S. David Nathanson

Insights into the mechanisms of lymph node metastasis

The mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and interrelated. Although the phenomenon of lymph node metastasis has been recognized for over 200 years, the exact mechanisms have only recently been the subject of intense interest and sophisticated experimentation. Sentinel lymph node biopsy has rapidly entered the clinical mainstream for melanoma and breast carcinoma, and this technique has provided confirmation of the orderly anatomic progression of tumor cells from primary site to the RLNs through lymphatic capillaries and trunks. Exciting studies involving the pathophysiology of interstitial fluid pressure in tumors and the peritumoral extracellular matrix have focused on lymphatic flow and tumor microenvironment and microcirculation. Molecular techniques have led to the definition of unique markers found on lymphatic endothelial cells. These markers have enabled scientists to identify peritumoral and intratumoral lymphatics and to visualize the ingrowth of tumor cells into the lumena of lymphatic capillaries. Tumor‐secreted cytokines, such as vascular endothelial growth factors (VEGF)‐C and ‐D, bind to VEGF receptors on lymphatic endothelial cells and induce proliferation and growth of new lymphatic capillaries; this process is similar to the well‐known mechanism of angiogenesis, which results from the proliferation of new blood vessel capillaries. Lymphangiogenesis is associated with an increased incidence of RLN metastasis, and it is possible that this step is essential to the metastatic process. Directional movement toward lymphatics and lymph nodes appears to follow a chemokine gradient, and it is likely that some tumor cells that express certain types of chemokine receptors are more likely to metastasize to the RLNs. In contrast, tumor cells that do not express specific receptors that are responsive to lymphatic chemokines may not metastasize. New knowledge regarding the molecules involved in these processes should enable improvements in prognostic and possibly therapeutic approaches to the management of malignant tumors. Cancer 2003;98:413–23.

Comparison of mammographically guided breast biopsy techniques.

OBJECTIVE To determine which mammographically guided breast biopsy technique is the most efficient in making a diagnosis in women with suspicious mammograms. SUMMARY BACKGROUND DATA Mammographically guided biopsy techniques include stereotactic 14-gauge core-needle biopsy (SC bx), stereotactic 11-gauge suction-assisted core biopsy (Mammotome [Mbx]), stereotactic coring excisional biopsy (Advanced Breast Biopsy Instrument [ABBI]), and wire-localized biopsy (WL bx). Controversy exists over which technique is best. METHODS All patients undergoing any one of these biopsy methods over a 15-month period were reviewed, totaling 245 SC bx, 107 Mbx, 104 ABBI, and 520 WL bx. Information obtained included technical success, pathology, discordant pathology, and need for open biopsy. RESULTS Technical success was achieved in 94.3% of SC bx, 96.4% of Mbx, 92.5% of ABBI, and 98.7% of WL bx. The sensitivity and specificity were 87.5% and 98.6% for SC bx, 87.5% and 100% for Mbx, and 100% and 100% for ABBI. Discordant results or need for a repeat biopsy occurred in 25.7% of SC bx, 23.2% of Mbx, and 7.5% of ABBI biopsies. In 63.6% of ABBI and 50.9% of WL bx, positive margins required reexcision; of the cases with positive margins, 71.4% of ABBI and 70.4% of WL bx had residual tumor in the definitive treatment specimen. CONCLUSION Although sensitivities and specificities of SC bx and Mbx are good, 20% to 25% of patients will require an open biopsy because a definitive diagnosis could not be reached. This does not occur with the ABBI excisional biopsy specimen. The positive margin rates and residual tumor rates are comparable between the ABBI and WL bx. The ABBI avoids operating room and reexcision costs; therefore, in appropriately selected patients, this appears to be the most efficient method of biopsy.

Molecular mechanisms of metastasis.

A major topic covered at the First International Symposium on Cancer Metastasis and the Lymphovascular System was the molecular mechanisms of metastasis. This has become of major interest in recent years as we have discovered new metastasis-related genes and gained understanding of the molecular events of lymphatic metastasis. The symposium covered new aspects and important questions related to the events of metastasis in both humans and animals. The basic and clinical related research covered in this topic represented many disciplines. The presentations showed novel findings and at the same time, raised many new unanswered questions, indicating the limited knowledge we still have regarding the molecular events of metastasis. The hope is that further unraveling of the direct and indirect molecular events of lymphatic metastasis will lead to new approaches in developing effective therapeutics.

Racial differences in the presentation and surgical management of breast cancer

BACKGROUND African American women are seen with more advanced breast cancers, are less likely to be treated with breast-conserving surgery, and generally have poorer prognoses than white women. There are a myriad of potential causes for these phenomena. The purpose of this study was to measure racial differences in the surgical treatment of breast cancer among women with comparable health care access and delivery. METHODS The Breast Cancer Registry of the Department of Surgery at Henry Ford Hospital was accessed for all patients between January 1, 1990, and December 31, 1997 for whom data on race, tumor characteristics, stage, and treatment specifics were available. Socioeconomic information was collected with use of 1990 census block data. Proportions of women who received each treatment were compared for African Americans and whites with use of the relative risk (RR) and 95% confidence intervals (CI). We used multiple logistic regression to obtain estimates of the relative risk, controlling for potential confounding factors. RESULTS Of the 1699 patients in the database, 1250 had sufficient information for analysis. A total of 8.7% of African American women were diagnosed with late-stage disease (i.e., stage III or IV) compared with 7.9% of whites. Nevertheless, African American women had a lower frequency of stage I disease (30.5% vs 36.2%) and a higher frequency of stage II disease (36.8% vs 31.4%). Overall and adjusted risk estimates for age, tumor stage, marital status, median income, and type of insurance revealed no substantive or statistically significant differences between African American and white patients. The adjusted RR for local excision was 1.39 (95% CI 0.78 to 2.49), for lumpectomy and axillary dissection RR 0.92 (95% CI 0.66 to 1.29), for simple mastectomy RR 0.84 (95% CI 0.41 to 1.72), and for modified radical mastectomy RR 1.00 (95% CI 0.73 to 1.36). CONCLUSIONS In this setting of equal access to health care, African American women still have higher frequencies of stage II disease, although the frequencies for late-stage disease are similar. Nevertheless, no surgical differences were found in this population, even after the effects of socioeconomic indicators and stage at diagnosis were controlled for Survival differences between African American and white women are unlikely to be explained by differences in treatment.

Pathways of Lymphatic Drainage From the Breast

Background: The current standard for obtaining accurate sentinel lymph node SLN mapping is intraparenchymal lymphophilic dye/radiocolloid injection close to the breast tumor. We hypothesized that common lymphatic trunks drain both a large volume of breast parenchyma and skin and that intradermal or intraparenchymal routes flow to the same axillary node.Methods:99mTc-labeled filtered sulfur colloid was injected intradermally directly over the breast tumor in 119 patients. Blue dye was injected intraparenchymally in the same quadrant as the primary tumor concordant quadrant in 66 and in a discordant quadrant in 53 patients. During axillary exploration, both blue and gamma-emitting hot nodes were found. End points were SLNs that were hot and blue, either the same node or different nodes.Results: In 62 93.9% of 66 of concordant quadrant and in 49 92.5% of 53 of discordant quadrant patients, the same SLN was both hot and blue P = .99; Fisher’s exact test. In eight cases in which two distinct nodes were blue and not hot and hot but not blue, the lymph nodes were very close to each other.Conclusions: The dermal and parenchymal lymphatics of the breast seemed to drain to the same axillary lymph nodes. Lymph from the entire breast seemed to drain through a small number of lymphatic trunks to one or two lymph nodes.

Pathogenesis, prevention, diagnosis and treatment of breast cancer

Breast cancer is the most common cancer affecting women worldwide. Prediction models stratify a womans risk for developing cancer and can guide screening recommendations based on the presence of known and quantifiable hormonal, environmental, personal, or genetic risk factors. Mammography remains the mainstay breast cancer screening and detection but magnetic resonance imaging and ultrasound have become useful diagnostic adjuncts in select patient populations. The management of breast cancer has seen much refinement with increased specialization and collaboration with multidisciplinary teams that include surgeons, oncologists, radiation oncologists, nurses, geneticist, reconstructive surgeons and patients. Evidence supports a less invasive surgical approach to the staging and management of the axilla in select patients. In the era of patient/tumor specific management, the advent of molecular and genomic profiling is a paradigm shift in the treatment of a biologically heterogenous disease.

Noninitiation of Adjuvant Chemotherapy in Women With Localized Breast Cancer: The Breast Cancer Quality of Care Study

PURPOSE For some women, adjuvant chemotherapy for nonmetastatic breast cancer decreases recurrences and increases survival; however, patient-physician decisions regarding chemotherapy receipt can be influenced by medical and nonmedical factors. PATIENTS AND METHODS We used a prospective cohort design and multivariate modeling to investigate factors related to noninitiation of chemotherapy among women with newly diagnosed breast cancer recruited from three US sites. We interviewed patients at baseline and during treatment on sociodemographic, tumor, and treatment decision-making factors. Patients were categorized according to National Comprehensive Cancer Network guidelines as those for whom chemotherapy was definitely indicated, clinically discretionary, or discretionary based on age greater than 70 years. RESULTS Of 1,145 patients recruited, chemotherapy was clinically indicated for 392 patients, clinically discretionary for 459 patients, discretionary because of age for 169 patients, and not indicated for 93 patients; data were insufficient for 32 patients. Chemotherapy rates were 90% for those in whom chemotherapy was clinically indicated, 36% for those in whom it was discretionary because of clinical factors, and 19% for those in whom it was discretionary based on age greater than 70 years. Nonreceipt of chemotherapy was associated with older age, more negative beliefs about treatment efficacy, less positive beliefs about chemotherapy, and more concern about adverse effects. In the two discretionary groups, clinical predictors of worse outcome (greater tumor size, positive nodes, worse grade, and estrogen receptor- and progesterone receptor-negative status) were associated with increased chemotherapy initiation. CONCLUSION Utilization of adjuvant chemotherapy was most common among patients who, based on clinical criteria, would most likely benefit from it, patients with more positive than negative beliefs regarding treatment efficacy, and patients with few concerns about adverse effects.

Use of guideline recommended follow-up care in cancer survivors: routine or diagnostic indications?

Background:After potentially curative cancer treatment, patients may receive procedures for routine monitoring for recurrence or for evaluation of symptoms or signs. Objective:We sought to characterize surveillance care guideline-recommended and other procedures performed in cancer survivors according to routine versus diagnostic indications. Methods:This was a retrospective cohort study of paper and electronic medical records between 1990 and 2000 from a large midwestern U.S. integrated health care delivery system of 500 patients who received curative treatment of breast, colorectal, endometrial, lung, or prostate cancer. Our measures were the indications for potential surveillance procedures as recommended by clinical practice guidelines or otherwise. Results:Among 14,670 procedures of interest received, 82.0% were performed for routine surveillance, whereas 10.6% were performed for diagnostic indications and 7.3% had indeterminate indications. Office visits most were often delivered for routine indications (91.6%), followed by guideline recommended tests for local recurrence (range 74.1–98.4%, depending on the specific test and cancer). In general, tests that were not recommended in established guidelines were for the purposes of detection of metastatic recurrence and were less often delivered for routine indications (overall frequency 59.2%, P < 0.0001 compared with recommended testing). Conclusion:Office visits and testing for local recurrence of cancer generally are performed for routine surveillance, regardless of recommendation by practice guidelines. Because procedures not recommended by practice guidelines were more often for diagnostic purposes, classification of patients as undergoing intensive surveillance may be misleading and may require record review to confirm.

The breast cancer quality of care study (BQUAL): A multi-center study to determine causes for noncompliance with breast cancer adjuvant therapy

Abstract:  In oncology, quality of care is a major issue for patients and providers. Significant variations in care, including nonreceipt of adjuvant systemic therapy, nonadherence to therapy, and/or early discontinuation of therapy, occur frequently and may impact survival. Reasons for these variations are not well understood, but may play a role in the prominent disparity in breast cancer survival between blacks and whites. Since May 2006, the Breast Cancer Quality of Care Study (BQUAL) has recruited 1158 women with nonmetastatic breast cancer from several centers across the country, with completed data on 1057 participants to date. Detailed information on demographic, behavioral, biomedical, and emotional factors related to chemotherapy use was collected on each participant at baseline and at two follow‐up interviews during the first 6 months. In addition, for women with ER+ tumors, further questionnaires were completed every 6 months regarding hormonal therapy use. Each participant was also asked to provide a DNA sample, and to allow medical record review. We surveyed physicians providing care to the study participants regarding attitudes toward adjuvant treatment. The mean age of participants was 58 years (SD 11.6), and 15% (n = 160) were black. The majority had an annual household income <

Regional lymph node and pulmonary metastases after local hyperthermia of melanomas in C57BL/6 mice

90,000 (n = 683), had college education or higher (n = 802), 55.9% were married, and 57.9% were not currently employed. Seventy‐six percent had hormone‐receptor‐positive tumors, 49.9% initiated chemotherapy and 82.7% started hormonal therapy. Blacks were more likely to have lower annual household income (p < 0001), less education (p = 0.0005), ER negative tumor status (p = 0.02), and poorly differentiated cancer (p = 0.0002). The main endpoints of the study are noninitiation of chemotherapy or hormonal therapy, nonadherence to therapy and early discontinuation of therapy. Treatment and outcomes will be compared on the 15% of participants who are black versus other participants. The BQUAL Study will be a rich ongoing source of information regarding reasons for differences in receipt of both adjuvant chemotherapy and hormonal therapy. This information may be useful in planning interventions to improve quality of care.