57% decline in Rhode Island invasive breast cancer mortality between 1987 and 2017: mammography predominates in preventing mortality.

BACKGROUND: Controversy exists regarding proportional contributions of mammographic screening versus systemic therapy to declining disease-specific mortality of female invasive breast cancer (IBC) in the United States. Understanding relative contributions may help address allocation of medical resources. METHODS: A 31-year (1987-2017) review of Rhode Island (RI) Cancer Registry data of female IBC was carried out in a state with high rates of mammographic screening. RESULTS: Over 31 years in RI, statistically significant improvements occurred at initial diagnosis of IBC: mean and median maximum cancer diameters decreased by 21% and 30% respectively. Despite 1997 introduction of more accurate sentinel lymph node biopsy, the proportion of patients with axillary lymph node metastases (LNM) decreased by 27%. Extent of LNM also decreased as patients with over three node metastases decreased 67%. By 2017, 53% of all patients with LNM had only one. Poorly differentiated cancers decreased 50%. Disease-specific mortality decreased 57%. DISCUSSION: Improvements in initial presentation of IBC are consistent with most having progressive growth, from cellular origin to palpable mass, the currently accepted biological model. Breast cancers identified earlier at initial diagnosis through screening mammography are characterized by smaller size, fewer axillary LNMs, better grade differentiation, and decreased mortality. Statistical analysis from these improved diagnostic parameters indicate that the majority of mortality decline from invasive breast cancer in RI can be attributed to earlier detection. Thus, mammography predominates in preventing mortality.

The 20-year effort to reduce access to mammography screening: historical facts dispute a commentary in Cancer.

Mammography screening fulfills all requirements for an effective screening test. It detects many cancers earlier when they are at a smaller size and earlier stage, and it has been demonstrated that this reduces breast cancer deaths in randomized controlled trials. When screening is introduced into the population, the death rate from breast cancer declines. Nevertheless, scientifically unsupported arguments that appear in the medical literature are passed on to the public and continue to confuse women and physicians regarding the value of screening. Methodologically flawed challenges to mammography have been almost continuous since the 1990s. And, as each challenge has been invalidated, a new, specious challenge has been raised. The authors of this report address the long history of misinformation that has developed in the effort to reduce access to screening, and they address the issues raised by commentators concerning their recent publication in this journal.

A failure analysis of invasive breast cancer: most deaths from disease occur in women not regularly screened.

BACKGROUND: Mortality reduction from mammographic screening is controversial. Individual randomized trials and meta-analyses demonstrate statistically significant mortality reductions in all age groups invited to screening. In women actually screened, mortality reductions are greater. Individual trials and meta-analyses show varying rates of mortality reduction, leading to questions about screening's value and whether treatment advances have diminished the importance of early detection. This study hypothesized that breast cancer deaths predominantly occurred in unscreened women. METHODS: Invasive breast cancers diagnosed between 1990 and 1999 were followed through 2007. Data included demographics, mammography use, surgical and pathology reports, and recurrence and death dates. Mammograms were categorized as screening or diagnostic based on absence or presence of breast signs or symptoms, and were substantiated by medical records. Breast cancer deaths were defined after documentation of prior distant metastases. Absence of recurrent cancer and lethal other diseases defined death from other causes. RESULTS: Invasive breast cancer failure analysis defined 7301 patients between 1990 and 1999, with 1705 documented deaths from breast cancer (n = 609) or other causes (n = 905). Among 609 confirmed breast cancer deaths, 29% were among women who had been screened (19% screen-detected and 10% interval cancers), whereas 71% were among unscreened women, including > 2 years since last mammogram (6%), or never screened (65%). Overall, 29% of cancer deaths were screened, whereas 71% were unscreened. Median age at diagnosis of fatal cancers was 49 years; in deaths not from breast cancer, median age at diagnosis was 72 years. CONCLUSIONS: Most deaths from breast cancer occur in unscreened women. To maximize mortality reduction and life-years gained, initiation of regular screening before age 50 years should be encouraged.

Improving size, lymph node metastatic rate, breast conservation, and mortality of invasive breast cancer in Rhode Island women, a well-screened population.

The beneficial impact of screening mammography on breast cancer outcome continues to be debated as demonstrated by guidelines published by the United States Preventive Services Task Force. A previous report from Rhode Island, which has a very high rate of mammographic screening, demonstrated significant improvements in invasive breast cancer presentation and mortality through 2001. This report updates data through 2008 to determine whether previous favorable trends continued. Rhode Island Cancer Registry data regarding invasive breast cancer presentation and mortality in 17,522 female residents diagnosed between 1987 and 2008, inclusive, were analyzed for demographic and pathological factors. Data were analyzed by four time periods: 1987-1992, 1993-1998, 1999-2003, and 2004-2008 and overall. Statistically significant improvements occurred over the four successive time periods, in mean cancer size (23.7, 20.9, 19.6, and 19.3 mm, p < 0.0001), pathologic grade (Grade I: 12, 15, 19, and 17 %; Grade III 57, 41, 36, and 35 %, p < 0.0001), breast conserving surgery (38, 56, 67, and 71 %, p < 0.0001) and mortality (37.3, 31.4, 25.1, and 22.6 per 100,000/year, p < 0.0001). The results showed that high screening rates favorably impacted presentation of and mortality from invasive breast cancer in Rhode Island. From 1987 to 2008, there has been a 39 % decline in breast cancer mortality considering 5 year periods (37.3 vs. 22.6 deaths per 100,000) and 41 % comparing the period from 1990 to 2008, which may exceed the goal of 50 % mortality reduction by 2015 established by the American Cancer Society.

Adjuvant therapy in stage I carcinoma of the breast: the influence of multigene analyses and molecular phenotyping.

A consensus conference was held in order to provide guidelines for the use of adjuvant therapy in patients with Stage I carcinoma of the breast, using traditional information, such as tumor size, microscopic character, Nottingham index, patient age and co-morbidities, but also incorporating steroid hormone and Her-2-neu data as well as other immunohistochemical markers. The role of the genetic analysis of breast cancer and proprietary gene prognostic signatures was discussed, along with the molecular profiling of breast cancers into several groups that may predict prognosis. These molecular data are not currently sufficiently mature to make them part of decision making algorithms of recommendations for the treatment of individual patients.

The connectivity of lymphogenous and hematogenous tumor cell dissemination: biological insights and clinical implications.

Although tumor cells are found in the blood early after tumorigenesis, dissemination through the lymphatic system and in particular the formation of lymph node metastases has long been considered to be a driving force behind the formation of secondary tumors in distant vital organs. Contemporary experimental observations and clinical trial results suggest that this may not be the case. In this review we survey the evidence for both points of view, and examine the hypothesis that the prognostic relevance of lymph node metastases may lie in their ability to indicate that primary tumors are producing soluble factors that have the potential to promote metastasis at these distant sites, for example by releasing tumor cells from dormancy. Furthermore, the interconnectivity between the lymphatic and blood circulatory systems underscores the relevance of the analysis of the properties of circulating and disseminated tumor cells for prognostic evaluation, patient stratification and understanding the biology of metastasis. We therefore give an overview of the current state of the art in this field.

Unique patterns of metastases in common and rare types of malignancy.

This review on the unique patterns of metastases by common and rare types of cancer addresses regional lymphatic metastases but also demonstrates general principles by consideration of vital organ metastases. These general features of successfully treated metastases are relationships to basic biological behavior as illustrated by disease-free interval, organ-specific behavior, oligo-metastatic presentation, genetic control of the metastatic pattern, careful selection of patients for surgical resection, and the necessity of complete resection of the few patients eligible for long-term survival after resection of vital organ metastasis. Lymph node metastases, while illustrating these general features, are not related to overall survival because lymph node metastases themselves do not destroy a vital organ function, and therefore have no causal relationship to overall survival. When a cancer cell spreads to a regional lymph node, does it also simultaneously spread to the systemic site or sites? Alternatively, does the cancer spread to the regional lymph node first and then it subsequently spreads to the distant site(s) after an incubation period of growth in the lymph node? Of course, if the cancer is in its incubation stage in the lymph node, then removal of the lymph node in the majority of cases with cancer cells may be curative. The data from the sentinel lymph node era, particularly in melanoma and breast cancer, is consistent with the spectrum theory of cancer progression to the sentinel lymph node in the majority of cases prior to distant metastasis. Perhaps, different subsets of cancer may be better defined with relevant biomarkers so that mechanisms of metastasis can be more accurately defined on a molecular and genomic level.

Impact of axillary lymph node dissection on breast cancer outcome in clinically node negative patients: a systematic review and meta-analysis.

BACKGROUND: The regional lymph node control and survival impact of axillary dissection in breast cancer has been the subject of multiple randomized trials, with various results. This study reviews and conducts a meta-analysis of contemporary trials of axillary dissection in patients with early stage breast cancer. METHODS: A systematic MEDLINE review identified 3 randomized trials published between January 2000 and January 2007 of axillary dissection versus no dissection in clinically lymph node negative early stage breast cancer patients. A fourth trial of axillary radiotherapy versus no axillary treatment was also identified and included in this review. Meta-analyses were performed for survival, axillary recurrence, metastatic disease, and ipsilateral breast recurrence. RESULTS: All trials reported a higher rate of axillary recurrence (1.5%-3%, median follow-up 5-15 years) in the absence of axillary dissection or radiotherapy. Overall survival was similar with and without definitive axillary treatment in 3 of the 4 trials, with an increased rate of nonbreast cancer-related death in the observation arm of the fourth trial. Meta-analyses found no significant difference in overall survival (odds ratio [OR] 1.55; 95% confidence interval [CI], 0.74-3.24), metastases (OR 0.91; 95% CI, 0.65-1.29), or ipsilateral breast recurrence (OR 1.11; 95% CI, 0.68-1.83) associated with axillary treatment. A significantly lower rate of axillary recurrence was seen after lymphadenectomy (OR 0.28; 95% CI, 0.11-0.73, P<.01). CONCLUSIONS: Axillary dissection does not confer a survival benefit in the setting of early stage clinically lymph node negative breast cancer. Although the rate of axillary failure was increased in the absence of dissection, the absolute risk was found to be extremely low.

Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007.

A consensus conference including thirty experts was held in April, 2007, to discuss risk factors for breast cancer and their management. Four categories of risk were outlined, from breast cancer "average" through "very high" risk, the latter including individuals with high penetrance BRCA1/2 gene mutations. Guidelines for management of patients in each of these categories were discussed, with the major portion of the conference being devoted to individuals with BRCA1/2 mutations. Prevalence of these mutations in the general populations was estimated to be 1 in 250-500 individuals, with an increased prevalence in Ashkenazic Jews and other founder groups. Risk reduction strategies for these individuals include surveillance, with or without chemoprevention drugs, or surgical procedures to remove the organs at risk, i.e., bilateral mastectomy and/or bilateral salpingo-oophorectomy. These risk reduction strategies were evaluated fully, and recommendations were made for the care of patients in each of the risk categories. These guidelines for patient care were approved by the entire group of experts.

Treatment variation by insurance status for breast cancer patients.

Few studies have examined the relationship of insurance status with the presentation and treatment of breast cancer. Using a state cancer registry, we compared tumor presentation and surgical treatments at presentation by insurance status (private insurance, Medicare, Medicaid, or uninsured). Student's t-test, Chi-square test, and ANOVA were used for comparison. P-values reflect a comparison to insured patients. From 1996 to 2005, there were 6876 cases of invasive breast cancer with either private (n = 3975), Medicare (n = 2592), Medicaid (n = 193), or no insurance (n = 116). The median age (years) at presentation was 55 for private, 76 for Medicare, 54 for Medicaid and 54 for uninsured. The mean and median tumor size (mm) were 18.5 and 15 for private; 20.9 and 15 for Medicare; 24.2 and 18 for Medicaid; and 29.5 and 17 for uninsured, respectively; (p < 0.001 for all). Fewer women with Medicare and Medicaid presented with node negative breast cancers: private, 73.4% node negative; Medicare, 79.5% (p < 0.001); Medicaid, 60.9% (p < 0.001); and uninsured, 58% (p = 0.005). Significantly more uninsured women had no surgical treatment of their breast cancer: 15.5% versus 4.3% for private (p < 0.001). Among women with non-metastatic T1/T2 tumors, 71.5% with private insurance underwent breast-conserving surgery (BCS), compared with 64.2% of Medicare (p < 0.001), 65% of Medicaid (p = 0.097), and 65.4% of uninsured (p = 0.234). The rate of reconstruction following mastectomy was higher for private insurance (36.6%), compared with Medicare (3.8%, p < 0.0001), Medicaid (26.1%, p = 0.31), and uninsured (5.0%, p = 0.0038). The presentation of breast cancer in women with no insurance and Medicaid is significantly worse than those with private insurance. Of concern are the lower proportions of BCS and reconstruction among patients who are uninsured or have Medicaid. Reduction of disparities in breast cancer presentation and treatment may be possible by increasing enrollment of uninsured, program-eligible women in a state-supported screening and treatment program.

Axillary lymph nodes: US-guided fine-needle aspiration for initial staging of breast cancer--correlation with primary tumor size.

PURPOSE: To retrospectively assess the sensitivity and specificity of ultrasonographic (US)-guided fine-needle aspiration (FNA) of axillary lymph nodes for preoperative staging of breast cancer across a range of primary tumor sizes, by using histologic findings as a reference standard. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study; informed consent was waived. US-guided FNA results in 74 patients with breast cancer (75 axillae) were compared with final pathologic results. Lymph nodes were classified as benign, indeterminate, or suspicious on the basis of US characteristics at retrospective review. US-guided FNA in the most suspicious node at US, or the largest node if all appeared benign, was performed. Final pathologic results (sentinel lymph node biopsy [SNB] or axillary lymph node dissection [ALND]) were compared with US and preoperative US-guided FNA results. Results were assessed according to tumor size. Sensitivity, specificity, and positive predictive value of US and US-guided FNA were calculated. RESULTS: Primary tumor sizes were 0.3-12 cm (mean, 3 cm). Patient age range was 31-81 years (mean age, 51 years). Sensitivity of US-guided FNA for predicting positive results at ALND or SNB was 71%-75%. Specificity was 100%. Sensitivity of US-guided FNA increased with primary tumor size. CONCLUSION: US-guided FNA of axillary lymph nodes in patients with newly diagnosed breast cancer had a sensitivity that increased with increasing size of the primary tumor.

Predicting the risk of local recurrence in patients with breast cancer: an approach to a new computer-based predictive tool.

OBJECTIVE: To develop a new web-based tool, designated IBTR!, which integrates prognostic factors for local recurrence (LR) into a model to predict the 10-year risk of LR after breast conserving surgery (BCS) with or without radiation therapy (RT) with the goal of assisting with patient counseling and medical decision-making. METHODS: All available randomized trials of BCS alone versus BCS plus RT, meta-analyses, and institutional reports were reviewed to identify the principal prognostic factors for LR after breast-conserving therapy. Patient age, margin status, lymphovascular invasion (LVI), tumor size, tumor grade, use of chemotherapy, and use of hormonal therapy were found to consistently and significantly impact LR across multiple studies. Based upon a composite analysis of the relevant published randomized and nonrandomized studies, relative risk (RR) ratios were estimated and assigned to each prognostic category. These RR ratios were entered into a mathematical model with the 10-year baseline rates of recurrence with and without RT, 7% and 24%, respectively, to predict patient-specific LR risk. RESULTS: Individual data entered into this computer model with regards to patient age, margin status, LVI, tumor size, tumor grade, use of chemotherapy, and use of hormonal therapy will generate patient-specific predicted 10-year LR risk with and without RT. A graphic representation of the relative risk reduction with RT will also be displayed alongside the numerical display. CONCLUSION: IBTR! is a first attempt at a computer model incorporating LR prognostic factors in an evidence-based fashion to predict individual LR risk and the potential additional benefit from RT.

Regional lymph node metastases, a singular manifestation of the process of clinical metastases in cancer: contemporary animal research and clinical reports suggest unifying concepts.

The multistep complex metastatic cascade in cancer has been extensively studied in recent years. In addition, the concept of metastatic organ specificity has been elaborated. Histological studies in clinical situations have become far more sophisticated, enabling the frequent discovery of minor collections of cells in bone marrow and lymph nodes. Pertinent clinical evidence of the selective nodal metastatic pattern exists in differentiated thyroid cancer in younger, low-risk patients, yet none of the published risk group definitions indicate that lymph node metastases have a relationship to thyroid cancer survival. This unique clinical situation with very frequent nodal metastases but excellent survival is replicated in carcinoid cancers of the gastrointestinal tract. The lymph node metastatic frequency without distant organ metastases in these two human cancers help cement the understanding gained from laboratory and animal research regarding metastatic specificity and hopefully will help place the role of lymph node metastases generally and their surgical removal on a more scientifically and logically based understanding. More broadly, the elaboration of the frequency of metastatic cell dissemination to distant organs as well as lymph nodes, and comprehension of the metastatic cascade with metastatic specificity may reorient our understanding of the evolution from metastatic cells to clinical metastatic disease. Additionally, these concepts reemphasize that lymph node metastases are indicators, not governors, of distant metastases and survival, and add the assumption that metastatic tumor cells and tumor cell clusters, and perhaps even micrometastases in other organs, are themselves only indicators and not governors of distant metastases and survival in human cancers since they represent dormant metastases prior to their host microenvironmental changes that, on rare occasions, lead to angiogenesis and clinical metastases. Thus, the future may allow us to abandon some aspects of our surgical or systemic attack on clinical cancer metastases, such as lymph node removal or use of toxic chemotherapy, but open the door to more physiological and hopefully less traumatic approaches to the highly manipulable multistep genetic and physiological process of metastatic development. The future biological models of clinical cancer behavior will have to incorporate aspects of understanding the intricate metastatic cascade, and particularly the host microenvironmental factors that permit or prevent progressive growth of dormant cells or cell clusters to clinical metastases.