Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial.

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline. RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients.

BACKGROUND: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma. PATIENTS AND METHODS: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS). RESULTS: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma. CONCLUSION: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

Measuring the quality of melanoma surgery - Highlighting issues with standardization and quality assurance of care in surgical oncology.

In an attempt to ensure high standards of cancer care, there is increasing interest in determining and monitoring the quality of interventions in surgical oncology. In recent years, this has been particularly the case for melanoma surgery. The vast majority of patients with melanoma undergo surgery. Usually, this is with combinations of wide excision, sentinel lymph node biopsy and lymphadenectomy. The indications for these procedures evolved during a time when no effective systemic adjuvant therapy was available, and whilst the rationale has been sound, the justification for differences in extent and thoroughness has generally been supported by inadequate or low-level evidence. This has led to a substantial variation among melanoma centres or even among surgeons within a centre in how these procedures are done. With recent rapid progress in the efficacy of systemic treatments that are impacting on overall survival, the prospect of long-term survival in these previously high risk patients means that more than ever long-term locoregional control of melanoma is imperative. Furthermore, the understanding of effects of systemic therapy on locoregional disease will only be interpretable if surgeons use standardized, high quality techniques. This article focuses on standardization and evolution of quality indicators for melanoma surgery and how these might have a positive impact on patient care.

Regional variation in immediate breast reconstruction in Australia.

BACKGROUND: Breast reconstruction following mastectomy has proven benefits and is the standard of care in many high-income countries. This audit documented regional variation in immediate breast reconstruction rates across Australia. METHODS: The Breast Surgeons of Australia and New Zealand (BreastSurgANZ) Quality Audit database and geospatial software were used to model the distribution of breast reconstructions performed on women having mastectomy in Australia in 2013. Geospatial mapping identified the distribution of these procedures in relation to the Greater Capital City Statistical Areas (GCCSAs) of the five largest states. Data were analysed using χ2 tests of independence and an independent-samples t test. RESULTS: Of 3786 patients having a mastectomy, 692 underwent breast reconstruction of which 679 (98·1 per cent) were immediate reconstructions. Rates of reconstruction differed significantly between jurisdictions (χ2 = 164·90), and were significantly higher in GCCSAs (χ2 = 144·60) and private hospitals (χ2 = 50·72) (all P < 0·001). Immediate breast reconstruction was not reported for 43·8 per cent of hospitals where mastectomy was conducted by members of BreastSurgANZ, including 29·8 per cent of hospitals within GCCSAs. A wider age range of women appeared to have had immediate reconstructions at hospitals within GCCSAs, although the difference in mean age between regions was not significant. Immediate breast reconstruction was considerably less likely to be performed in women who lived in areas of lower to mid socioeconomic status. CONCLUSION: Variations in the rate of immediate breast reconstruction may not be purely resource-driven.

Patterns and outcomes of breast reconstruction in older women - A systematic review of the literature.

PURPOSE: Older age is associated with lower rates of breast reconstruction (BR) for women requiring mastectomy. The purpose was to assess the available evidence on uptake, outcome and quality of life (QoL) after BR in older women. METHODS: A systematic literature review was performed via Medline, Embase and Cochrane databases using the search terms breast reconstruction, breast cancer, and mastectomy. Eligible studies reported rates of BR, rates of different reconstructive techniques, complication rates, and/or patient reported outcome measures (PROMs) of BR in women aged 60 years or older undergoing mastectomy for ductal carcinoma in situ or invasive carcinoma. RESULTS: A total of 42 eligible studies were included, with 32 of these reporting BR rates, 10 reporting rates of different reconstructive techniques, 10 reporting rates of complications, and four reporting PROMs. The studies reported 24,746 cases of BR in 407,570 mastectomy patients aged 60 years or older from 1987 to 2012. Implant based BR was more common than autologous techniques. Mostly, complication rates were not higher in older women, and QoL outcomes were similar to younger women. CONCLUSIONS: This review confirms that BR rates are lower in older women despite recent studies demonstrating its efficacy. The perception among some surgeons and women requiring mastectomy that the potential risks of BR in older women outweigh the benefits needs to be revisited. Education of consumers and surgeons along with public advocacy for offering BR to all clinically eligible women are the most promising means of changing practice.

Quality assurance in melanoma surgery: The evolving experience at a large tertiary referral centre.

BACKGROUND: The quality of melanoma surgery needs to be assessed by oncological outcome and complication rates. There is no published consensus on complication rates for common melanoma surgeries, namely wide excision (WE), sentinel node biopsy (SNB) and regional lymph node dissection (RLND). Consequently there are no agreed standards by which surgeons can audit their practices. METHODS: Surgical standards were proposed in 2008 following review of the literature and from expert opinion. Melanoma Institute Australia (MIA) self-reported audit data from 2011 and 2012 were compared with these standards. To quality check the self-reported audit, RLND data were extracted from the MIA database. RESULTS: Six surgeons performed a mean of 568 surgeries each quarter; with a mean of 106 major procedures. Following WE with primary closure or flap repair, wound infection or dehiscence occurred in <1% of cases. When skin grafting was required non-take of >20% of the grafted area was observed in 5.9% of cases. Following SNB wound infection and significant seroma occurred in 1.8% of cases. RLND node counts were below the 90% standard in 4 of 409 procedures. In comparison, data extraction identified 405 RLNDs, with node counts below the 90% standard in eight procedures. Two of these patients had previously undergone surgery removing nodes from the field and two had gross coalescing disease with extensive extra-nodal spread. CONCLUSION: The quality standards proposed in 2008 have been validated long-term by high volume caseloads. The data presented provide standards by which melanoma surgeons can audit their surgical performance.

Survivorship care plans in cancer: a systematic review of care plan outcomes.

BACKGROUND: Eight years after the Institute of Medicine recommended survivorship care plans (SCPs) for all cancer survivors, this study systematically reviewed the evidence for their use. METHODS: Studies evaluating outcomes after implementation of SCPs for cancer survivors were identified by searching databases (MEDLINE, EMBASE and Cochrane). Data were extracted and summarised. RESULTS: Ten prospective studies (2286 survivors) met inclusion criteria (5 randomised controlled trials (RCTs)). Study populations included survivors of breast, gynaecological, colorectal and childhood cancer. Several models of SCP were evaluated (paper based/on-line, oncologist/nurse/primary-care physician-delivered and different templates). No significant effect of SCPs was found on survivor distress, satisfaction with care, cancer-care coordination or oncological outcomes in RCTs. Breast cancer survivors with SCPs were better able to correctly identify the clinician responsible for their follow-up care. One study suggested a positive impact on reducing unmet needs. Levels of survivor satisfaction with, and self-reported understanding of, their SCP were very high. Feasibility was raised by health professionals as a significant barrier, as SCPs took 1-4 h of their time to develop. CONCLUSIONS: Emerging evidence shows very few measurable benefits of SCPs. Survivors reported high levels of satisfaction with SCPs. Resource issues were identified as a significant barrier to implementation.

High discordance rates between sub-areolar and peri-tumoural breast lymphoscintigraphy.

OBJECTIVE: To test the hypothesis that sub-areolar (SA) lymphoscintigraphy (LSG) identifies the same sentinel node as peri-tumoural (PT) injections. BACKGROUND: It is commonly believed that all LSG techniques will identify the same sentinel lymph nodes (SLN) draining the breast. Hybrid imaging technology (SPECT/CT) allows accurate identification of the exact location of SLNs. Using SPECT/CT SA and PT LSG techniques were compared. METHOD: In a multi-centre trial 39 patients sequentially underwent LSG (SA followed by PT) separated by 2-7 days. Patients were referred by 4 surgeons to 3 LSG centres, with standardization of isotope (99mTc-antimony sulfide colloid), LSG and SPECT/CT evaluation techniques. LSG were evaluated for SLN concordance and degree of discordance in the axilla and internal mammary nodes (IMN). RESULTS: 39 eligible patients, median age 62 years, were recruited. Successful axillary SLN mapping for SA and PT injection techniques was 87% and 95% respectively. Successful internal mammary SLN mapping occurred with SA and PT LSG in 5% and 36% respectively. Discordance was identified in the IMN (39%) and axilla (21%), with an overall rate of discordance between SA and PT LSG of 56%. CONCLUSIONS: There is a high level of discordance in the localization of SLN by these commonly used LSG injection techniques. This discordance has implications for accuracy of axillary and extra-axillary staging and could impact on patient outcome.

Uptake and predictors of post-mastectomy reconstruction in women with breast malignancy--systematic review.

PURPOSE: There is enormous range in the reported rates of breast reconstruction. This study explored reasons for this variation by reviewing the published literature to examine rates of reconstruction, factors associated with uptake, and possible barriers. METHODS: A systematic review of the literature was performed. Eligible studies reported rates of breast reconstruction and variables associated with uptake in women undergoing mastectomy for early invasive or in situ breast malignancy. RESULTS: Twenty-eight eligible studies were included, reporting 159,305 cases of breast reconstruction in 940,678 women. In these studies 16·9% of women underwent immediate or delayed reconstruction (range 4·9-81·2%, median 23·3%). Variables associated with reconstruction were: patient/tumour factors (early stage, no adjuvant therapy, young age, white race, private insurance, higher education/income), surgeon/hospital factors and psychological/other factors (including patient choice). CONCLUSION: Rates of breast reconstruction were highly variable. Reconstruction appeared to be offered to a minority of women; around half took up the offer. The main reasons reported for no reconstruction included patient-related and adjuvant therapy-related factors. Clinicians' beliefs about reconstruction may be an important factor. Rates of reconstruction could be increased with early discussion of the options when mastectomy is chosen or required.

The management of cervical lymph nodes in patients with cutaneous melanoma.

BACKGROUND: The aim of this study was to review the management of cervical lymph nodes in patients with cutaneous melanoma and to analyze factors influencing prognosis. METHODS: This was a retrospective cohort study of patients who had cervical node surgery at the Sydney Melanoma Unit from 1990 to 2004. RESULTS: Of 716 patients who met the study criteria, 339 had a sentinel node biopsy (SNB) and 396 had a neck dissection. Locoregional recurrence occurred in 27.6 % of those undergoing therapeutic neck dissection and 60 % eventually developed distant metastases. Radiotherapy was given as adjuvant treatment in 110 of the patients who had a therapeutic neck dissection (41 %), but this was not associated with improved regional control (p = .322). Multivariate analysis showed that nodal positivity (p < .001) and primary tumor ulceration (p = < .027) were the most important predictors of locoregional recurrence and that primary tumor Breslow thickness (p = .009) and node positivity (p = .046) were the most important factors predicting survival. SNB-positive patients who underwent immediate completion lymphadenectomy had a 5-year survival advantage over those who had a therapeutic neck dissection for macroscopic disease (54 % vs 47 %, p = .028). CONCLUSIONS: Nodal status was the most important factor predicting disease-free and overall survival in patients with melanoma of the head and neck. Adjuvant radiotherapy was not associated with better locoregional control in the non-randomized cohorts of patients in this study.

SPECT/CT scans allow precise anatomical location of sentinel lymph nodes in breast cancer and redefine lymphatic drainage from the breast to the axilla.

BACKGROUND: Historical studies of lymphatic drainage of the breast have suggested that the lymphatic drainage of the breast was to lymph nodes lying in the antero-pectoral group of nodes in the axilla just lateral to the pectoral muscles. The purpose of this study was to confirm this is not correct. METHODS: The hybrid imaging method of SPECT/CT allows the exact anatomical position of the sentinel lymph node (SLN) in the axilla to be documented during pre-operative lymphoscintigraphy (LS) in patients with breast cancer. We have done this in a series of 741 patients. The Level I axillary nodes were defined as anterior, mid or posterior. This was related to the anatomical location of the primary cancer in the breast. RESULTS: A SLN was found in the axilla in 97.8% of our patients. Just under 50% of SLNs located in the axilla were not in the anterior group and lay in the mid or posterior group of Level I axillary nodes. There was a SLN in a single node field in 460 patients (63%), two node fields in 261(36%), three node fields in 6 and four node fields in 1 patient. CONCLUSION: Axillary lymphatic drainage from the breast is not exclusively to the anterior (or antero-pectoral) group of Level I nodes. SYNOPSIS: SPECT/CT lymphoscintigraphy shows that the breast does not always drain to the anterior group of Level I lymph nodes in the axilla but may drain to the mid axilla and/or posterior group in about 50% of patients with breast cancer regardless of the location of the cancer in the breast. These data redefine lymph drainage from the breast to axillary lymph nodes.

Accuracy of sentinel lymph node biopsy in large and multifocal/multicentric breast carcinoma--a systematic review.

BACKGROUND: While sentinel lymph node biopsy (SLNB) is established in the management of small unifocal breast cancer its role in management of multifocal (MF), multicentric (MC) and larger tumors is still evolving. METHODS: Medline was searched; studies meeting pre-determined criteria were included. Data were extracted and entered into evidence tables. RESULTS: Twenty six studies met inclusion criteria and reported data on accuracy; no randomized trials were identified. For MF cancers (n = 314 cases), success rate for identification of an SLN was 86-94%, SLN positivity rate 42-59%, false negative rate (FNR) 0-33% and overall accuracy 78-100%. For MC (n = 294 cases): success rate 92-100%, SLN positivity rate 25-61%, FNR 4-8% and accuracy 96-100%. For 'multiple breast cancer' (studies combining MF/MC cases; n = 996 cases): success rate 92-100%, SLN positivity rate 12-63%, FNR 0-25%, and accuracy 82-100%. For larger tumors (n = 1912 cases): success rate 86-100%, SLN positivity rate 49-77%, FNR 3-18% and accuracy 85-98%. For MC/MF and larger cancers overall non-SLN positivity rates were up to 82%; axillary recurrence rates were low but seldom reported. CONCLUSION: There are no randomized trials evaluating the safety of SLNB in MF/MC and larger breast cancers. Based on limited evidence, success rate and FNR appear to be similar to those for small unifocal cancers, however node positivity rates are higher and rates of non-SLN positivity are very high. Awareness of these issues is essential when recommending SLNB based axillary management for these higher-risk tumors.

Internal mammary lymph node metastasis in breast cancer: predictive models to assist with prognostic influence.

BACKGROUND: Metastatic breast cancer in the internal mammary nodes (IMN) indicates a poor prognosis. Several recent epidemiological surveys have determined a reduction in survival for patients with medial compared to lateral sector tumors attributing this to a higher rate of unrecognized IMN metastasis and hence these patients are undertreated with adjuvant therapy.(1-6) AIM: Through mathematical modeling based on large datasets we aim to quantify the impact on survival of IMN metastases at different tumor and axillary stages. METHODS: Mathematical models were created to estimate the survival of patients with and without IMN metastasis. It was assumed that the different rate of survival between medial and lateral sector breast cancers was a result of the differential rate of unrecognized IMN metastases with resultant under-staging and under treatment. We applied these models on a retrospective database analysis from the Surveillance, Epidemiology and End-Results (SEER) registries from 1994 to 2003. RESULTS: The 10-year odds of death (OOD) from breast cancer for patients with medial compared with lateral sector tumors ranged from 1.2 to 1.5 depending on stage. The predicted odds of breast cancer death for patients with unrecognized IMN metastases ranged from 2.4 to 20, with the highest OOD in the groups with small tumors and no axillary node metastasis. CONCLUSIONS: Through modeling we have been able to predict and quantify the significantly worse survival outcomes for patients with undiagnosed IMN metastasis.