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.

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.

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.

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.

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.

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.

A novel approach to T classification in tumor-node-metastasis staging of breast cancer.

BACKGROUND: The aim of this study was to examine the effect of measurement bias in breast cancer and to create a more rational T-size categorization in tumor-node-metastasis staging in response to smaller, screen-detected cancers and measurement bias. METHODS: From 1987 to 2003, 10,853 invasive nonmetastatic breast cancers enlisted in the Rhode Island Cancer Registry with a known dimension were reviewed. Data analyzed by proposed classifications included the rate of lymph node metastases and the mortality rate from breast cancer. RESULTS: The median diameter was 16 mm. Cancer measurements reflected the bias in pathologists' dimension recording, which is centered strongly about whole- and half-centimeter sizes. A new T classification is proposed with the following sizes and frequencies in the Rhode Island Cancer Registry: 1 to 2 mm = T1 mic (3% of registered cases); 3 to 7 mm = T1a (11%); 8 to 12 mm = T1b (23%); 13 to 17 mm = T1c (18%); 18 to 22 mm = T2a (17%); 23 to 27 mm = T2b (8%); 28 to 32 mm = T2c (8%); 33 to 42 mm = T3a (6%); 43 to 52 mm = T3b (3%), and greater than 52 mm = T3c (4%). The unadjusted odds ratio for the probability of node metastases was 1.43 (confidence interval, 1.40-1.46; P < .001) with each increase in proposed grouping. The range in the lymph node metastatic rate was 5.5% for tumors 1 to 2 mm to 64% for cancers greater than 52 mm. By Cox proportional hazard, the unadjusted hazard ratio for death from breast cancer for each increase in proposed grouping was 1.33 (confidence interval, 1.29-1.37; P < .001). The 10-year survival rate ranged from 98.3% for tumors 1 to 2 mm to 70.3% for cancers greater than 52 mm. CONCLUSIONS: A more rational T category for use in tumor-node-metastasis staging is presented to reflect the much smaller invasive breast cancers encountered by screening and to account for the dimension recording bias of pathologists. This new T category shows a clinically and statistically significant linear relationship for both incidence of lymph node metastases and hazard ratio of death.

Role of ultrasound-guided axillary fine-needle aspiration in the management of invasive breast cancer.

BACKGROUND: Previous studies from Women & Infants' Hospital have reported the accuracy of ultrasound-guided fine-needle aspiration biopsy examination of axillary lymph nodes (USFNAB) for locally advanced breast cancer. The aim of this article is to report our further experience with USFNAB in staging the axilla and determining its affect on management decisions. METHODS: We performed a retrospective review of prospectively collected data between January 1998 and June 2005. RESULTS: A total of 220 patients underwent USFNAB for breast cancer. Of these, 52 were excluded. Of the 168 remaining patients, 79 had positive and 89 had negative USFNAB results. A total of 107 (63%) patients underwent primary surgery and 61 (37%) patients underwent neoadjuvant chemotherapy. In these patients, the sensitivity and specificity of USFNAB was 35% and 96% for T1, and 67% and 100% for T2, respectively. CONCLUSIONS: The high specificity of USFNAB could safely eliminate sentinel lymph node biopsy examination before axillary lymph node dissection, particularly in T2 lesions.

Preliminary results of a phase I/II study of HDR brachytherapy alone for T1/T2 breast cancer.

PURPOSE: To investigate the feasibility, toxicity, cosmetic outcome, and local control of high-dose-rate (HDR) brachytherapy alone without whole breast external beam irradiation for early-stage breast carcinoma. METHODS AND MATERIALS: Between June 1997 and August 1999, 32 women diagnosed with a total of 33 AJCC Stage I/II breast carcinomas underwent surgical breast excision and postoperative irradiation using HDR brachytherapy interstitial implantation as part of a multi-institutional clinical Phase I/II protocol. Eligible patients included those with T1, T2, N0, N1 (< or =3 nodes positive), and M0 tumors of nonlobular histologic features with negative surgical margins, no extracapsular lymph node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, reexcision, or either sentinel or full-axillary sampling. Direct visualization, surgical clips, and ultrasound and/or CT scan assisted in the delineation of the target volume, defined as the excision cavity plus a 2-cm margin. High-activity 192Ir (3-10 Ci) was used to deliver 340 cGy/fraction, 2 fractions/d, for 5 consecutive days, to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. RESULTS: The median follow-up of all patients was 33 months, and the mean patient age was 63 years. The mean tumor size was 1.3 cm, and 55% had an extensive intraductal component. Three patients had positive axillary nodes. Two patients experienced moderate perioperative pain that required narcotic analgesics. No peri- or postoperative infections occurred. No wound healing problems and no significant skin reactions related to the implant developed. The Radiation Therapy Oncology Group late radiation morbidity scoring scheme was applied to the entire 33-case cohort. In the assessment of the skin, 30 cases were Grade 0-1 and 3 cases were Grade 2. Subcutaneous toxicity was scored as 11 patients with Grade 0, 3 with Grade 1, 8 with Grade 2, 3 with Grade 3, and 8 with Grade 4. Clinically evident fat necrosis occurred in 8 patients at a median of 7.5 months after HDR brachytherapy completion. The only variables significantly associated with Grade 3-4 toxicity were the number of source dwell positions and the volume of tissue encompassed by the prescription isodose shell. The global cosmetic scores after a minimum of 18 months' follow-up were 0 cases with poor, 4 with fair, 5 with good, and 24 with excellent scores. One case of ipsilateral breast tumor recurrence was diagnosed 23 months after HDR brachytherapy, for a 4-year actuarial recurrence rate of 3%. This failure appeared to be a new primary tumor, because it was histologically distinct from the initial tumor and was located 9 cm from the initial tumor bed and 3 cm from the edge of the implant volume. CONCLUSION: Radiotherapy of the tumor bed alone with HDR interstitial brachytherapy is associated with a 33% incidence of Grade 3-4 s.c. toxicity, but with generally favorable overall cosmetic results. The risk of toxicity appears to be primarily related to the implant volume. With limited follow-up, the incidence of ipsilateral breast tumor recurrence was low.