Purpose: To compare the clinical features, natural history, and outcomes for women with “triple-negative” breast cancer with women with other types of breast cancer. Experimental Design: We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women9s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. Results: The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P P Conclusions: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.

https://clincancerres.aacrjournals.org/content/clincanres/13/15/4429.full.pdf

Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence

Background The inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. Methods This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. Results We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0900212

Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer. This review focuses on its origin, molecular and clinical characteristics, and treatment.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1001389

Triple-negative breast cancer.

Introduction
In breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype.

/pdf/phenotypic-and-molecular-characterization-of-the-claudin-low-1xn36frlen.pdf

Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer

Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.

Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease

Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells Breast cancers arising in carriers of germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age- and grade-matched controls, for downregulation of BRCA1 Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P=072), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P=0008) ID4, a negative regulator of BRCA1, was expressed at 91-fold higher levels in basal-like breast cancer (P<00001), suggesting a potential mechanism of BRCA1 downregulation BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls (P<00001) The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer

BRCA1 dysfunction in sporadic basal-like breast cancer.

BACKGROUND. The treatment of Paget disease by mastectomy has been challenged recently in favor of breast-conserving techniques. A large series of patients treated with mastectomy has been reviewed to assess the feasibility of less radical surgery. METHODS. The cases of 70 women with a clinical diagnosis of Paget disease were reviewed. The type, grade, receptor and node status, and the mammographic and pathologic extent of the underlying breast malignancy were determined. The survival of patients with invasive disease was compared with matched controls without Paget disease. RESULTS. The underlying malignancy was invasive in 58% of cases. Despite the fact that only one third of women presented with a palpable mass, the malignancy was frequently extensive, being confined to the retroareolar region in only 25% of cases. The true extent of the disease was underestimated by mammography in 43% of cases. Of the patients with ductal in situ carcinoma, 96.5% had high-grade carcinomas and 100% had invasive carcinomas of high cytonuclear grade. Overexpression of the c-erb-B2 oncogene was detectable in 83% of cases. Patients with Paget disease had a significantly worse survival than matched controls, but this difference was eliminated if they were also matched for c-erb-B2 status. CONCLUSIONS. Paget disease is often associated with extensive underlying malignancy, which is difficult to assess accurately either clinically or mammographically. As a consequence, cone excision of the nipple would have resulted in incomplete excision in 75% of cases. The underlying disease is of high grade and is frequently c-erb-B2 positive with a resulting poor prognosis. Aggressive local and systemic treatment would seem to be merited. Cancer 2002;95:1–7.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.10638

Paget disease of the nipple: a multifocal manifestation of higher-risk disease.

Tumor grade is an established indicator of breast cancer outcome, although considerable heterogeneity exists even within-grade. Around 25% of grade III invasive ductal breast carcinomas are associated with a “basal” phenotype, and these tumors are reported to be a distinct subgroup. We have investigated whether this group of breast cancers has a distinguishing pattern of genetic alterations and which of these may relate to the different clinical outcome of these patients. We performed comparative genomic hybridization (CGH) analysis on 43 grade III invasive ductal breast carcinomas positive for basal cytokeratin 14, as well as 43 grade- and age-matched CK14-negative controls, all with up to 25 years (median, 7 years) of clinical follow-up. Significant differences in CGH alterations were seen between the two groups in terms of mean number of changes (CK14+ve − 6.5, CK14−ve − 10.3; P = 0.0012) and types of alterations at chromosomes 4q, 7q, 8q, 9p, 13q, 16p, 17p, 17q, 19p, 19q, 20p, 20q and Xp. Supervised and unsupervised algorithms separated the two groups on CGH data alone with 76% and 74% accuracy, respectively. Hierarchical clustering revealed distinct subgroups, one of which contained 18 (42%) of the CK14+ve tumors. This subgroup had significantly shorter overall survival ( P = 0.0414) than other grade III tumors, regardless of CK14 status, and was an independent prognostic marker ( P = 0.031). These data provide evidence that the “basal” phenotype on its own does not convey a poor prognosis. Basal tumors are also heterogeneous with only a subset, identifiable by pattern of genetic alterations, exhibiting a shorter overall survival. Robust characterization of this basal group is necessary if it is to have a major impact on management of patients with breast cancer.

https://clincancerres.aacrjournals.org/content/clincanres/10/18/5988.full.pdf

Molecular cytogenetic identification of subgroups of grade III invasive ductal breast carcinomas with different clinical outcomes

Many studies have investigated the relationship between the E-cadherin/catenin axis and breast cancer biology and yet, unlike the studies in other tumour systems, which have shown a relationship between down-regulation and poor survival, no clear association has emerged in breast. Since accumulating evidence suggests that ductal carcinoma of no special type (NST) represents a diverse group of biologies, this study has focused on grade III ductal carcinoma, in order to reduce the heterogeneity of the study population. A total of 470 breast tumours were studied. Consecutive sections were labelled with antibodies which recognize E-cadherin and the arm proteins with which it interacts: alpha-, beta-, and gamma-catenin. Membrane-bound and cytoplasmic E-cadherin and membrane-bound alpha-catenin expression were associated with a positive oestrogen receptor (ER) status, gamma-catenin with a negative ER status, and, surprisingly, all three with poor survival. Taken together, these findings suggest that a conserved E-cadherin/catenin axis may play a part in determining adverse outcome in grade III breast carcinoma.

Retention of the expression of E-cadherin and catenins is associated with shorter survival in grade III ductal carcinoma of the breast.

The significance of occult metastases in axillary lymph nodes in patients with carcinoma of the breast is controversial. Additional sections were cut from the axillary lymph nodes of 477 women with invasive carcinoma of the breast, in whom no metastases were seen on initial assessment of haematoxylin and eosin stained sections of the nodes. One section was stained with haematoxylin and eosin, and one using immunohistochemistry with two anti-epithelial antibodies (CAM5.2 and HMFG2). Occult metastases were found in 60 patients (13%). The median follow-up was 18.9 years with 153 breast cancer related deaths. There was no difference in survival between those with and those without occult metastases. Multivariate analysis, however, showed that survival was related to tumour size and histological grade. This node-negative group was compared with a second group of 202 patients who had one involved axillary node found on initial assessment of the haematoxylin and eosin sections; survival was worse in the patients in whom a nodal metastasis was found at the time of surgery. Survival was not related to the size of nodal metastases in the occult metastases and single node positive groups. Some previous studies have found a worse prognosis associated with occult metastases on univariate analysis, but the evidence that it is an independent prognostic factor on multivariate analysis is weak. We believe that the current evidence does not support the routine use of serial sections or immunohistochemistry for the detection of occult metastases in the management of lymph node negative patients, but that the traditional factors of histological grade and tumour size are useful.

/pdf/occult-axillary-lymph-node-metastases-are-of-no-prognostic-1359asxfg3.pdf

K Ryder

Papers

BRCA1 dysfunction in sporadic basal-like breast cancer.

Paget disease of the nipple: a multifocal manifestation of higher-risk disease.

Molecular cytogenetic identification of subgroups of grade III invasive ductal breast carcinomas with different clinical outcomes

Retention of the expression of E-cadherin and catenins is associated with shorter survival in grade III ductal carcinoma of the breast.

Occult axillary lymph node metastases are of no prognostic significance in breast cancer