The risk of local and regional relapse associated with each breast cancer molecular subtype was determined in a large cohort of patients with breast cancer. Subtype assignment was accomplished using ...a validated six-marker immunohistochemical panel applied to tissue microarrays.
Semiquantitative analysis of estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin (CK) 5/6 was performed on tissue microarrays constructed from 2,985 patients with early invasive breast cancer. Patients were classified into the following categories: luminal A, luminal B, luminal-HER2, HER2 enriched, basal-like, or triple-negative phenotype-nonbasal. Multivariable Cox analysis was used to determine the risk of local or regional relapse associated the intrinsic subtypes, adjusting for standard clinicopathologic factors.
The intrinsic molecular subtype was successfully determined in 2,985 tumors. The median follow-up time was 12 years, and there have been a total of 325 local recurrences and 227 regional lymph node recurrences. Luminal A tumors (ER or PR positive, HER2 negative, Ki-67 < 1%) had the best prognosis and the lowest rate of local or regional relapse. For patients undergoing breast conservation, HER2-enriched and basal subtypes demonstrated an increased risk of regional recurrence, and this was statistically significant on multivariable analysis. After mastectomy, luminal B, luminal-HER2, HER2-enriched, and basal subtypes were all associated with an increased risk of local and regional relapse on multivariable analysis.
Luminal A tumors are associated with a low risk of local or regional recurrence. Molecular subtyping of breast tumors using a six-marker immunohistochemical panel can identify patients at increased risk of local and regional recurrence.
Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial ...randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.
Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.
Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2(+) tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors n = 94; HR, 1.1; 95% confidence interval (CI), 0.6-2.1 for RFS and HR, 1.3; 95% CI, 0.7-2.5 for OS.
HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.
The incidence of local recurrence at 5 years was low among women with T1N0 grade 1 or 2 luminal A breast cancer who had undergone breast-conserving surgery and received endocrine therapy, but not ...radiotherapy.
Background
Basal-like breast cancers, originally recognized by gene expression profiling, can be clinically identified using immunohistochemical (IHC) definitions that require estrogen receptor (ER) ...negativity. However, some basal cases are ER positive and are mistakenly considered to be luminal by standard IHC approaches, leading to suboptimal treatment choices. Nestin, an intermediate filament expressed in many stem cells, is a recently identified positive marker of basal-like phenotype independent of ER status. In this study, we evaluated its clinical associations and prognostic capacity in a large breast cancer cohort.
Methods
A tissue microarray series of clinically annotated invasive breast cancers with 12.6-year median follow-up was assessed for nestin expression by IHC. Kaplan–Meier and Cox regression models were used to evaluate the prognostic significance of nestin status, for the primary endpoint of breast cancer-specific survival (BCSS).
Results
Among 3641 cases interpretable for nestin by IHC, positive staining was found in 371 cases (10%) and was significantly associated with poor prognostic factors including other markers of basal-like differentiation. Patients with nestin-positive tumors had a significantly lower 10 year BCSS (HR 1.97, 95% CI 1.62–2.40;
P
< 0.001). Importantly, within the large group of 2323 ER+ cases, nestin positivity identified a subgroup of 120 patients (5%) with a significantly inferior 10-year BCSS (HR 1.50, 95% CI 1.10–2.13;
P
= 0.02).
Conclusions
Nestin IHC positivity is associated with the poor clinical outcomes and reduced survival rates that characterize the gene expression basal-like subtype. This easily applicable tool identifies ER+ poor prognosis basal phenotype patients that are currently being missed by “Triple negative” or “Core basal” IHC definitions.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
We have previously demonstrated in a pilot study of 348 invasive breast cancers that mast cell (MC) infiltrates within primary breast cancers are associated with a good prognosis. Our aim was ...to verify this finding in a larger cohort of invasive breast cancer patients and examine the relationship between the presence of MCs and other clinical and pathological features.
Experimental design
Clinically annotated tissue microarrays (TMAs) containing 4,444 cases were constructed and stained with c-Kit (CD-117) using standard immunoperoxidase techniques to identify and quantify MCs. For statistical analysis, we applied a split-sample validation technique. Breast cancer specific survival was analyzed by Kaplan–Meier KM method and log rank test was used to compare survival curves.
Results
Survival analysis by KM method showed that the presence of stromal MCs was a favourable prognostic factor in the training set (
P =
0.001), and the validation set group (
P =
0.006). X-tile plot generated to define the optimal number of MCs showed that the presence of any number of stromal MCs predicted good prognosis. Multivariate analysis showed that the MC effect in the training set (Hazard ratio HR = 0.804, 95% Confidence interval CI, 0.653–0.991,
P =
0.041) and validation set analysis (HR = 0.846, 95% CI, 0.683–1.049,
P =
0.128) was independent of age, tumor grade, tumor size, lymph node, ER and Her2 status.
Conclusions
This study concludes that stromal MC infiltration in invasive breast cancer is an independent good prognostic marker and reiterates the critical role of local inflammatory responses in breast cancer progression.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The molecular chaperone αB-crystallin is expressed in estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 "triple-negative" breast carcinomas and promotes brain and ...lung metastasis. We examined αB-crystallin expression in primary breast carcinomas with metastatic data to evaluate its association with prognosis and site-specific metastases.
αB-crystallin gene (
) expression was examined using publically available global-gene expression data (n=855 breast tumors) with first site of distant metastasis information ("855Met"). αB-crystallin protein expression was determined by immunohistochemistry using the clinically annotated tissue microarray (n=3987 breast tumors) from British Columbia Cancer Agency (BCCA). Kaplan-Meier and multivariable Cox regression analyses were used to evaluate the prognostic value of αB-crystallin. Multivariable logistic regression analysis was used to evaluate risks of αB-crystallin and other markers for site of metastasis.
In the 855Met dataset, αB-crystallin gene (
expression was an independent predictor of brain as the first distant site of relapse (HR = 1.2, (95% CI 1.0-1.4),
= 0.021). In the BCCA series, αB-crystallin protein expression was an independent prognostic marker of poor breast cancer specific survival (HR = 1.3, (95% CI 1.1-1.6),
= 0.014). Among patients with metastases, αB-crystallin was the strongest independent predictor of brain metastasis (OR = 2.99 (95% CI 1.83-4.89),
< 0.0001) and the only independent predictor of brain as the first site of distant metastasis (OR = 3.15 (95% CI1.43-6.95),
= 0.005). αB-crystallin was also associated with worse survival (3.0 versus 4.7 months,
= 0.007).
αB-crystallin is a promising biomarker to identify breast cancer patients at high risk for early relapse in the brain, independent of ER and HER2 status.
LBA501
Background: Adjuvant breast RT is usually prescribed following BCS to reduce the risk of local recurrence (LR). However, this treatment is inconvenient, costly, and associated with acute and ...late toxicity. Traditional clinical pathological factors (CPFs) alone are limited in their ability to identify women with a low enough risk of LR to omit RT. Molecular defined intrinsic subtypes of BC provide additional prognostic information with luminal A having the lowest risk of recurrence. A retrospective analysis of a previous trial suggested that women >60 years with luminal A grade 1-2 T
1
N
0
BC treated by BCS and endocrine therapy alone had a low rate of LR ( JCO 2015; 33:2035). The utility of identifying luminal A subtype combined with CPFs has not been prospectively evaluated for its ability to guide RT decision-making. Methods: A prospective multicenter cohort study was performed. Eligibility criteria were: women ≥ 55 years; having undergone BCS for grade 1-2 T
1
N
0
BC; ≥ 1mm margins of excision; luminal A subtype (defined as: ER ≥ 1%, PR>20%, HER2 negative and Ki67 ≤ 13.25%); and treated with adjuvant endocrine therapy. ER, PR and HER2 were performed locally as per ASCO guidelines. Patients meeting clinical eligibility with ER ≥ 1%, PR>20%, HER2 negative BC were registered and had Ki67 immunohistochemistry performed centrally in one of three Canadian laboratories using International Ki67 Working Group methods. Proficiency testing between laboratories was performed yearly. Patients with Ki67 ≤ 13.25% were enrolled in the trial and were assigned to not receive RT. The primary outcome was LR defined as time from enrollment to any invasive or non-invasive cancer in the ipsilateral breast. Assuming a 5-year LR rate of 3.5%, 500 patients were required to show that the upper bound of a two sided 90% (one-sided 95%) confidence interval (CI) was <5%. Patients were followed every six months for the first two years and then yearly. The probability of LR was estimated using the cumulative incidence function with death as a competing risk. Secondary outcomes were contralateral BC; relapse free survival (RFS) based on any recurrence; disease free survival (DFS) based on any recurrence, second cancer or death; and overall survival (OS). Results: From August 2013 to July 2017, 501 of 727 registered patients from 26 centers had a Ki67 ≤ 13.25% and were enrolled. Median follow-up was 5 years. Median age was 67 and 442 (88%) patients were <75 years. Median tumor size was 1.1 cm. The 5-year rate of LR satisfied our pre-specified boundary (see Table). Conclusions: Women ≥ 55 years with grade 1-2 T
1
N
0
luminal A BC following BCS treated with endocrine therapy alone had very low rates of LR at 5 years and are candidates for omission of RT. Clinical trial information: NCT01791829. Table: see text
Purpose: Basal-like breast cancer is associated with high grade, poor prognosis, and younger patient age. Clinically, a triple-negative
phenotype definition estrogen receptor, progesterone receptor, ...and human epidermal growth factor receptor (HER)-2, all negative
is commonly used to identify such cases. EGFR and cytokeratin 5/6 are readily available positive markers of basal-like breast
cancer applicable to standard pathology specimens. This study directly compares the prognostic significance between three-
and five-biomarker surrogate panels to define intrinsic breast cancer subtypes, using a large clinically annotated series
of breast tumors.
Experimental Design: Four thousand forty-six invasive breast cancers were assembled into tissue microarrays. All had staging, pathology, treatment,
and outcome information; median follow-up was 12.5 years. Cox regression analyses and likelihood ratio tests compared the
prognostic significance for breast cancer death-specific survival (BCSS) of the two immunohistochemical panels.
Results: Among 3,744 interpretable cases, 17% were basal using the triple-negative definition (10-year BCSS, 6 7%) and 9% were basal
using the five-marker method (10-year BCSS, 62%). Likelihood ratio tests of multivariable Cox models including standard clinical
variables show that the five-marker panel is significantly more prognostic than the three-marker panel. The poor prognosis
of triple-negative phenotype is conferred almost entirely by those tumors positive for basal markers. Among triple-negative
patients treated with adjuvant anthracycline-based chemotherapy, the additional positive basal markers identified a cohort
of patients with significantly worse outcome.
Conclusions: The expanded surrogate immunopanel of estrogen receptor, progesterone receptor, human HER-2, EGFR, and cytokeratin 5/6 provides
a more specific definition of basal-like breast cancer that better predicts breast cancer survival.
Here we report targeted sequencing of 83 genes using DNA from primary breast cancer samples from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) ...patients to determine interactions between somatic mutation and prognosis. Independent validation of prognostic interactions was achieved using data from the METABRIC study. Previously established associations between MAP3K1 and PIK3CA mutations with luminal A status/favorable prognosis and TP53 mutations with Luminal B/non-luminal tumors/poor prognosis were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutations were also a poor outcome driver that was validated in METABRIC. For MA12, poor outcome associated with PIK3R1 mutation was also reproducible. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false discovery correction (q = 0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typifies ER+ breast cancer.
Whole breast irradiation delivered once per day over 3–5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) ...delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation.
We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5–8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035.
Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3–9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9–4·0) in the APBI group and 2·8% (1·8–3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84–1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 28% of 1070 patients) than whole breast irradiation (484 45% of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 32% of 1070 patients) than whole breast irradiation (142 13% of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5–15·0), 5 years (16·5%, 12·5–20·4), and 7 years (17·7%, 12·9–22·3).
External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied.
Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
