Cytosol protein content and prognosis in operable breast cancer

Summary Several biochemical parameters quantitated in tumor cytosols from malignant breast tumors have been evaluated as possible prognostic factors. Cytosol protein content has always been regarded as a reference parameter, to correct for cellularity and representativity of tumor samples. But recent studies have suggested an altered protein distribution in malignant tissues. The present study on 382 women with histologically proven breast cancer, Stage I and Stage II, therefore evaluates whether cytosol protein content by itself may add information as a prognostic factor in the clinical management of breast cancer.Cytosol protein content was found to be significantly correlated (p<0.001) to tumor size, and inversely correlated to progesterone receptor (PgR) content (p=0.015) and age at operation (p=0.021). Using the median value of protein (4.15 mg/ml) as a cut-off value, two groups could be constructed. The number of node-positive patients in the protein-poor group was significantly decreased (p=0.018) compared to the protein-rich group, which also contained a significantly (p<0.001) lower number of patients with estrogen receptor (ER) positive tumors (i.e. ER10 pmol/g). An increased number of events was observed in the protein-rich group (p<0.001), with a great contribution to the number of deaths due to breast cancer. In a multivariate analysis of the likelihood to predict axillary nodal involvement, protein category was found to be a significant (p<0.031) independent predictive factor. As to relapse free survival (RFS), protein category did not reveal any prognostic power. A subgroup containing Stage II patients with ER+ tumors was included in a prospective, randomized study on the role of tamoxifen as an adjuvant endocrine therapy. In a multivariate analysis, treatment option (tamoxifen vs. control) (p=0.0008) and axillary nodal tumor burden (p=0.009) were significant independent prognostic factors for RFS in protein-rich patients. In protein-poor patients, only tumor size showed a positive association with RFS, but without reaching statistical significance (p=0.062).The present observations make cytosol protein content interesting in the context of tumor biology and breast cancer prognosis. Further studies are needed to evaluate cytosol protein content as a possible prognostic factor useful in the clinical management of breast cancer.     

Early operable breast cancer

Opinion statement Early operable breast cancer is a potentially curable disease. However, a substantial number of patients are at risk for systemic recurrence and death. Breast conservation therapy (BCT) should be considered the preferred surgical option for most women with early operable breast cancer. Adjuvant systemic chemotherapy or hormonal therapy can substantially reduce, although not eliminate, the risk of recurrence and death. Neoadjuvant or primary systemic therapy (PST) in operable breast cancer slightly increases the number of women treated with breast conservation versus mastectomy. Although PST may identify women who are likely to have a better prognosis (those with a pathologic complete response), current PST strategies do not offer a survival advantage over standard adjuvant approaches. Early results of high-dose chemotherapy trials thus far have not shown any advantage over conventional dose therapy in high-risk patients with 10 or more positive lymph nodes. The role of adjuvant radiation therapy after mastectomy for all patients with high-risk early operable breast cancer is not fully defined.     

Parity is associated with axillary nodal involvement in operable breast cancer

Summary Introduction. Although multiparous women have a decreased incidence of breast cancer, several series have observed that multiparous women have a higher risk of axillary nodal metastases and diminished survival. Methods. To study this hypothesis in greater detail, this study analyzed data from 223 consecutive women with clinically operable (T1-3, N0-1, M0) breast cancer, all of whom had undergone axillary node dissection (AND) by one surgeon (83 mastectomy/AND, 140 lumpectomy/AND). The number of pregnancies and other hormonally related factors were recorded. Results were compared to pathologic data (node status, tumor size, estrogen and progesterone receptors). Results. Seventy-eight patients (35.0%) had positive axillary nodes. Increasing parity was associated with an increased likelihood of positive nodes (Odds ratio 1.22 (95% CI: 1.04–1.42), p = 0.012) as was increasing tumor size (Odds ratio 1.31 (1.07–1.59), p = 0.007). The effect of parity was independent of tumor size, age, or hormone receptors. Conclusions. In this series, which includes only operatively staged patients, increasing parity is associated with nodal positivity. This effect is of a magnitude similar to that of increasing tumor size, and confirms observations from other studies. Information regarding parity may be useful for prognostic purposes, as well as providing insights into basic breast cancer biology.     

Prognostic factors in operable breast cancer

A series of 743 consecutive cases of operable breast cancer, admitted and treated at the Istituto Nazionale Tumori of Milan from 1969 to 1970, was analyzed by a multivariate statistical method to evaluate a) the variables of the host and the primary tumor associated with the frequency of nodal metastases, b) the variables that significantly affect survival, and c) the identification of homogeneous risk groups. As regards the frequency of regional node metastases, they were more frequently observed in young than in old patients with large tumors (P values 10(-5) and 3 X 10(-5), respectively). Tumors that originated in the axillary tail, upper, outer and central quadrants were significantly associated with a higher rate of node metastases (P = 0.002). Each of these variables maintained its significant value when adjusted by the other two. Survival was affected at a statistically significant level by the age of the patients (P = 2 X 10(-4) ), the pathologic diameter of the primary tumor (P less than 10(-6) ), and the number of metastatic regional nodes (P less than 10(-6) ). The number of involved nodes appears to be the most relevant factor in the assessment of prognosis of patients with positive nodes, Age of the patients, size of the primary tumor, and number of involved nodes maintain their own statistical significance when each is adjusted by the remaining two. The site of origin of the primary tumor, even if associated with the frequency of regional node metastases, did not affect survival. Three groups with a significantly different risk of death were identified in patients with negative lymph nodes and three groups in patients with positive nodes. It is concluded that age, size of the primary, and number of involved lymph nodes are important pieces of information that clinicians should have at hand following radical surgery, not only to make a prognosis, but also to identify groups of patients with high risk of death on which the role of adjuvant treatment should be evaluated.     

Neoadjuvant chemotherapy in operable breast cancer

Primary chemotherapy in localised breast cancer may prevent tumour spread during surgical treatment and reduce proliferation of micrometastases. A randomised clinical trial, in 196 premenopausal and postmenopausal patients with operable (T2-3, N0-1b) breast cancer, was started in November 1983 at the Institut Curie to compare neoadjuvant and adjuvant regimens of chemotherapy with radiotherapy with or without surgery. The patients have been followed up for 35–70 months (median 54). A neoadjuvant group received two monthly cycles of intravenous doxorubicin/cyclophosphamide/5-fluorouracil before locoregional therapy and four cycles subsequently. Six months cycles following locoregional therapy were administered to the adjuvant group. Because of inclusion of postmenopausal and/or node-negative patients, compliance was less than optimal in 39 patients who were analysed separately according to actual dose received. Tumour response, evaluated after two cycles of neoadjuvant chemotherapy, was significantly associated with dose (P = 0.003). Survival showed a slight non-significant advantage for the neoadjuvant group. Survival plotted by actual dose was also similar. Neoadjuvant chemotherapy was safe and at least as effective as the adjuvant regimen. Patients have been accrued to a subsequent larger trial of chemotherapy as first-line treatment.     

Preoperative breast MRI in early-stage breast cancer

Rapid uptake of new imaging technology is a major contributor to rising healthcare costs. Preoperative breast magnetic resonance imaging (MRI) for patients with early-stage breast cancer has dramatically increased in use without the evidence of improved outcomes compared to standard assessment and is associated with higher rates of mastectomy. A decision analytic model was developed to evaluate the impact of adding breast MRI to the preoperative evaluation of women with early-stage breast cancer who were candidates for breast-conserving therapy on patient outcomes measured in quality-adjusted life years (QALYs). Model inputs, including survival, recurrence rates, and health utilities, were obtained from a comprehensive literature review. One-way sensitivity analyses were performed to estimate threshold values for key parameters at which adding MRI would become the optimal imaging strategy over standard assessment. Preoperative MRI resulted in 17.77 QALYs compared to 17.86 QALYs with standard assessment, a decrease of 0.09 QALYs or 34?days. In sensitivity analyses, standard assessment was associated with better patient outcomes than preoperative breast MRI across all plausible probabilities for mastectomy, local recurrence, and health utilities. For routine preoperative breast MRI to become the optimal strategy, the conversion rate to mastectomy after preoperative MRI would need to be <1?% (versus the range of 3.6-33?% reported in the literature). Routine preoperative breast MRI appears to confer no advantage over the standard diagnostic evaluations for early-stage breast cancer and may lead to worse patient outcomes.     

Post-surgical highly sensitive C-reactive protein and prognosis in early-stage breast cancer

Obesity, associated with inflammation, has been linked to poor prognosis in breast cancer. Research investigating the potential role of C-reactive protein (CRP), an obesity-associated systemic marker of inflammation, as a mediator of adverse prognostic effects of obesity has yielded inconsistent results. We examined the association of highly sensitive CRP (hsCRP) with obesity-related factors and breast cancer outcome. A cohort of 535 non-diabetic women diagnosed with T1-3, N0-1, M0 breast cancer, was assembled between 1989 and 1996 and followed prospectively. Circulating levels of hsCRP were analyzed on blood obtained postoperatively, prior to systemic therapy, in 501 women. Correlations and prognostic associations were analyzed using one-way analysis of variance, Spearman’s rank correlation coefficients (r) and Cox models. hsCRP was significantly correlated with body mass index (r = 0.60), insulin (r = 0.44), leptin (r = 0.54), and lipids, but not T or N stage, grade or estrogen receptor/progesterone receptor. At a median follow-up of 12 years, hsCRP was not associated with distant disease-free survival or overall survival in univariable [Q4 vs. Q1 hazard ratio (HR) 1.03, 95 % confidence interval (CI) 0.69–1.52, P = 0.9 and HR 1.27, 95 % CI 0.86–1.86, P = 0.24, respectively] or multivariable [Q4 vs Q1 HR 1.02, 95 % CI 0.66–1.59, P = 0.93 and HR 1.17, 95 % CI 0.76–1.81, P = 0.48 respectively] analyses. hsCRP was associated with age, comorbidities, and the insulin resistance syndrome but not with breast cancer outcome.     

Isotopic bone examination in operable breast cancer

In the pre-treatment work-up in breast carcinoma cases the bone scan findings could be of major interest. If the presence of occult metastases is discovered management may be modified accordingly. In a group involving 78 cases of breast carcinoma, classified as primary, operable, in three cases only scintigraphy revealed bone metastases before they produced clinical and radiological signs. In two of them there was agreement, in one disagreement over the findings. Moreover, in 5 cases a bone metastasis was revealed and immediately confirmed on a complete bone assessment.     

Radical mastectomy for operable breast cancer

The experience with radical mastectomy in the treatment of 152 cases of operable breast cancer at the Hadassah University Hospital has been analyzed. An overall 5 year survival of 75% and a 10 year survival of 62% are reported and compared with results from other methods of treatment. Based on the excellent survival rates achieved and the low incidence of local recurrence (9.8%), the present study suggests that radical mastectomy is still the most suitable surgical procedure in the treatment of operable breast cancer.     

Neoadjuvant chemotherapy for operable breast cancer

Adjuvant systemic chemotherapy has been shown to prolong survival in all subsets of patients with breast cancer. In addition, among patients with locally advanced breast cancer, neoadjuvant orpreoperative chemotherapy has improved the ability to perform breast-conserving therapy. This observation, combined with multiple preclinical hypotheses and the results of laboratory studies, has prompted investigation of neoadjuvant chemotherapy as a treatment strategy for operable breast cancer. In this article, both the evidence supporting this treatment approach and some of the problems associated with it are reviewed. Currently, seven randomized studies comparing neoadjuvant chemotherapy followed by surgery or surgery followed, in turn, by adjuvant chemotherapy have been completed and their results analyzed. Despite exciting preclinical evidence, no trial to date has shown a survival advantage for the neoadjuvant treatment approach. Nonetheless, evidence from more recent phase III trials and the fact that neoadjuvant chemotherapy is not harmful topatients validate its use in operable breast cancer.     

Prognostic and predictive indicators in operable breast cancer

Because of its biological heterogeneity and wide spectrum of responsiveness to different treatments, breast cancer is a complex disease of difficult clinical management. Over the past several years, knowledge of the molecular mechanisms regulating normal and aberrant cell growth leading to cancer has been enhanced. These advances have enabled the identification of an increasing number of surrogate biomarkers, which have been correlated with prognosis or used as predictors of response to specific treatments. Axillary nodal status, age, tumor size, pathologic grade, and hormone receptor status are the established prognostic and/or predictive factors for selection of adjuvant treatments. The role of new biomarkers, such as p53, HER2/neu, angiogenesis, and the proliferation index value, is promising; however, the clinical value of their determination must be provided by prospective clinical studies.     

Predicting distant metastases in operable breast cancer patients

Risk factors for distant metastases following mastectomy and axillary node dissection for breast cancer were analyzed in a review of 1022 women. From diagnosis until the end of the adjuvant treatment, six stages were identified that corresponded well to patient data acquisition. At each stage, a prognosis study based on the Cox model was carried out using all acquired information from the first stage. The results demonstrated that tumor size, nuclear pleomorphism, mitotic index, and nodal status at the top of axilla were stable independent risk factors in predicting metastasis-free survival (MFS). These analyses also revealed those factors that were significantly related to MFS at one or several stages and losing their significance at a subsequent stage. This was the case with clinical node status, age, and vascular tumor emboli. Other factors such as estrogen, progesterone, histologic grade, and clinical stage were never identified as independent factors at any stage. The four major stable risk factors were used to define a stratification of reference. The results demonstrated that the mere knowledge of clinical information such as tumor size, clinical node status, and age would enable 51% of the patients to be universally well classified according to that stratification. Knowledge of additional factors, such as nuclear pleomorphism and mitotic index, would bring the rate up to 61%, and then to 64% if supplementary information such as vascular tumor emboli were acquired. These percentages did not appear high enough to claim that the physician may make a reliable prognosis of operable breast cancer patients before acquiring information from the axillary node dissection. However, it was proven that there exist some subsets of patients with stable prognosis, i.e., subsets of patients who will belong permanently to the same risk group through the stages.