Breast Cancer, a Heterogeneous Disease Entity: The Very Early Stages

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Although several molecular targets have been identified in complex diseases, only a few targeted therapies and other novel treatment approaches have been found to be effective in the management of malignant diseases. Another concern, which also has roots in underlying molecular changes driving the malignant phenotype, is the development of drug resistance, which results in therapeutic failure.

Although multidisciplinary research efforts have identified main pathways as well as some specific genetic determinants implicated in this phenomenon, innate or acquired resistance of cancer cells remains a significant challenge of translational medicine [ 33 , 34 ]. Gastrointestinal malignancies are highly aggressive and currently used standard therapies showed only a modest effect on improving survival and preventing recurrence [ 35 ]. Targeted therapies, based on antibodies or small molecule compounds, targeting specific molecular aberrations associated with gastric tumors, could offer improved outcomes and potentially fewer adverse effects.

current state of breast cancer classification | Annals of Oncology | Oxford Academic

Antineoplastic monoclonal antibodies, currently being evaluated in clinical trials for the treatment of gastric cancer. The Phase III ToGA study NCT , which evaluated the addition of trastuzumab to chemotherapy for treatment of advanced gastric cancer and gastroesophageal junction GEJ cancer, was one of the first studies that clearly demonstrated the benefits of targeted therapy in a selected group of patients [ 40 , 41 ]. Additional post hoc exploratory analyses investigated the correlations between HER2 overexpression and clinical and epidemiological features of patients [ 44 ].

Overexpression or amplification of HER2 was more common in intestinal GCs than diffuse or mixed types of GC, which was in concordance with other studies [ 45 , 46 ]. In addition, GEJ tumors showed higher rate of HER2 overexpression or amplification than stomach tumors, indicating that GEJ adenocarcinoma differs in etiology and pathogenesis from distal stomach tumors. HER2 testing and trastuzumab treatment have been integrated in clinical settings in several developed countries. Based on previous more or less promising results in the treatment of glioblastoma, colon, breast and lung cancers targeting angiogenesis with monoclonal antibody bevacizumab directed against VEGFA, Avagast clinical study was launched with the aim to evaluate the benefit of bevacizumab for GC patients [ 53 — 61 ].

Unadjusted overall survival rate did not reach statistical significance.

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Subgroup analyses demonstrated differences in the efficacy of bevacizumab addition to chemotherapy between examined populations. Although the response rate was higher in bevacizumab arm, the difference was not significant. Inconsistencies in overall survival of patients receiving bevacizumab in addition to chemotherapy, prompted further research, focused on evaluating plasma and tumor biomarkers and clinical outcomes [ 63 ]. In particular, this mechanism could affect the ability of circulating tumor cells, which are shed from primary tumor mass, to evade immune system and establish secondary tumor niches.

It should be noted that this study was preliminary, the number of tested patients was small and the majority of patients had prior to enrolment in this study received two or more systemic or adjuvant therapies. Studies on gastric cell lines confirmed its antiproliferative activity [ 82 ]. Currently, the results are still inconclusive, due to termination of some of these studies or negative results regarding the lapatinib efficacy. Nevertheless, interesting conclusions could be drawn from the observations from two larger studies involving lapatinib testing.

A total of eligible patients were evaluated, and lapatinib efficacy analyses were performed in a group consisting of patients with FISH confirmed amplification of HER2 primary efficacy population, PEP. The underlying reason for this stratification was based on the results of previous studies performed on breast cancer patients, which showed that lapatinib administration benefits only a selected population of patients with HER2 amplification, regardless of the status of HER2 expression, determined with IHC [ 84 ].

Additional analyses revealed that lapatinib was more effective in Asian patients and younger patients. In addition, lapatinib was less effective in patients, who had undergone gastrectomy with pylorus removed, than in patients with intact pylorus [ 45 ]. This group was used to evaluate the concordance between different HER2 assay methods, which were performed in two central laboratories and local laboratory.

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These findings correlated well with the fact that these patients had higher levels of HER2 gene amplification. Interestingly, other studies also reported similar outcomes in GC patients with high HER2 amplification status when treated with monoclonal antibody trastuzumab [ 87 , 88 ].

First, HER2 expression patterns differ between GC and breast cancer and furthermore, in GC the expression patterns are frequently heterogeneous [ 44 , 46 , 86 , 88 ]. The optimal cutoff for selecting patients with GC who would benefit from addition of lapatinib to chemotherapy should be evaluated in further studies; however, at present, the results indicated that the cutoff value, based on FISH assays, could be the ratios 5.

Second, it was also recognized that other alterations could affect the treatment with lapatinib.

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Two patients who presented with additional histologically proven chest wall involvement were classified with T4c disease. Of these 94 patients, 26 patients including both patients who had T4c tumors showed distant metastases Stage IV at the first diagnosis. The diagnosis of invasive carcinoma was confirmed histologically in all patients. Hormone receptor assays and assessments of tumor grade according to the Nottingham modification of the Scarff—Bloom—Richardson grading scheme also were performed.

There was no standard therapeutic approach during the study period Table 3. The Mann—Whitney U test was used to analyze nonnormally distributed data. Comparisons between nominal parameters were made with the Fisher exact test. All analyses were carried out with SPSS software version Patient, tumor, and treatment characteristics of the patients in the study are summarized in Table 3. Table 4 demonstrates the distribution of patients in each stage subgroup according to the current TNM classification and according to the classification that implements our proposal of a revised T4 category.

The corresponding DSS curves are shown in Figures 1 and 2. Because of the reclassification, the number of patients in Stage III decreased from to They showed significant clinicopathologic differences: They were older median age, 73 years vs. In the literature concerning patients with Stage III breast cancer, it is emphasized, usually immediately in the introduction, that this classification includes a wide spectrum of heterogeneous clinicopathologic entities.

In terms of TNM categories, or stages, this heterogeneity signals a profound weakness of the current classification scheme, because a grouping of tumors without a unifying malignancy profile in 1 T category or stage violates the principles of the stage model upon which the TNM system is based. The TNM classification is focused appropriately on stratifying patients into clinically meaningful prognostic subsets by classifying exactly the anatomic extent of the malignant disease on the basis of clinical and pathologic criteria.

The utility of the system arises from its ability to order patients by a decreasing probability of survival. Through the differentiation between inflammatory and noninflammatory groups of Stage III breast cancer, the heterogeneity of the entire group may be decreased. It is surprising, however, that no effective efforts have been undertaken to eliminate the persistent high degree of heterogeneity. A certain degree of this heterogeneity is caused by tumors with noninflammatory skin involvement T4b.

Analyzing current patient collectives, a dichotomy within this clinicopathologic entity is found. Consequently, it was proposed to revise the T4 category by eliminating the subdivisions T4a, T4b, and T4c from the TNM classification and classifying tumors with extension to the chest wall or skin simply through their components T tumor size and N lymph node status. This procedure represents a TNM classification rule similar to the V classification for venous invasion in colorectal tumors. Another reason in favor of revising the T4 category is the often inconsistent application and applicability of the clinicopathologic findings when using the current TNM classification guidelines and recommendations.

An international survey confirmed this assessment and demonstrated a considerable lack of uniformity in the classification of skin involving tumors.

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Even after disregarding the clinical features and focusing on the histopathologic criteria as decisive factors for the classification of breast carcinoma with noninflammatory skin involvement, this dilemma cannot be solved. Most experts consider tumor invasion of the epidermis the crucial point for confirming histologic skin involvement. However, in tumors of limited size, it was not tumor invasion into the epidermis but, rather, tumor invasion into the papillary dermis that was shown to be a significant prognostic factor for lymph node involvement.

Carcinomas in patients with tumors of limited extent, according to their true extent and prognosis, will be classified in Stages I and II. Compared with patients who remained in Stage III, these downstaged patients had a significantly improved DSS and made up a distinct clinicopathologic entity: Not only did they show the characteristic features for classification in favorable stages smaller tumor size, a lower number of involved lymph nodes , they also were significantly older, and their tumors were less likely to have established indicators of tumor aggressiveness, such as poor differentiation and negative ER status.

Therefore, a removal of these lower risk patients from the Stage III groups seems to be justified and will lead to an effective reduction in unwanted heterogeneity and to a more precise depiction of the accepted image of this disease stage. In the upcoming era of molecular and genetic characterization of breast cancer, it is possible that the significance of traditional prognostic determinants will take a back seat to the new indicators.

These assays have been clinically validated in several studies demonstrating the high predictive value of an HER2-positive status for the efficacy of HER2-targeted treatments. Tumor proliferation is one of the most important prognostic parameters in breast cancer. In the clinical practice, the evaluation of the tumor proliferative fraction is most commonly performed by the immunohistochemical staining of the Ki67 antigen [ 12 ]. The use of Ki67 immunolabeling as a prognostic and predictive marker has been extensively investigated in both the neo-adjuvant and adjuvant settings [ 13 , 14 ].

Gallen Consensus have included the assessment of Ki67 among the useful parameters to inform the choice of adding chemotherapy to endocrine therapies for patients with ER-positive and HER2-negative disease [ 8 ].


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However, mainly due to the lack of standardization in the performance of the assay and in the interpretation and scoring of the results, the measurement of Ki67 has not been considered a useful prognostic marker in the updated recommendations for the use of tumor markers in breast cancers issued by aSCO in [ 15 , 16 ]. Certainly, to unveil the actual value of Ki67 as a prognostic and predictive marker in breast cancer, we have to improve standardization and reproducibility of its assessment.

Due to the limited prognostic and predictive power of the existing classifications, at the beginning of the new century, new approaches have been considered to unveil the molecular basis for heterogeneity of breast cancer. By using a hierarchical clustering analysis of gene expression profiling, Perou et al. This molecular classification has been shown to have prognostic value and to be predictive of the response to chemotherapy in the setting [ 21 ]. The original molecular classification has been derived from investigations on fresh frozen tissue, and it is not applicable to formalin-fixed and paraffin-embedded FFPE material.

This jeopardized the wide application of the new classification in the clinical practice. The assay, based on quantitative real-time reverse transcription-polymerase chain reaction qRT-PCR , accurately identifies the major molecular subtypes of breast cancer and generates risk-of-relapse scores [ 22 ]. Its prognostic value has been confirmed in several retrospective investigations using tumor samples of patients with long-term follow-up data and of patients enrolled in randomized, clinical trials [ 23 , 24 ]. It should be noted, however, that the immunohistochemically and molecularly defined classes do not overlap completely.

Despite the lack of complete overlapping among the molecular classes and their immunohistochemical surrogate, the panelists of the last St. Gallen Consensus have endorsed the use of the immunohistochemical assays to identify breast cancer subtypes and to inform the choice of the systemic treatments [ 27 ]. Heterogeneity of breast carcinoma should not be viewed as an obstacle to a better understanding of the biology of the disease, or to the chances of designing more appropriate systemic treatments.

On the contrary, heterogeneity may represent a tremendous opportunity for better tailoring the therapy of the patients. To achieve this goal, however, a general agreement on breast cancer classification should be reached. It is likely that the adoption of the clinically oriented classification endorsed by the St. Gallen panelists [ 27 ] may help to overcome the intrinsic limitations of the previous schemes, and prove to be effective in informing the choice of the systemic interventions.

The proposed schema takes into account the modern concepts of the molecular classification of breast cancer, but endorses the use of the immunohistochemical surrogates, thus making the classification easily applicable in all the clinical settings. Therefore, the current pathological report of breast carcinoma should include the histopathological classification of the tumors [ 1 ] and their histopathological grade, and the immunohistochemical parameters ER, PgR, HER2 and Ki67 that would allow the treating physicians to tailor properly the systemic interventions.

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