Residual Breast Cancer Research Articles

Breast MR imaging during or soon after radiation therapy.

To investigate the degree and prevalence of radiation-induced changes on breast magnetic resonance (MR) images in patients who were undergoing radiation therapy at that time or soon after, to assess prospectively whether possible radiation-induced effects impair diagnostic accuracy of imaging, and to investigate the prevalence of residual ipsilateral and synchronous contralateral breast cancer in patients undergoing radiation therapy after resection of a supposedly solitary breast cancer. A total of 116 dynamic bilateral breast MR studies were performed during and up to 12 months after radiation therapy in 72 patients who had undergone breast-conservation surgery without preoperative MR imaging. Patients were assigned to four groups according to the time span between imaging and radiation therapy. Structural changes, parenchymal enhancement pattern, and prevalence and imaging features of incidental lesions were analyzed and compared with those of the nonirradiated breast. Radiation therapy led to parenchymal edema and a significant (two-tailed paired Student t test) increase in enhancement rates in the irradiated compared with those in the contralateral breasts during and up to 3 months after radiation therapy. Neither during nor at any time after radiation therapy did the mean enhancement rates reach diagnostically relevant rates. Unsuspected residual or recurrent breast cancers were identified in irradiated breasts of five patients and in contralateral breasts of two patients. False-positive MR findings resulted in a biopsy in three patients with irradiated and in one patient with nonirradiated breasts. There was no difference in enhancement kinetics or morphology of benign or malignant lesions in irradiated versus nonirradiated breasts. Radiation-induced changes occur at MR imaging during or up to 3 months after radiation therapy but are much less severe than reported. Detection and characterization of lesions were feasible with comparable diagnostic accuracies in irradiated and nonirradiated breasts.

In vitro induction of tumor-specific HLA class I-restricted CD8+ cytotoxic T lymphocytes from patients with locally advanced breast cancer by tumor antigen-pulsed autologous dendritic cells

Background. Early dissemination of treatment-resistant tumor cells remains the major cause of metastatic recurrence and death in breast cancer patients. Dendritic cells (DCs) are the most powerful antigen-presenting cells, and recently DC-based vaccination has shown great promise for the treatment of human malignancies by immunological intervention. Materials and methods. CD8+ T lymphocytes derived from peripheral blood mononuclear cells stimulated in vitro with autologous breast tumor antigen-pulsed DCs were tested for their ability to induce a HLA class I restricted cytotoxic T lymphocyte (CTL) response against autologous tumor cells. To correlate cytotoxic activity by CTL with T cell phenotype, two-color flow cytometric analysis of surface markers and intracellular cytokine expression was performed. Results. DC pulsed with breast tumor extracts consistently elicited a tumor-specific HLA class I restricted CTL response in vitro in three consecutive patients harboring locally advanced breast cancer. CTL expressed strong cytolytic activity against autologous tumor cells but did not lyse autologous Epstein Barr virus-transformed lymphoblastoid cell lines and showed variable cytotoxicity against the natural killer-sensitive cell line K-562. In all patients, two color flow cytometric analysis of surface markers and intracellular cytokine expression demonstrated that tumor-specific CTL exhibited an heterogeneous CD8+/CD56+ expression and a striking Th1 cytokine bias (IFNγ high/IL-4 low). Conclusions. Tumor lysate-pulsed DCs can consistently stimulate specific CD8+ CTLs able to kill autologous tumor cells in patients with locally advanced breast cancer in vitro. Tumor antigen-pulsed DC-based vaccinations may be appropriate for the treatment of residual and/or chemotherapy-resistant breast cancer refractory to standard salvage treatment modalities.

Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy.

Our study investigated the usefulness of contrast-enhanced MR imaging for accurately measuring the size of residual tumor after patients have undergone neoadjuvant (pre-operative) chemotherapy. The imaging analysis method was optimized for identifying residual disease in the treated breast. Tumor sizes measured on the MR images and at the clinical examination were compared with the size of residual disease measured at pathology after surgery. Before undergoing surgery, 52 patients were imaged before and after receiving neoadjuvant chemotherapy. For each patient, specific malignancy criteria were applied to MR images before chemotherapy to identify the location of tumor, and residual disease was then identified as any remaining enhancement in the same area on the MR images after chemotherapy. Residual tumor size was measured using both the MR technique and the clinical examination findings, and the degree of measurement error for each method was assessed in comparison with the pathologic findings. The correlation with pathology was an r value of 0.89 for MR measurements compared with an r value of 0.60 for clinical measurements. In addition, MR imaging revealed all cases of residual disease, whereas clinical assessment resulted in five false-negative interpretations in the 52 treated lesions. The high correlation between measurements of residual disease obtained on MR images and those obtained at pathology validates the sensitivity of MR imaging of the breast after chemotherapy.

A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes.

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene ‘BRCA3’, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021–0.125%) and of BRCA2 0.068% (95% CI: 0.033–0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families.British Journal of Cancer (2002) 86, 76–83. DOI: 10.1038/sj/bjc/6600008 www.bjcancer.com© 2002 The Cancer Research Campaign

Effectiveness of dynamic MRI for diagnosing pericicatricial minimal residual breast cancer following excisional biopsy

The purpose of this study was to investigate the effectiveness of dynamic MRI for diagnosing pericicatricial minimal residual breast cancer following excisional biopsy. Twenty-six patients who underwent excisional biopsy of a tumor or calcified lesion of the breast underwent gadolinium-enhanced dynamic MRI by the fat-saturated 2D fast spoiled gradient echo (SPGR) sequence (group 1), 24 patients by the spectral IR enhanced 3D fast gradient echo (Efgre3d) sequence (group 2). Pericicatricial residual cancer was confirmed histologically in 29 of the 50 patients. The overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of MRI for residual cancer diagnosis was 66, 81, 72, 83 and 63%. A nodular, thick and discontinuous enhanced rim around the scar is indicative of a residual tumor. However, false-positive findings due to granulation or proliferative fibrocystic change remain limitations.

Primary breast tumor levels of suspected molecular determinants of cellular sensitivity to cyclophosphamide, ifosfamide, and certain other anticancer agents as predictors of paired metastatic tumor levels of these determinants. Rational individualization of cancer chemotherapeutic regimens.

Cyclophosphamide is one of the most frequently used agents in the neoadjuvant, adjuvant, and high-dose chemotherapeutic treatment of breast cancers. Preclinical models indicate that cellular sensitivity to cyclophosphamide and other oxazaphosphorines, e.g., ifosfamide, is inversely related to the cellular content of two aldehyde dehydrogenases, viz ALDH1A1 and ALDH3A1, and glutathione. Breast tumor levels of these "determinants of cellular sensitivity to the oxazaphosphorines" are known to vary widely, and the decision as to whether or not to use an oxazaphosphorine as part of the therapeutic strategy to treat breast cancer in any given patient is likely to depend, in large part, on the levels of these determinants in that cancer. ALDH1A1, ALDH3A1, and glutathione levels can be easily quantified in primary breast tumors and in detectable metastatic breast tumors present in axillary lymph nodes because the amounts of tissue required for the desired analysis can be readily obtained, whereas these levels cannot be quantified in residual metastatic breast cancer cell populations, i.e., those that escape detection and/or that are inaccessible to surgical harvest. The inability to directly quantify residual metastatic breast cancer cell ALDH1A1, ALDH3A1, and glutathione levels would not preclude a rational decision with regard to the inclusion/exclusion of an oxazaphosphorine as part of the chemotherapeutic strategy intended to eradicate residual metastatic breast cancer cells if primary breast tumor levels of these determinants reliably predicted those in metastatic breast cancer cells. ELISAs and spectrophotometric assays were used to quantify enzyme and glutathione levels in paired human primary and locally advanced metastatic breast tumor samples. Primary breast tumor ALDH1A1 and ALDH3A1 levels were highly predictive of their respective levels in paired metastatic breast tumors present in axillary lymph nodes (r2 = 0.80 and 0.85, respectively). On the other hand, those of glutathione were relatively poorly predictive of its levels in paired metastatic offshoots (r2 = 0.35). Primary breast tumor levels of some additional enzymes known to catalyze the detoxification/toxification of various anticancer agents, though not of cyclophosphamide, were poorly predictive (DT-diaphorase and glutathione S-transferases alpha, mu, and pi) or not predictive (cytochrome P450 1A1) of their respective levels in paired metastatic offshoots. Since ALDH1A1, ALDH3A1 and, to a lesser extent, glutathione levels in primary breast tumors reliably predicted those in detectable and easily accessible metastatic breast cancer cell populations, viz those in axillary lymph nodes, they are also likely to be predictive of these levels in undetectable and/or relatively inaccessible metastatic breast cancer cell populations. Thus, quantification of primary breast tumor ALDH1A1, ALDH3A1 and, to a lesser extent, glutathione levels prior to the initiation of not only neoadjuvant but also adjuvant and high-dose breast cancer chemotherapy is likely to be of value in the rational design of individualized chemotherapeutic regimens intended to eradicate breast cancer cells with a minimum of untoward effects.

Accuracy of contrast‐enhanced computed tomography in the prediction of residual breast cancer after neoadjuvant chemotherapy

Accuracy of contrast‐enhanced computed tomography in the prediction of residual breast cancer after neoadjuvant chemotherapy

Accuracy of contrast-enhanced computed tomography in the prediction of residual breast cancer after neoadjuvant chemotherapy.

Determination of the extent of residual disease after neoadjuvant chemotherapy is sometimes inaccurate by conventional diagnostic methods. The purpose of this study was to evaluate the accuracy of contrast-enhanced computed tomography (CE-CT) in depicting the extent of residual carcinomas. Fifty-seven patients with breast carcinomas of 3 cm diameter or more received neoadjuvant chemotherapy with four cycles of AT (doxorubicin and docetaxel). Before surgery, the patients underwent clinical examination, mammogram (MMG), ultrasonography (US), and CE-CT. Thirteen patients were not evaluated by CE-CT before surgery. Enhancement patterns on CE-CT were classified into multiple spots, tumor and spots, solid tumor type, and no enhancement. When all types of cancers were included in the analysis, clinical examination showed the best correlation with the pathology of the extent of residual carcinomas. However, except in invasive lobular carcinoma (ILC) and inflammatory breast carcinoma (IBC), CE-CT showed the best correlation (R insertion mark2 = 0.537). More than half of the residual microcalcifications on MMG after neoadjuvant chemotherapy suggested residual viable tumor. In conclusion, CE-CT is the most accurate noninvasive technique for identifying the extent of the residual carcinoma after neoadjuvant chemotherapy if cases of IBC and ILC are excluded.

MR imaging of the breast in patients with positive margins after lumpectomy: influence of the time interval between lumpectomy and MR imaging.

Postsurgical contrast enhancement resulting from inflammatory changes at the site of surgery limits the accuracy of MR imaging of the breast in diagnosing residual breast cancer. This study was undertaken to evaluate the influence of the time interval between lumpectomy and MR imaging on the diagnosis of residual breast cancer. Sixty-eight patients who had undergone excisional biopsy with positive resection margins underwent MR imaging for evaluation of residual breast cancer and possible breast conservation. Patients were retrospectively stratified according to the time interval between lumpectomy and MR imaging. Dynamic and morphologic enhancement features were used for lesion characterization. Imaging findings were correlated with results of histopathology. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for patients waiting 7, 14, 21, 28, 35, and 42 days after initial surgery before undergoing MR imaging of the breast. The time interval between lumpectomy and MR imaging of the breast had the greatest influence on the specificity and negative predictive value of MR imaging, increasing progressively over time. A plateau of highest values of 75% specificity and 86% negative predictive value was reached at 28 and 35 days after surgery, respectively. Although the sensitivity and positive predictive value showed smaller variations over time, peak values of 95% sensitivity and 92% positive predictive value were obtained at 35 and 28 days after surgery, respectively. We recommend scheduling patients with positive resection margins no earlier than 28 days after initial surgery for evaluation of residual cancer using MR imaging of the breast.

Biological markers of risk in nipple aspirate fluid are associated with residual cancer and tumour size.

We previously demonstrated that nipple aspirate fluid (NAF) can be obtained from virtually all non-Asian women between the ages of 30 and 72. The focus of this report is to (1) determine the association of candidate markers of breast cancer risk in NAF obtained from fresh mastectomy specimens with residual breast carcinoma, and (2) evaluate the association of the markers with breast tumour progression. Nipple aspiration was performed on 97 specimens. Cytology, DNA index (including % hypertetraploid cells), cell cycle parameters (S phase fraction, % cells in G2/M), prostate-specific antigen (PSA), epidermal growth factor (EGF), testosterone, carcinoembryonic antigen (CEA) and prostaglandin D synthase (PGDS) were evaluated in NAF for their association with (1) residual ductal carcinoma in situ (DCIS) or invasive cancer, and (2) pathologic tumour size. NAF was obtained from 99% (96/97) of specimens. Atypical and malignant NAF cytology were significantly associated with residual DCIS or invasive cancer (P = 0.001) and with larger tumours (P = 0.004). One hundred per cent and 88% of subjects with malignant and atypical NAF cytology, respectively, had residual carcinoma. The percentage of cells in G2/M and DNA index were associated both with risk of residual carcinoma (P = 0.01 for each) and larger tumour size (DNA index, P = 0.03; G2/M, P = 0.05), although neither biomarker improved the ability of NAF cytology, to predict residual breast cancer. Higher DNA index was associated with atypical cytology (P = 0.0001). In summary, atypical and malignant NAF cytology are associated with larger tumour size, and are highly predictive of residual carcinoma after needle or excisional biopsy of the breast. © 1999 Cancer Research Campaign

Clinical use of contrast-enhanced computed tomography for decision making in breast conserving surgery

BACKGROUND: A reduction in local residual breast cancer is important to avoid local recurrence after breast conserving treatment (BCT). Previous studies suggested the usefulness of contrast-enhanced computed tomography (CE-CT) in detecting extensive intraductal component(EIC), which is associated with local recurrence. This study investigates the practical role of CE-CT in BCT. METHODS: In 130 women whose breasts were examined by CE-CT preoperatively, intraductal spread detected using ultrasound (US), mammography (MMG) and CE-CT, and EIC detected by histological examination were analyzed to determine possible correlations among the extent and subtypes of intraductal components. RESULTS: The sensitivities of EIC detection by US, MMG and CE-CT were 29%, 53% and 88%, respectively, and the corresponding specificities were 58%, 70% and 72%, respectively. In 6 patients, EIC could only be visualized using CE-CT. CE-CT demonstrated the extent of cancerous lesions more accurately than standard diagnostic modalities. Intraductal components with a higher histological grade tended to show stronger enhancement. Most false negative intraductal components obtained on CE-CT (6/7) were of a low histological grade. CONCLUSIONS: CE-CT is useful for visualizing EIC and small invasive foci of breast cancer, and can suggest the optimal extent of resection.

Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain reaction.

Detection of occult carcinoma in patients with breast cancer may aid the establishment of prognosis and development of new therapeutic approaches. To improve on existing methods of detection, we have developed a reverse-transcriptase polymerase chain reaction (RT-PCR) assay for keratin 19 (K19) transcripts to identify mammary carcinoma cells in the peripheral blood and bone marrow of patients with breast cancer. Peripheral-blood or bone marrow samples obtained from 34 patients with stages I to IV breast cancer and 39 control subjects without breast cancer were screened for K19 mRNA by nested primer PCR. In reconstitution experiments, K19 RT-PCR reliably detected 10 mammary carcinoma cells in 1 million normal peripheral-blood mononuclear (PBMN) cells. Four of 19 patients with stage IV breast cancer had detectable K19 transcript in peripheral blood. Five of six patients with histologically negative bone marrow biopsies following preablative chemotherapy and before autologous bone marrow transplant (BMT) were positive by this assay. Stem-cell apheresis harvests obtained from one of these patients and three additional patients immediately before BMT were all K19-negative. K19 RT-PCR analysis of CSF from a breast cancer patient with known carcinomatous meningitis was also positive. Thirty-eight of 39 non-breast cancer patients had negative K19 RT-PCR assays. The one exception was a patient with chronic myelogenous leukemia. RT-PCR of K19 is a sensitive, specific, and rapid method for detection of occult mammary carcinoma cells in the peripheral blood and bone marrow of patients with breast cancer. The presence of residual breast cancer cells in histologically normal bone marrow aspirates but not in stem-cell apheresis harvests is a frequent finding. This assay may be useful in diagnosing metastatic disease, as well as in monitoring the effectiveness of systemic therapy.

Hormone replacement therapy in women treated for breast cancer

We must still maintain the conventional advice that unopposed low dosages of oestrogen should not be used for the treatment of menopausal symptoms in women treated previously for breast cancer. There is, however, epidemiological, laboratory and clinical evidence that certain combinations of oestrogen and progestogen are more likely to be beneficial than harmful, in respect to the risk of reactivating subclinical residual breast cancer or causing progression in premalignant lesions. It is no longer justifiable to deprive a woman with a history of breast cancer treatment of a hormonal therapy capable of safely relieving symptoms which are making her life intolerable. A clinical trial of such treatment is reported.