage I, II, and III disease was 94.8% (95% CI, 92.8%-96.3%), 88.3% (95% CI, 86.0%-90.2%), and 80.4% (95% CI, 73.6%-85.6%), respectively. Among women agedxa0≥ 50 years, the corresponding EFS rates were 94.8% (95% CI, 93.8%-95.6%), 86.3% (95% CI, 85.0%-87.5%), and 73.8% (95% CI, 69.1%-77.8%). EFS varied significantly by grade. The 10-year recurrence risk wasxa0< 10% with stage I cancer (any grade) and for stage II (node-negative and node-positive), grade I cancer.nnnCONCLUSIONnOur data have identified BCs associated with a very low recurrence risk 5 to 10 years after diagnosis, providing women with such cancers confidence about a decision to discontinue AHT after 5 years.

Response to "Do metastasis-free interval less or more than 24 months for recurrent metastatic breast cancer and primary surgery for de novo metastatic breast cancer matter for survival?"

With respect to Dr Altundag’s commentary on our recent article ‘‘Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed’’ by den Brok et al. [1], there are two points of interest: First, overall survival (OS) as it relates to disease-free interval (DFI) and second, OS as it relates to surgery of the primary tumor. With respect to OS as it relates to DFI in relapsed metastatic breast cancer, the results of our study showed that DFI 2 years and [2 to 5 years compared to [5 years were statistically significant in all three breast cancer subtypes with longer DFI resulting in a decreased risk of death. Similar findings were reported by Dawood et al. [2] in a similar large patient cohort (N = 3524). Although the studies by Marshall [3] and Lobbezoo [4] showed differing results from ours, with either no difference in OS or improved survival only when compared to DFI 2 years in the relapsed cohort, it may be that these results simply reflect the sheer difference in numbers studied. Whereas our study included 2796 cases, the Marshall and Lobbezoo reported on 622 and 815 cases, respectively. Clinically, patients who relapse late (C5 years) tend to have more indolent disease course, whereas those relapsing early (2 years) generally have a more aggressive disease course. Given the heterogeneity of breast cancer, it stands to reason that there is a subgroup of patients who fall somewhere between an indolent and a more aggressive biology. This is likely most relevant for patients with HR?/HER2breast cancer since patients with TNBC and, to a large extent, HER2? (and HR-) are more likely to relapse early. There is a relative paucity of data reporting on the nuances of DFI (i.e., 2 years vs. 2–5 years) and its impact on OS, but our results add to the literature from which clinicians can refer to when discussing prognosis with patients. With respect to OS as it relates to surgery of the primary tumor, we agree that the randomized trial by Soran et al. [5] suggests a possible contribution of primary surgery to longer median survival among patients with de novo metastatic disease after 5 years of followup. However, other recent randomized trials [6, 7] suggest no benefit. Although the systemic therapy in the Badwe trial [6] was not optimal by today’s standards, the question of surgery for the primary tumor remains unsettled. It was not the standard of care to remove the primary tumor among patients with confirmed metastatic disease in British Columbia during the era that our study spanned. At the BC Cancer Agency, where these patients were treated, primary tumor surgery in patients with known metastatic disease would generally be performed only to enhance local control if systemic measures and radiotherapy failed or were deemed inadequate. In addition, patients sometimes have primary curative intent surgery, and systemic metastases are subsequently identified on post-operative workup. Within our cohort of 711 cases with de novo metastatic disease, we identified 113 (16%) who had breast conserving surgery and 163 (23%) who had mastectomy (with/without axilla surgery) within 6 months of breast This rebuttal letter refers to the letter to the editor article available at doi: 10.1007/s10549-017-4109-8.

Abstract P5-12-10: Comparison of the efficacy of tamoxifen and aromatase inhibitors on survival in adjuvant menopausal breast cancer

Background Meta-analyses of postmenopausal endocrine therapy and recent studies in premenopausal women suggest that aromatase inhibitors (AI) may be superior to tamoxifen (T) in preventing recurrence in early hormone receptor positive (HR+) breast cancer (BC), although there are recent concerns about the impact on overall survival (OS). The BC Cancer Agency adopted ASCO guidelines of an AI as part of adjuvant therapy for menopausal HR+ BC in 2003. Using our population based data, we sought to compare the 10 year survival outcomes for patients starting either T or AI following surgery for HR+BC. Methods Histopathologic and demographic data were collected for all menopausal patients referred to the BC Cancer Agency with a T1-2, node negative, HR+, HER2 negative BC diagnosed between 01/2003 and 12/2009. Patients with prior or synchronous contralateral BC were excluded. Data was cross-referenced to the provincial pharmacy database, which tracks hormone therapy. Significant factors affecting survival were identified using Cox proportional hazard model for OS and Fine and Gray9s (FG) model for BC specific and Cardiac Specific Survival (CSS) with causes other than event of interest defined as competing. Results We identified a cohort of 3421 cases with median follow up of 7.8 years (y) for T and 7.4 y for AI. Median age was 65y in both groups, and 8.5% received chemotherapy. 47.8% of tumors were T1c and 22.2% were T2; 15.8 % were grade 3. 10 year OS was 84.4% (95% Confidence Intervals [CI] 82.4%, 86.2%) and 82.7% (95% CI 79.4%, 85.6%) for T and AI cohorts, respectively, (p= 0.02). BCSS did not differ between the groups (p=0.54). We categorized causes of death in each cohort as from BC (20.4% T, 20.6% AI), other cancers (25.4% T, 22.1% AI), cardiovascular-related (CVS) (25.8% T, 34.6% AI), thromboembolic (0.3% T, 0.7% AI %) and other (25.4%T, 19.1 % AI). Table 1 shows Univariate (U), multivariable (M), hazard ratios (Hz) and 95% CI. Conclusion While trials show that AIs improve relapse free survival after menopausal HR+BC, their impact on BCSS has been minimal. By contrast they may contribute to CVS deaths, as suggested by our data. We plan to explore this observation further by examining baseline cardiac risk factors within our T and AI cohorts, and by exploring OS, BCSS, and CSS among patients switching to AI after starting T, to identify the optimal adjuvant hormone therapy strategy for menopausal women with HR+ early BC. Citation Format: Chay WY, Speers C, Gondara L, Tyldesley S, Ellard SL, Lohrisch CA, Gelmon KA. Comparison of the efficacy of tamoxifen and aromatase inhibitors on survival in adjuvant menopausal breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-10.

Abstract P2-15-01: Impact of adjuvant trastuzumab (AT) on survival in metastatic (M1) her2 positive breast cancer

Background: Recurrence rates have declined since AT was added to chemotherapy (chx) for her2+ early breast cancer (BC). This has led to under-representation of patients (pts) relapsing after AT in M1 anti-her2 therapy trials. Trastuzumab was introduced in British Columbia in 1998 for M1 disease and 2005 for adjuvant therapy (at inception, pts completing chx within 1 year prior could receive delayed AT).nnMethods: We examined patterns of relapse and median survival from M1 among 3 cohorts of M1 her2+ BC: 1. de novo M1; 2. recurrence with no prior AT; 3. recurrence despite AT. Cohorts were drawn from the BCOU, which tracks outcomes for all referred pts to British Columbia Cancer Agency (BCCA) since 1989. Pts were excluded if they had a contralateral invasive BC (CLBC) within 10 years prior, or synchronous BC if one was her2-, unless M1 site was biopsied and her2+; previous (within 10 years) or synchronous other cancer; or died without BC relapse. Relapse was first ipsilateral local, regional, or distant recurrence, or death from breast cancer. Subsequent isolated CLBC was not counted as a recurrence. Last contact date was used as censoring date for survival among pts still alive on that date; date of death was recorded for deceased pts.nnView this table:nnCohort characteristicsnnnnnnResults: 80% of cohort 3 and 19% of cohort 2 had adjuvant anthracycline plus taxane chx. 14 (10.5%) of cohort 3 pts relapsed while on AT. Age at M1 and% ER+ was similar in all cohorts. Cohort 3 had the lowest rate of liver and highest rate of CNS metastases at M1 presentation. CNS metastases rates over the entire M1 course was similar in all cohorts, however. Despite differences in follow up duration, survival estimates are mature, as at least 75% of pts have died. Median survival was shortest in pts relapsing after AT (p<0.001) despite potential access within clinical trials to more anti-her2 therapy due to later chronologic diagnosis. Pts with denovo M1 had the longest survival despite high rates of initial liver and similar rates of CNS metastases during their M1 course.nnConclusions: AT alters the presentation and survival of M1 disease. Pts with prior AT should be screened for CNS M1 at relapse. It may be particularly important to use a combination of anti-her2 agents in pts relapsing despite AT. Future her2+ M1 trials should stratify by denovo M1 versus prior AT.nnCitation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-01.

Abstract P1-13-01: Risk of recurrence following 5 years of adjuvant hormone therapy for hormone receptor positive early breast cancer.

Background Introduction The MA.17 study and combined analysis of the ATLAS and aTTom studies provide evidence of DFS and modest OS benefit from 10 years of hormone therapy (HT) for hormone receptor positive early breast cancer. The benefit may be less for women diagnosed today, due to advances in chemotherapy, initial HT, and radiation therapy since the era when these trials were conducted. Side effects accrue to all users of longer HT while benefit is experienced only by those who avoid recurrence, which is related to the baseline prognostic factors such as stage, grade, and disease biology. Methods To enhance informed patient-physician discussions, starting with a cohort of 10815 stage I-III hormone receptor breast cancer diagnoses between 1989 and 2004, we examined event-free survival (EFS) in years 5 to 10 among 1,061 premenopausal ( Results Median follow up for the 7676 patients is 11 years. Event rates (including CLBC) in the second 5 years from diagnosis for stage I, II and III cancers were 6%, 12%, 23% for the pre-menopausal cohort, and 5%, 14%, 26% for the post-menopausal cohort. EFS in years 5-10 varied significantly by grade as shown below: Recurrences (excluding CLBC) after 10 years was 2% for the 10815 cases (representing 12% of all recurrences). Conclusion These data suggest that pre and postmenopausal women with stage I cancers of any grade, and postmenopausal women with stage II grade 1 cancers who have not experienced a relapse in the first five years can expect a less than 10% risk of recurrence, breast cancer death, or CLBC without further HT over the next 5 years. Prolonged HT in the identified groups may result in higher probability of harm than benefit and may best be avoided, although long term data will be needed to fully inform this risk benefit analysis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-01.