Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor.

BACKGROUND: Currently, therapy for breast cancer patients with stage IV disease and an intact primary tumor is metastasis directed; the primary tumor is treated only when it causes symptoms. A recent review suggested that surgery may improve long-term survival in such patients. We evaluated the effect of surgery in such patients on long-term survival and disease progression. METHODS: We reviewed the records of all breast cancer patients treated at our institution between 1997 and 2002 who presented with stage IV disease and an intact primary tumor. Information collected included demographics, tumor characteristics, site(s) of metastases, type/date of operation, use of radiotherapy, chemotherapy and hormonal therapy, disease progression (time to progression and location of progression) in the first year after diagnosis, and last follow-up. Overall and metastatic progression-free survival were compared between surgery and nonsurgery patients. RESULTS: Of 224 patients identified, 82 (37%) underwent surgical extirpation of the primary tumor (segmental mastectomy in 39 [48%] and mastectomy in 43 [52%]), and 142 (63%) were treated without surgery. The median follow-up time was 32.1 months. After adjustment for other covariates, surgery was associated with a trend toward improvement in overall survival (P=.12; relative risk, .50; 95% confidence interval, .21-1.19) and a significant improvement in metastatic progression-free survival (P=.0007; relative risk, .54; 95% confidence interval, .38-.77). CONCLUSIONS: Removal of the intact primary tumor for breast cancer patients with synchronous stage IV disease is associated with improvement in metastatic progression-free survival. Prospective studies are needed to validate these findings.

Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy.

PURPOSE: To retrospectively assess mammography, high-frequency-transducer ultrasonography (US), and color Doppler US for the initial and subsequent evaluation of breast cancer diagnosed and treated with chemotherapy during pregnancy. MATERIALS AND METHODS: A retrospective study of clinical records between January 1989 and December 2003 of women with breast cancer diagnosed and treated with chemotherapy during pregnancy was performed after waiver of informed consent was obtained. The study was approved by an institutional review board and was HIPAA compliant. Mammograms and sonograms were reviewed by two mammographers using the Breast Imaging Reporting and Data System (BI-RADS) mammographic and US lexicon. US assessment of the regional lymph node basins, including the axillary, infraclavicular, internal mammary, and supraclavicular regions, was documented. US was used to evaluate response to therapy in the breast and the regional lymph nodes in women who underwent neoadjuvant chemotherapy. RESULTS: Twenty-three women with 24 cancers that were imaged prior to surgery with mammography (n = 3), US (n = 4), or mammography and US (n = 17) were included in the study. The histologic diagnosis of the primary tumor was invasive ductal cancer in 22 lesions, and the diagnosis was invasive carcinoma in the two other cancers. The median age in this study was 34 years (range, 24-45 years). Of the 20 women who underwent preoperative mammography, findings were positive for malignancy in 18 of 20 (90%) cancers despite dense breast parenchymal patterns (BI-RADS types 3 and 4). A mass in all 21 cancers (100%) was depicted in the 20 women who underwent breast and nodal US. US correctly depicted axillary metastasis in 15 of 18 women who underwent US nodal assessment. Of the 12 patients who were evaluated for response to chemotherapy, US demonstrated complete response in two patients, partial response in three, stable findings in one, and progression of disease in six. CONCLUSION: Breast cancer diagnosed during pregnancy is mammographically evident despite dense parenchymal background. US, when performed, demonstrates all masses and provides information regarding response to neoadjuvant chemotherapy.

Breast carcinoma during pregnancy. International recommendations from an expert meeting.

BACKGROUND: Breast carcinoma during pregnancy (BCP) is a difficult clinical situation, as it appears to put the health of the mother in conflict with that of the fetus. METHODS: An international expert meeting was conducted to form guidelines on how to diagnose and treat women with BCP. RESULTS: The goal for treatment of the pregnant woman with breast carcinoma is the same as that of the nonpregnant breast carcinoma patient: local control of disease and prevention of systemic metastases. However, certain treatment modalities need to be modified because of the potential for adverse effects on the fetus. There is evidence to support the safety of anthracycline-based chemotherapy during the second and third trimesters of pregnancy (Oxford Level of Evidence [LOE] 2b). Because of the lack of evidence, the expert opinion was not to recommend the routine use of newer cytotoxic drugs like the taxanes during pregnancy (LOE 5). CONCLUSION: The recommendations provided should help to reach informed decision making by the patient. The ongoing prospective collection of data on BCP, such as that at the University of Texas M.D. Anderson Cancer Center (UTMDACC) and that of the German Breast Group/Breast International Group (GBG/BIG), is necessary to further our knowledge regarding the treatment of this unique group of breast carcinoma patients.

Children exposed to chemotherapy in utero.

The majority of the information on the effects of in utero exposure to chemotherapy has been derived from retrospective case reports and series. Overviews of the available data have concluded that the timing of chemotherapy exposure (first trimester versus second and third trimesters) as well as the chemotherapeutic agent or agents used affect the risk of spontaneous abortion and miscarriage as well as that of congenital abnormalities. Although there are data from a prospective series of 24 pregnant breast cancer patients treated at the University of Texas M.D. Anderson Cancer Center, there are limited case series in women with hematologic malignancies, with the largest series having 89 pregnancies, that indicate that the fetuses exposed to chemotherapy in utero in the second and third trimesters can be carried to term, be born without evidence of congenital abnormalities, and develop normally. Clearly, ongoing prospective collection of data on the children born to women undergoing therapy for cancer is necessary.

Paclitaxel chemotherapy in a pregnant patient with bilateral breast cancer.

In this article, we report on a case of a pregnant patient with synchronous bilateral breast cancer treated with weekly paclitaxel. She presented after right mastectomy and anthracycline-based chemotherapy at an outside facility. Staging studies at our hospital before taxane administration demonstrated a 19-20-week gravid uterus and tumor in the remaining left breast. Weekly paclitaxel was given preoperatively during pregnancy. A normal male infant was delivered. Upon completion of chemotherapy, the patient underwent mastectomy and axillary lymph node dissection followed by comprehensive radiation therapy to the chest wall.

Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma.

BACKGROUND: Few studies have addressed the issue of whether delays in the interval between medical consultation and the diagnosis and treatment of breast carcinoma are greater for African American women than for white women. The authors examined differences with respect to these delays and analyzed the factors that may have contributed to such differences among women ages 20-54 years who had invasive breast carcinoma diagnosed between 1990 and 1992 and who lived in Atlanta, Georgia. METHODS: A total of 251 African American women and 580 white women were interviewed and had their medical records reviewed. The authors estimated racial differences in delay times and used polytomous logistic regression to determine the contributions of various factors (socioeconomic and other) to these differences. RESULTS: Although most women in both groups were treated within 3 months of initial consultation, 22.4% of African American women and 14.3% of white women had clinical delays of > 3 months. Compared with white women, African American women were more likely to experience delays in diagnosis and treatment. Access to care (as represented by method of detection and insurance status) and poverty index partially accounted for these differences in delay time; however, racial differences in terms of delayed treatment and diagnosis remained even after adjustment for contributing factors. CONCLUSIONS: The findings of the current study suggest that among women ages 20-54 years who have breast carcinoma, potentially clinically significant differences in terms of delayed diagnosis and treatment exist between African American women and white women. Improvements in access to care and in socioeconomic circumstances may address these differences to some degree, but additional research is needed to identify other contributing factors.

Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features.

BACKGROUND: Breast carcinoma is one of the most common carcinomas in pregnant women. The incidence of breast carcinoma may increase in the future because of the trend toward delayed childbearing and increased screening. However, very few contemporary studies have attempted to identify the combined histopathologic and immunohistochemical features of breast carcinoma in these patients. METHODS: The authors evaluated 39 patients with breast carcinoma occurring coincident with pregnancy. This was comprised of a critical histologic review and immunohistochemical evaluation to determine the status of prognostic and predictive markers including estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, Ki-67, and p53. RESULTS: The mean age at presentation was 33 years (range, 24-44 years). Densities and/or masses were noted on mammograms in 14 of 16 patients with available radiographic information. The primary tumors were a mean of 4.5 cm in greatest dimension (range, 0.1-13.5 cm). Two of the 39 patients had clinical (American Joint Committee on Cancer) Stage I disease, 19 patients had Stage II disease, 16 had Stage III disease, and 2 patients had Stage IV disease at the time of presentation. Histologically, high-grade invasive ductal carcinomas were found in 32 of 38 patients. The primary tumor was not available for review in one patient. A predominantly solid pattern of growth was observed in nine patients. Lymphovascular invasion was identified in 61% of cases. Ductal carcinoma in situ was identified in 72% of tumors and was high grade in all cases. Of the 25 patients tested, ER positivity was found in 7 patients, PR positivity was found in 6 patients, HER-2/neu positivity was found in 7 patients, and p53 positivity was found in 12 patients. The proliferation rate as shown by Ki-67 staining was high in 60% of the cases. Follow-up information was available for 35 patients and the mean follow-up period was 43 months (range, 2-163 months). Distant metastasis occurred in seven patients. The mean time to disease recurrence was 20.4 months (range, 10-33 months). Of 35 patients, 4 have died, 22 were alive with no evidence of disease, and 9 were alive with disease at the last follow-up. The remaining four patients died of unknown causes. CONCLUSIONS: Pregnant women with breast carcinomas generally present with advanced-stage disease and the tumors have poor histologic and prognostic features. The findings from the follow-up indicated that these tumors do not follow a very aggressive clinical course as was proposed in earlier reports. Breast carcinomas occurring during pregnancy share many histologic and prognostic similarities with breast carcinoma occurring in other young women.

Total RNA yield and microarray gene expression profiles from fine-needle aspiration biopsy and core-needle biopsy samples of breast carcinoma.

BACKGROUND: Gene expression profiling should be applicable to needle biopsy samples if microarray technology is to become practically useful for clinical research or management of breast carcinoma. This study compared gene expression profiles derived from fine-needle aspiration biopsy (FNAB) and from core needle biopsy (CBX). METHODS: Total RNA was extracted from single FNAB and CBX samples. Corresponding pairs of FNAB and CBX were analyzed for similarity of gene expression profiles using cDNA microarrays that contain 30721 human sequences. A subset of genes that distinguished CBX samples from FNAB samples was evaluated in a larger group of needle biopsy samples and in a published genomic database derived from 78 sporadic breast carcinomas with known clinical outcome. RESULTS: Sixty-eight patients with newly diagnosed breast carcinoma were included in the current study. Sixty-five patients underwent FNAB (17 had both FNAB and CBX) and 3 underwent CBX only. Extracted RNA was of suitable quality for hybridization in 46 (71%) FNABs and 15 (75%) CBXs. Total RNA yield in those samples was similar for single-pass FNAB (mean = 3.6 microg and median = 2.2 microg; n = 46) and CBX (mean = 2.8 microg and median = 2.0 microg; n = 15), with 1 microg or more of total RNA in all cases. Transcriptional profiling was performed successfully in all cases when it was attempted, in a total of 50 samples (38 FNABs and 12 CBXs), including matched FNAB and CBX samples from 10 patients. There were differences in gene expression profiles in 10 matched FNAB and CBX sample pairs. Genes that were expressed differently in CBX samples, compared with FNAB samples, were recognized as being predominantly from the endothelium, fibroblasts, myofibroblasts or smooth muscle, and histiocytes. Corresponding microscopic cell counts from FNABs demonstrated means of 80% tumor cells, 15% lymphocytes, and 5% stromal cells, whereas CBXs contained 50% tumor cells, 20% lymphocytes, and 30% stromal cells. Considering that CBXs are approximately six-fold richer in nonlymphoid stromal cells than FNABs and that CBXs differentially express a set of recognized stromal genes, the authors used these biopsies to define a transcriptional profile of breast carcinoma stroma. A set of 120 genes differentially expressed in CBXs was assessed independently in a published breast carcinoma genomic database to classify breast carcinomas based on stromal gene expression. Subgroups of tumors with low or high stromal signal were identified, but there was no correlation with the development of systemic metastases within 5 years. CONCLUSIONS: Both FNAB and CBX yield a similar quality and quantity of total RNA and are suitable for cDNA microarray analyses in approximately 70-75% of single-pass samples. Transcriptional profiles from FNAB and CBX of the same tumor generally are similar and are driven by the tumor cell population. The authors concluded that each technique has relative advantages. The FNABs provide transcriptional profiles that are a purer representation of the tumor cell population, whereas transcriptional profiles from CBXs include more representation from nonlymphoid stromal elements. Selection of the preferred needle biopsy sampling technique for genomic studies of breast carcinomas should depend on whether variable stromal gene expression is desirable in the samples.

Intention to pursue genetic testing for breast cancer among women due for screening mammography.

Because few studies have addressed the intention to pursue testing for breast cancer susceptibility among women in the general population, we examined whether women due for routine mammography would want such testing and what factors might impact on their decision to pursue testing. A questionnaire was mailed to women > or =50 years of age who had undergone a screening mammogram 12 to 14 months before the study. Univariate and multivariable analyses were conducted to identify factors associated with intention to pursue genetic testing. Approximately 41% of respondents probably or definitely intended to pursue testing. In univariate analysis, the intention to undergo testing was not significantly associated with age, education, marital status, potential effects on health or life insurance, or physician recommendation. Although significant in univariate analysis, family history of breast cancer and ethnicity were not significant in multivariable analysis. In both univariate and multivariable analysis, factors significantly associated with intention to undergo testing included awareness of genetic testing, cancer worry, and insurance coverage of testing cost. Intention also was associated with the respondent wanting to know whether she possessed the susceptibility gene, even if that knowledge would not impact on options for early detection or treatment. Given the relatively high level of interest in testing among women at average risk of breast cancer, these results may help health care professionals educate and counsel women regarding the appropriate use of genetic testing as well as breast cancer risk factors.

Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachidonic acid to prostaglandins. Overexpression of the COX-2 gene in mammary glands of transgenic mice was sufficient to induce tumorigenesis. We analyzed COX-2 expression in human breast cancers (and breast cancer cell lines) and adjacent ductal carcinoma in situ (DCIS) as well as its association with HER2/neu and clinicopathological variables. Archival primary breast carcinomas (n = 57), adjacent DCIS (n = 14) and DCIS alone (n = 2) were analyzed for COX-2 and HER2 expression by immunohistochemistry using specific monoclonal antibodies. An immunohistochemical scoring system was used. HER2 gene amplification had been analyzed previously by fluorescence in situ hybridization (n = 20). Histology of carcinomas included infiltrating ductal (n = 44), lobular (n = 2), and other (n = 7). Frozen breast cancers and adjacent normal tissue pairs (n = 9) were analyzed for COX-2 mRNA by reverse transcription-PCR. COX-2 and HER2 expression were also analyzed in human breast cancer cell lines (MCF-7, MCF-7/HER2, SK-BR-3, and MDA-MB-231) by immunoblotting. Cytoplasmic COX-2 expression was detected at an intermediate or high level in epithelial cells in 18 of 42 (43%) invasive breast cancers and in 10 of 16 (63%) cases of DCIS. Normal-appearing breast epithelia adjacent to cancer expressed COX-2 in 81% of cases and was generally focal and of similar or decreased intensity relative to adjacent neoplastic epithelia. COX-2 mRNA was detected in all samples analyzed by reverse transcription-PCR and was increased in eight of nine breast cancers relative to paired normal tissue. In archival tumors, no significant correlation was found between COX-2 and HER2 expression/amplification and clinicopathological variables. COX-2 expression was induced in MCF-7 cells stably transfected with HER2, in contrast to parental MCF-7 cells, and was detected in MDA-MB-231, but not SK-BR-3 cells. COX-2 is frequently overexpressed in invasive breast cancers and in adjacent DCIS and, thus, may be an early event in mammary tumorigenesis. Forced HER2 expression in MCF-7 cells was shown to up-regulate COX-2, although no association was found in human tumors. Our results suggest that nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors may be useful in the chemoprevention and therapy of human breast cancer.

Multidisciplinary management of breast cancer concurrent with pregnancy.

The management of PABC is very difficult. The incidence of PABC is low, but may be increasing because of the number of women who are becoming pregnant at a later age. More investigation is needed to understand whether the biology of PABC is different from that of breast cancer in nonpregnant women. One exciting area of further research is the potential relationship between mutations in known breast cancer susceptibility genes and breast cancer development during pregnancy. Diagnosis or PABC remains challenging because of the anatomic and physiologic changes that occur in the breast during pregnancy. Understanding the generic influences on PABC may help physicians in diagnosing this disease earlier, and understanding the tumor-receptor characteristics of PABC can help physicians deliver effective treatment. The various modalities available for treatment of PABC and their risks and benefits must be discussed openly with patients and their families. Abortion is not usually recommended. Modified radical mastectomy is the recommended treatment for PABC diagnosed during the first trimester. Neoadjuvant or adjuvant chemotherapy can be given with minimal risks to the fetus during the second or third trimester. Radiation therapy is contraindicated during pregnancy because of the potential for injury to the fetus. Breast conservation therapy, with radiation treatments given after delivery or after neoadjuvant chemotherapy, is an option for women with PABC diagnosed late in pregnancy. Once the appropriate treatment modality is chosen, its implementation must not be delayed because of the pregnancy. Most of the literature shows that women with PABC have the same survival stage for stage as nonpregnant women with breast cancer. But some studies suggest that the prognosis is worse for patients who present with advanced-stage PABC. Finally, recurrence and survival in most patients previously treated for breast cancer do not appear to be adversely affected by subsequent pregnancy. Above all, the patient with breast cancer diagnosed during pregnancy is best served by early and continued involvement of a multidisciplinary cancer treatment team.

Chemoprevention of colorectal cancer.

Colorectal cancer is the third most incident cancer in the United States and is second only to lung cancer as a cause of cancer-related mortality. Colorectal cancer develops through a multistep process characterized by histopathological precursor lesions and molecular genetic alterations. This sequential process of tumorigenesis provides opportunities for the development and testing of both primary and secondary prevention strategies. This review focuses on chemoprevention, which is defined as the use of natural or synthetic agents to reverse the process of carcinogenesis. Epidemiological studies have consistently shown that chronic intake of nonsteroidal anti-inflammatory drugs (NSAIDs), principally aspirin, can reduce the incidence of colorectal adenomas and carcinomas. Evaluation of NSAIDs, including newer selective cyclo-oxygenase-2 inhibitors, in carcinogen-induced and genetically manipulated animal models of colorectal cancer demonstrates that these drugs are effective chemopreventive agents. In humans, the NSAID sulindac has been studied in familial adenomatous polyposis patients and was found to regress colorectal adenomas in a placebo-controlled trial. More recently, the selective cyclo-oxygenase-2 inhibitor Celebrex was also shown to be effective in familial adenomatous polyposis and was approved by the Food and Drug Administration as a adjuct to usual care in these patients. NSAIDs, as well as other chemopreventive agents, are currently being studied in patients at increased risk of colorectal cancer, including those with sporadic adenomas. The outcome of these studies has the potential to impact patient management practices. However, chemopreventive agents cannot be recommeded at present for average-risk individuals or for those with sporadic colorectal neoplasia. In addition to demonstrating efficacy, chemopreventive agents must be safe and well tolerated for chronic administration and should be relatively cost-effective. Although still in its infancy, the field of chemoprevention is an exciting and rapidly advancing area of investigation. Chemopreventive strategies, if effective, offer the promise of producing a paradigm shift in our current approach to colorectal cancer.

Microsomal epoxide hydrolase polymorphisms and lung cancer risk in non-Hispanic whites.

Microsomal epoxide hydrolase (mEPHX) is a critical metabolic enzyme involved in the activation and subsequent detoxification of specific tobacco carcinogens. mEPHX harbors polymorphisms in exon 3 and exon 4 that modulate enzymatic activity. The exon 3 polymorphism decreases mEPHX metabolic activity, whereas the exon 4 polymorphism increases activity. We hypothesized that the mEPHX polymorphisms modulate lung cancer risk. Using a case-control study design and restriction fragment length polymorphism polymerase chain reaction assay, we determined the mEPHX polymorphic genotypes of 181 lung cancer cases among non-Hispanic whites and 163 controls (matched for age, sex, ethnicity, and smoking history). Our results showed that the variant allele of mEPHX exon 4 increased the overall lung cancer risk by 56% (odds ratio [OR]=1.56, 95% confidence interval [CI]=0.99-2.46). Additionally, the risk estimates were elevated significantly for younger people (<64 yr) (OR=2.27, 95% CI=1.15-4.50) and current smokers (OR=2.22, 95% CI=1.06-4.65). The variant allele of mEPHX exon 3 had no effect overall (OR=0.88, 95% CI=0.56-1.38), but there was a 53% protective effect (OR=0.47, 95% CI=0.22-0.99) in younger people. When we analyzed the exon 3 and exon 4 polymorphisms together, those people with the high enzymatic activity genotype had an elevated lung cancer risk of 1.72 (95% CI=0.90-3.29). This elevated risk was also evident only in younger people. These findings suggest that these variant alleles of exon 3 and exon 4 of mEPHX modulates lung cancer risk.