Expiratory scans significantly improved diagnostic accuracy in patients with inhomogeneous attenuation on inspiratory scans, and they helped in the diagnosis of diffuse lung disease.
Introduction: TNBC is heterogeneous disease with several molecularly defined subtypes (Lehman et al), each of which may be predictive of response to chemotherapy. TNBC molecular subtypes are associated with varied pathological responses to neoadjuvant chemotherapy. However, subtype specific long-term outcomes for TNBC patients treated with uniform adjuvant chemotherapy are not known. Aims: To characterize long-term outcomes of TNBC molecular subtypes (TNBCtypes) in patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) on S9313 Methods: SWOG 9313 accrued 3,125 women with early stage breast cancer to two alternative dose schedules of AC with no difference in outcomes between the two arms (J Clin Oncol 2007). From this trial we identified 425 (14%) patients with centrally determined TNBC for whom tissue was available. Microarray profiling was performed on genomic RNA extracted from pre-treatment FFPE tissue. A 101-gene expression model which has shown to reproduce the classification provided by the original 2188-gene algorithm (Ring et al) was applied to the microarray profiling to generate the following TNBCtypes–Basal-Like 1 (BL1), Basal-Like 2 (BL2), Mesenchymal (M), mesenchymal stem–like (MSL), and luminal androgen receptor (LAR). Immunomodulatory +/- (IM) status was assigned independent of the subtypes. Sequencing of BRCA1/2 from tumor DNA was also performed. The subtypes were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for nodal status. Results: For 425 TNBC patients, the median age was 45 years, 33% were node-positive and 10-year DFS and OS = 66.3% and 74.1%, respectively. A total of 381/424 (89.7%) cases could be classified into TNBCtypes with distribution as follows: BL1=24%, BL2=8%, M=24%, MSL=11%, LAR=9%, unclassified (UNL) =24%. No association between TNBCtypes and race or nodal status was noted. Compared to other subtypes LAR subtype was associated with older age at diagnosis (median age 53 vs 45, p<0.001). Overall 24% of samples were IM+ and 25% demonstrated deleterious tBRCA1/2 mutation. DFS, tBRCA1/2 mutation and IM+ status distribution across different subtypes are provided in the table. All subtypes except for LAR demonstrated a drop in hazard function for recurrence after 5 years. 5 year DFS (%)10 year DFS (%)DFS HR (95% CI), p valueDeleterious tBRCA1/2 mutationIM+ statusBL184.5%77.5%141%60%BL281.3%70.5%1.59 (0.81-3.13) p = 0.1816%12%M69.2%61.2%2.06 (1.25-3.40) p = 0.00528%0%MSL54.8%50.0%2.38 (1.33-4.28) p = 0.00418%7%LAR74.3%53.8%2.24 (1.22-4.14) p = 0.0112%8%UNL76.4%71.8%1.36 (0.80-2.33) p = 0.2620%30% Conclusions: In the presence of adjuvant AC, TNBC molecular subtypes have varied prognosis, with BL1 subtype demonstrating the best prognosis and MSL and LAR subtypes demonstrating the worst prognosis. LAR subtype is associated with older age at diagnosis and continued elevated hazard function for recurrence after year 5. tBRCA1/2 mutations are distributed across all subtypes with the highest prevalence in BL1 and M subtypes. IM+ status was infrequently noted in non-BL1 subtypes. These findings underscore TNBC heterogeneity and the need to account for this heterogeneity in prospective clinical trials. Citation Format: Sharma P, Barlow WB, Hout DR, Seitz RS, Bailey DB, Godwin AK, Pathak H, Timms KM, Solimeno C, Linden HM, Porter P, Tripathy D, Hortobagyi GN, Thompson A, Pusztai L, Hayes DF. Impact of molecular subtypes on long-term outcomes in triple-negative breast cancer (TNBC) patients treated with adjuvant AC chemotherapy on SWOG S9313 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-06.
Background: Postmenopausal early breast cancer patients, treated with endocrine therapy, have approximately 90% five year disease free survival (DFS). However, for patients at higher risk of relapse, additional adjuvant chemotherapy may be indicated. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients on tamoxifen (T) therapy into various risk groups potentially guiding treatment choices. We tested the efficacy of this panel in the TEAM trial (exemestane (E) versus T→E) to determine the relevance in patients treated with an AI. Patients & Methods: Pathology blocks from 4598 TEAM patients were collected and tissue microarrays constructed. The cohort overall was 47% node positive, and 36% also received adjuvant chemotherapy. Samples were stained, using triplicate 0.6mm2 TMA cores, and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 assessed. Each case was assigned a Mammostrat risk score and analysed for disease free survival (DFS) by marker positivity and risk score. Results: Preliminary results on the UK TEAM cohort (1059 cases) showed 18.9% stained positive for p53 (184/972), 21.3% for NRDG1 (204/956), 26.4% for SLC7A (253/957), 21.9% for HTF9C (220/1004), 18.3% for CEACAM5 (185/1009). Complete data was available for 919 cases including patients treated with chemotherapy, with 447 (49%) designated low risk, 213 (23%) medium and 259 (28%) high risk. In univariate analysis, Mammostrat scores were prognostic (p=0.02), with 5 year DFS (see comment above) results being 86.9±1.7%, 80.1±3.0% and 80.8±2.6% for patients with low, medium and high Mammostrat scores respectively. Analyses on the entire TEAM pathology cohort are ongoing, and further data with sufficient power to evaluate the impact of Mammostrat in multivariate regression analyses will be presented. Conclusion: Preliminary analysis of the impact of the Mammostrat score in both tamoxifen and exemestane treated patients suggests it retains its prognostic value in this context. Further analysis with the power to evaluate the impact of Mammostrat in multivariate regression analyses will be presented. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-33.
BackgroundChemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. MethodsWe report nal outcomes from a phase Ib trial evaluating pembrolizumab (200mg IV every 3 weeks) with either weekly paclitaxel (80mg/m 2 weekly) or at-dose capecitabine (2000mg orally twice daily for 7 days of every 14-day cycle) in the 1st /2nd line setting. The primary endpoint was safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥ 21-day delays). The secondary endpoint was e cacy (week 12 objective response rate). Exploratory aims were to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. ResultsBoth regimens met the pre-speci ed safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate was 29% for pembrolizumab/paclitaxel and 43% for pembrolizumab/capecitabine. Partial responses were observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens were associated with signi cant peripheral leukocyte contraction over time. Response was associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor in ltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). ConclusionsPembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens were lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted.
Introduction: Lehmann and colleagues (Lehmann et al., 2011) devised a gene expression classification system for triple negative breast cancer (TNBC) consisting of seven subtypes—IM, BL1, BL2, LAR, M, MSL, and UNS (unselected). We (Ring et al., 2016) recently modified this original algorithm of 2188 gene subtyping into a 101-gene algorithm. In addition to a reduction of genes, the 101-gene algorithm has two methodological differences: first, the immunomodulatory (IM) signature was treated not as a subtype but rather as a binary feature of one of the other subtypes (e.g. BL1/IM+, LAR/IM-); second, when tumors—by a predefined correlation coefficient—showed traits of more than one subtype, both subtypes were reported as “dual subtypes.” Aim: Our aim was to apply the 101-gene algorithm for TNBC subtyping and to establish the relation of TNBC subtypes with their IM-status across several independent data sets. Methods: 951 patients from four independent TNBC cohorts with available gene expression data were analyzed by the 101-gene algorithm. Of these 848 were classified with at least one subtype. Results: The distribution of the 5 TNBC subtypes in both single and dual subtypes was 47%,10%,15%,18%,11%, for BL1, BL2, LAR, M, and MSL respectively. The majority of cases gave only one subtype (572, 67%) with M (Mesenchymal) being 9% (n=54) of these. Given this frequency of 9% of M as a baseline, in the remaining 276 (33%) cases with dual subtypes, the expectation that M would be one of the two is 11% (64 subtype calls). However, M is one of the two of the dual subtypes at a much higher frequency of 40% (222 subtype calls, Chi-Squared, P<0.0001). IM+ is a common feature across these cohorts (n=310 or 37%). When examining the IM feature within the patients exhibiting the M subtype as either a single subtype or one of the two dual subtypes (n=276, 33%), IM positive tumors are never of the M phenotype (Chi-Squared, p<0.0001). Conclusions: We further have confirmed with the 101-gene algorithm that the IM signature inversely associates with the M subtype as it has been observed with the 2188 gene algorithm (Lehmann et al., 2016). Moreover, the M signature is occasionally a confounder of other subtypes however still identifies those tumors negative for immune infiltrates. This raises important opportunities to understand the relationships between intrinsic tumor biology reflected in TNBC subtypes and their interaction with variable immune cell stroma which are the subject of ongoing analyses. Citation Format: Grigoriadis A, Quist J, Mirza H, Cheang MC, Ring BZ, Hout DR, Bailey DB, Seitz RS, Tutt AN. Mesenchymal subtype negatively associates with the presence of immune infiltrates within a triple negative breast cancer classifier [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 P1-07-03.
#3026 Background: Patients with early stage ER+ve breast cancer have excellent prognosis with ca 90% 5 year disease free survival when treated with endocrine therapy. However for patients who relapse during endocrine therapy additional adjuvant therapy options, such as chemotherapy, are indicated. The challenge is to prospectively identify such patients. The Mammostrat® test comprises 5 simple immunohistochemical markers (p53, HTF9C, CEACAM5, NDRG1, SLC7A5) which stratify node negative tamoxifen treated patients into low, moderate and high risk groups. We have now tested the efficacy of this panel in a mixed population of node positive/node negative cases treated in a single centre (Edinburgh Breast Unit) with breast conserving surgery.
 Methods: TMAs from a consecutive series (1981-98) of 1,812 women managed by wide local excision and postoperative radiotherapy (45Gy in 20-25 fractions) were collected following appropriate ethical review. Of 1390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1044 received tamoxifen only as adjuvant therapy and 149 received a combination of hormonal and chemotherapy. Median age at diagnosis was 57, 71% were post-menopausal, 23.9% node positive, median size was 1.5 cm. Samples were stained, using triplicate 0.6mm2 TMA cores and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 recorded as previously described. Each case was assigned a Mammostrat score and RFS and OS analysed by marker positivity and Mammostrat score.
 Results: Staining for all 5 antibodies was successful in 1174/1390 (84%) of cases. In the primary analysis of 531 N0/ER+ve Tamoxifen only treated patients Mammostrat was significantly associated with relapse free survival (RFS) in univariate (p=0.025) & multivariate proportional hazards analysis (p=0.01, HR=1.3, 95%C.I. 1.08-1.74). PgR, multifocality and menopausal status were significant co-variates (p<0.05, HR 0.89, 2.0 & 0.6 respectively). The Nottingham prognostic index was non-significant. Of the 5 antibodies, only p53 (p=0.04) was independently predictive of survival.
 In a secondary univariate analysis of 781 patients (including N+ve and chemo/tam treated patients) Mammostrat was predictive of RFS & OS (p<0.01) with NDRG1/CEACAM5/p53 also predictive of RFS(p<0.05). However Mammostrat was not independent of nodal status, pathological size, grade or multifocality in a proportional hazards analysis.
 Discussion: In the Edinburgh BCS population Mammostrat was predictive of RFS (both local and distant relapses) in N-ve/ER+ve patients treated with tamoxifen alone irrespective of menopausal status. There was a strong correlation between Mammostrat scores and grade, however, in a multivariate analysis Mammostrat contributed significantly to prognostication along with PgR, multifocality and menopausal status. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3026.
Background In patients with triple-negative breast cancer (TNBC), tumor-infiltrating lymphocytes (TILs) have been reported to be associated with improved survival. Lehmann et al. identified 6 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), mesenchymal stem like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR)], and we previously reported that TNBC subtype is a predictor of pathologic complete response (pCR). Recently, the IM gene expression signature has been shown to be indicative of the presence of TILs and has been incorporated into TNBC subtyping as a modifier of the other groups rather than a separate subtype. However, the association between TNBC subtype and the presence of TILs is not known. We hypothesized that the BL2 and LAR subtypes, which have low pCR rates, have low rates of immune infiltration. Inflammatory breast cancer (IBC) is an aggressive cancer that is frequently triple-negative. The association between IBC and the presence of TILs also is not known. In this study, we analyzed the association between TNBC molecular subtype and the IM signature and determined whether the IM signature differed between patients with IBC and non-IBC. Methods We retrospectively analyzed 88 patients with TNBC from the World IBC Consortium dataset for whom IBC status was known (IBC, n=39; non-IBC, n=49) and tumor gene expression data were available. TNBC specimens were classified using the TNBCtype algorithm (Insight Genetics, Inc., TN, USA), which uses a 101-gene signature. For each tumor, the TNBCtype algorithm reports the TNBC molecular subtype (BL1, BL2, M, MSL, or LAR) and the IM status, which is described as positive (IM+) or negative (IM-). Recently, Fisher's exact test was used to analyze differences in subtype distribution between the IM+ and IM- tumors. Results The subtype distribution differed significantly between the IM+ and IM- tumors IM signature in TNBC subtypesSubtypeTotal (n=88)IM+ (n=32)IM- (n=56)BL13015 (50)15 (50)BL2202 (100)M808 (100)MSL3113 (42)18 (58)LAR121 (8)11 (92)Not determined53 (60)2 (40) (p=0.0087). The majority of IM+ cases occurred in the BL1 and MSL subtypes. No IM+ cases were observed in the BL2 or M subtypes, and only 1 was observed in the LAR subtype. IM+ cases occurred at roughly the same frequency in patients with IBC (33%) and non-IBC (37%, p=0.73). Conclusions TNBC molecular subtypes differ in their degree of immune infiltration, and most IM+ TNBCs are of the BL1 and MSL subtypes. Our finding that the proportion of IM+ cases was not different between IBC and non-IBC indicates that TILs are recruited to the tumor microenvironment similarly in IBC and non-IBC tumors. Further, Pietenpol et al recently showed that the MSL signature represents normal stromal cells rather than tumor cells by performing laser-capture microdissection of TNBC specimen. Validation studies are needed to corroborate and further expand upon our findings. Citation Format: Harano K, Wang Y, Lim B, Seitz RS, Morris SW, Bailey DB, Hout DR, Skelton RL, Ring BZ, Masuda H, Rao AUK, Woodward WA, Reuben JM, Ueno NT. Rates of immune infiltration in patients with triple-negative breast cancers by molecular subtype and in patients with inflammatory and non-inflammatory breast cancers [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 P1-07-14.
Background: TNBC molecular subtype classification updated by Lehmann et al. includes 4 subtypes: basal-like 1 and 2 (BL1), (BL2), mesenchymal (M), and luminal androgen receptor (LAR), and as a modifier of these subtypes, an Immunomodulatory (IM) gene expression signature. However, molecular subtypes have not been linked to morphological features of TNBC. Apocrine carcinoma has been proposed as a TNBC category that expresses androgen receptor. LAR-subtype TNBC has a poor response to neoadjuvant systemic therapy (NST). We hypothesized that defining the apocrine-featured TNBC by morphology and molecular subtype predict the prognosis of patients with residual disease after NST. Methods: We created the Pan-Pacific TNBC Consortium dataset, which contains paired samples of matched pre and post-NST TNBC tumors from 4 institutions. All patients received NST and didn't have a pathological complete response (pCR). Three pathologists examined hematoxylin and eosin-stained slides of 86 pre-NST samples and determined (1) the presence of apocrine differentiation, (2) the level of tumor-infiltrating lymphocytes (TILs), (3) the histological grade (HG), and (4) the rate of necrosis. These morphological features were compared among the subtypes. For a sample to be considered apocrine positive, apocrine differentiation had to be identified by 2 or more pathologists. Fisher's exact test was used to test the association of subtypes and morphological features. The log-rank test was used to compare disease-free survival (DFS). Results: Twelve of 24 (50%) apocrine-positive tumor samples were LAR subtype, and12 of 17 (70%) LAR-subtype tumor samples exhibited apocrine differentiation. The other subtypes showed following: BL1, 11/44 (25%); BL2, 0/7 (0%); M, 1/10 (10%); unclassified, 0/8 (0%). The median follow-up time was 22 months. In all populations, 2-year DFS rates were higher in patients with apocrine-positive tumors than in those whose tumors did not exhibit apocrine differentiation (P = .027; 2-year DFS, 85% vs 54%). The LAR subtype was also associated with lower HG, although LAR tumors had a similar prognosis to the other subtypes. In the combined analysis of subtypes and apocrine differentiation, patients with apocrine-positive LAR tumors had a higher 2-year DFS rate than did those with apocrine-negative LAR tumors (P = .044; 2-year DFS, 88% vs. 30%). However, patients with apocrine-positive BL1 tumors had no better DFS than did those with apocrine-negative BL1 tumors (P = .133). TIL levels and the presence of the IM signature were positively associated (P = .01), and apocrine differentiation positivity tended to be negatively associated with TIL level (P = .06). Neither TIL level nor IM signature was associated with survival. Conclusion: Apocrine differentiation was associated with the LAR subtype of TNBC and better prognosis in patients who did not have a pCR. The LAR subtype alone did not predict DFS; however, LAR tumors with apocrine differentiation had a better prognosis than did LAR tumors without apocrine differentiation. Using a combination of morphologic and genomic testing may be helpful in determining the prognosis of patients with apocrine-positive TNBC tumors who have residual disease after NST. Citation Format: Masuda H, Miura S, Harano K, Wang Y, Hirota Y, Matsunaga Y, Lim B, Lucci A, Parinyanitikul N, Lee HJ, Gong G, Rao A, Seitz RS, Morris SW, Hout DR, Nakamura S, Tripathy D, Harada O, Krishnamurthy S, Ueno NT. Apocrine morphology and LAR molecular subtype predict prognosis of TNBC patients with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-02-05.
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