Lymphovascular Invasion in Breast Cancer Essay
Lymphovascular Invasion in Breast Cancer Essay
First described in 1979, and initially believed to be an oncogene, p53 was the first tumour suppressor gene to be identified. p53 functions to eliminate and inhibit the proliferation of abnormal cells, thereby preventing neoplastic development. Abrogation of the negative growth regulatory functions of p53 occurs in many, perhaps all, human tumours. The p53 signalling pathway is in ‘standby’ mode under normal cellular conditions.
Pros and cons to essay on p53 and Its Mutants in Tumor Cell Migration and Invasion
In 1979, the p53 protein was first identified. Its discovery was a product of research into viral etiology and the immunology of cancer. In 1979, two groups simultaneously reported similar results about the existence of a protein of around 55 kDa that bound to large T antigen in various types of cancerous cells. The p53 protein was named from its protein weighing 53 KDa. The protein was actually regarded as an oncogene at that time, as many tumors produce abundant levels of this protein—a phenomenon that was not observed in normal tissue, and ectopic expression of newly cloned TP53 cDNA was shown to cooperate with oncogenic Ras to transform primary cells in culture. However, it was soon recognized that p53 overexpression could transform cells and promote in vivo tumor growth. Lymphovascular Invasion in Breast Cancer Essay. This discrepant finding can be attributed to the use of different mutated versions of p53, which originally derived from tumor cells. In 1989, the first murine wild type TP53 cDNA was cloned and it was found that there was an absence of oncogenic activity.
Citations about essay on Lymphovascular Invasion and Histologic Grade Are Associated With Specific Genomic Profiles in Invasive Carcinomas of the Breast
Recent studies point to the significance of DNA copy number aberrations (CNAs) in the etiology of cancer with the number and complexity of these aberrations being indicative of overall prognosis [Bergamaschi A, Kim YH, Wang P, 2006]. CNA investigation may assist the identification of regions containing oncogenes and tumor suppressor genes. Grade III breast tumors frequently harbor gains at 3q and 5p, and 8q amplifications. More recently, a 19q12 amplification was detected, primarily associated with grade III breast tumors in estrogen-negative samples, which encompasses the CCNE1 gene, among others. Lymphovascular Invasion in Breast Cancer Essay. Grade I tumors show less complex karyotypes with recurrent gain of 16p, as found in estrogen-positive tumors [Natrajan R, Lambros MB, 2009]. However, to the best of our knowledge, no study has investigated the genomic profile of CNAs related to the presence of LVI in breast carcinomas.
Conclusion to The p53 Pathway in Breast Cancer Essay
Obviously, mutant p53s, however, are very potent inducers of the metastatic phenotype. This owes, at least in part, to their ability to act via p63 to drive invasive-type migration. The contribution of TGF-β signaling and the trafficking of integrins and growth factor receptors to mutant p53-driven invasion suggests some interesting new candidates for antimetastatic drug development. However, many questions remain as to how the elements of this pro-invasive program are connected to one another. In particular, we anticipate that the link between p63 and the cell’s migratory and trafficking machinery will provide fertile ground for those interested in targeting the metastatic process.
References
Natrajan R, Lambros MB, Rodríguez-Pinilla SM, Moreno-Bueno G, Tan DS, Marchió C, et al. Tiling path genomic profiling of grade 3 invasive ductal breast cancers. Clin Cancer Res. 2009;15:2711–22.
Bergamaschi A, Kim YH, Wang P, Sørlie T, Hernandez-Boussard T, Lonning PE, et al. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosom Cancer. 2006;45:1033–40.
Hirose Y, Sasaki H, Abe M, Hattori N, Adachi K, Nishiyama Y, et al. Subgrouping of gliomas on the basis of genetic profiles. Brain Tumor Pathol. 2013;30:203–8.
Various prognostic indicators have been investigated in neoadjuvant chemotherapy (NAC) treated invasive breast cancer (BC). Our study examines if lymphovascular invasion (LVI) is an independent predictor of survival in women receiving NAC. Lymphovascular Invasion in Breast Cancer Essay.
Methods
We performed a retrospective analysis in 166 women with operable invasive BC who underwent adriamycin (A) and taxane (T)-based NAC between 2000-2013. Presence of LVI was noted in breast excisions following NAC. Associations between progression-free and overall survival and LVI and other clinicopathologic variables were assessed.
Results
Median follow-up was 31 months (range 1.4-153 months) with a total of 56 events and 24 deaths from any cause. LVI was found in 74 of 166 patients (45%). In univariate analysis, presence of LVI was associated with worse progression-free survival (HR 3.37 95% CI 1.87-6.06, p<0.01) and overall survival (HR 4.35, 95% CI 1.61-11.79, p<0.01). In multivariate models adjusting for breast cancer subtype, LVI was significantly associated with a decrease in progression-free survival (HR 3.76 95% CI 2.07-6.83, p<0.01) and overall survival (HR 5.70 95% CI 2.08-15.64, p<0.01).Lymphovascular Invasion in Breast Cancer Essay. When stratified by subtype, those with hormone receptor or HER2 positive BCs with no LVI had the most favorable progression-free and overall survival. Those with both LVI and triple negative BC had the worst progression-free and overall survival.
Conclusions
LVI is an important prognostic marker and is associated with worse clinical outcome in breast cancer patients receiving NAC.
Neoadjuvant chemotherapy (NAC) is a mainstay of treatment for operable and locally advanced breast cancer.[1-4] Several markers have been identified to help predict response to NAC including hormone receptor status, human epidermal growth factor receptor (HER-2) status, histological grade, tumor size, and nodal involvement.[5-10] In addition, response to NAC has been associated with tumor biology, with tumors achieving a pathologic complete response (pCR) being associated with a more favorable clinical outcome compared to those with residual disease.[3,11-15]
Lymphovascular invasion (LVI) is defined as carcinoma cells present within a definite endothelial-lined space (either lymphatic vessels or blood vessels) in the breast.[16,17] While the mechanism of lymphatic metastasis is still largely unknown,[18] the presence of LVI has been extensively studied as a prognostic indicator for progression-free and overall survival in invasive breast cancer. Some studies have shown LVI to be a marker for increased risk of axillary nodal metastases, distant metastases, and death.[19,16,20-22] Yet, others have shown that it is not an independent predictor of overall survival[23] and that its role may be limited to only high-risk groups such as those with positive nodes, tumor size >2cm, high grade, hormone receptor negative tumor, or age <35 years.[24]
The role of LVI as a prognostic marker in NAC treated breast cancer remains unclear. Some studies have shown that LVI is associated with “chemoresistant” cancers[25] and that its absence on core biopsies is associated with a complete pathological response (pCR) and improved survival.[7] However, few studies have examined the role of LVI as an independent predictor of survival with adriamycin (A) and taxane (T)-based NAC regimens.
Our study seeks to evaluate the association of LVI with progression free and overall survival in patients with operable breast cancer treated with NAC. Our hypothesis is that LVI is an independent predictor of survival in NAC treated patients. Lymphovascular Invasion in Breast Cancer Essay.
Methods
Patient Population
In accordance with Columbia University Medical Center (CUMC) IRB approved protocol (IRB # AAAJ8512), clinical database queries and physician referral were used to identify all women with invasive carcinoma of the breast who received at least part of their care at CUMC and underwent NAC between 2000-2013. Of the 382 patients identified, 33 were excluded for having no electronic/paper chart records (n=9) or incomplete records (n=24) that precluded full data collection. Of the remaining 349, six patients were excluded due to metastatic disease at diagnosis, 109 were excluded as they received no NAC upon further review, and an additional three were excluded as they received non-traditional NAC regimens (1 Mitomycin/Vinorelbine, 1 Herceptin/Vinorelbine, and 1 Cyclophosphamide/Methotrexate/Fluorouracil). Of the remaining 231 women who received adriamycin (A) or taxane (T)-based NAC, 14 were excluded, as they did not have a surgical pathology report performed at CUMC, 34 were excluded, given that none of their pathology reports addressed LVI, and 17 were excluded as the pathology reports could not confer a clear diagnosis of LVI (“cannot be ruled out”). Thus, a total of 166 women were assessed in this analysis. (Figure 1).
Selection of Patients
Clinical and Pathological Variables
Clinical and pathological data were abstracted from the medical record by two independent researchers. All data were double-verified, and any discrepancies were resolved by oncologists EC and KK. Age was defined in years at pathological diagnosis and was stratified into <50 years of age and ≥50 years of age. Tumor size was defined as the largest dimension on any imaging modality prior to any treatment and was stratified at 0-5cm and >5cm. Grade was defined as the highest grade seen on any biopsy and was defined as low/intermediate grade (grade 1 and 2) and high grade (grade 3). Lymphovascular Invasion in Breast Cancer Essay.Estrogen receptor (ER) and progesterone receptor (PR) positivity was defined as 10% or greater expression on any biopsy, as the majority of older pathological reports only specified <10% (negative) or ≥10% (positive). However, in accordance with American Society of Clinical Oncology/College of American Pathologist (ASCO/CAP) guidelines from 2010, a separate analysis was also performed where estrogen receptor (ER) and progesterone receptor (PR) positivity was defined as 1% or greater expression on any biopsy.[26] Tumors were considered HER2-positive if they were 3+ by immunohistochemistry (IHC) or demonstrated gene amplification with a ratio of Her-2 /CEP17 ≥2 by in situ hybridization on either the core biopsy or surgical pathology specimen.[27] Based on prior studies, subtype groups were defined as a) hormone receptor positive (ER and/or PR positive) and HER2 negative, b) HER2 positive regardless of hormonal status, and c) triple negative (ER, PR, and HER2 negative).[28] Clinical and pathological staging was determined based on the American Joint Committee on Cancer (AJCC) TNM Staging Manual, 7th edition. Pathological complete response (pCR) was defined as no residual invasive disease in the breast or lymph nodes on surgical pathology specimens (ypT0/Tis ypN0). To assess pathological response and nodal status after NAC, women were divided into three groups: pathological complete response (ypT0/Tis ypN0), those with invasive disease in the breast only (ypT+ ypN0), and those with any invasive disease in lymph nodes (any T and N+), based on prior studies.[29]
LVI was defined based on the CUMC standard pathological definition as presence of carcinoma cells within a definite endothelial-lined space (either lymphatic or blood vessels). This was rarely verified using D2-40 immuno-histochemical stain for lymphatic endothelium and CD31 for endothelium of all vessels. The presence of LVI was evaluated in post-NAC surgical pathology specimens, as well as pre-therapy core biopsies, although the latter less consistently. As only 70 core biopsies addressed the presence or absence of LVI and absence of LVI on core biopsies may represent sampling error, this data element is less reliable.Lymphovascular Invasion in Breast Cancer Essay. However, there was some agreement (46 out of 70, 66% k=0.4) between the two with 12 out of 70 surgical pathology specimens showing LVI that was not seen on the core biopsy and only 12 out of 70 core biopsies showing LVI that was not seen on surgical pathology specimens. Of the 12 where LVI was seen on the core but not surgical pathology biopsies, three surgical pathology biopsies showed pCR, three showed residual node-negative tumor, and six showed nodal disease only with no residual tumor after NAC. As with prior studies[19], 17 were excluded as the pathologist could not rule out LVI. All pathology specimens were interpreted by trained surgical pathologists.
All women received A-based, T-based, or A/T-based NAC. Women were considered to have received radiation therapy (XRT) if they received any type of whole breast radiation with or without nodal radiation. Hormonal therapy was defined as treatment with any selective estrogen-receptor modulator (SERM) or aromatase inhibitor (AI). Surgery type was stratified into lumpectomy or mastectomy with or without lymph node dissection.
Statistical Analysis
Chi square, Fisher’s exact and t-tests were used to compare relevant clinical and pathological variables according to presence or absence of LVI. Progression-free survival was based on the STEEP criteria[30], and events were defined as any local/regional or distant metastasis, contralateral invasive breast cancer (excluding in-situ disease), any secondary, non-breast, invasive cancer, and/or death by any cause. Progression free survival (PFS) and overall survival (OS) were calculated in months from date of definitive surgery to date of first event or death (for OS) or last follow-up in those women without events. Kaplan Meier survival analysis and the log-rank statistic were used to estimate survival differences between groups based on clinically relevant variables. Cox proportional hazard models were used to assess the association of LVI and PFS and OS after adjusting for other covariates, including age, tumor size, grade, subtype, and post-surgical nodal status. Stratified analyses were performed using the a priori determined variable of subtype (triple negative vs. not triple negative). All analyses were performed using SAS 9.4 and STATA 12.0 with significance defined as a two-sided p-value of 0.05. Lymphovascular Invasion in Breast Cancer Essay.
Results
Demographics
Of the 166 women, 74 had evidence of LVI on pathology (n=59 with invasion into lymphatics and n=15 with invasion into lymphatics and veins), and 92 had no evidence of LVI on post-NAC surgical pathology samples. Of the 166 women, 18 received A-based, 27 received T-based, and 121 received A/T-based NAC. All women completed the entire course of NAC with the exception of four women who had their NAC terminated early due to progression of disease (n=2), long delays in treatment (n=1) and progression as well as toxicity (n=1).
Mean age was 52 in the LVI group and 51 in the no LVI group (Table 1). In both groups, the majority of women self-reported as non-Hispanic White or Hispanic and had invasive ductal carcinomas, tumors between 0-5cm in size, and high-grade breast cancers. Both groups had a similar distribution of subtypes with hormone receptor positive/HER2 negative being the most common (LVI, n=37; no LVI, n=35), followed by HER2 positive (LVI, n=22; no LVI, n= 36), then triple negative breast cancer (TNBC) (LVI, n=15; no LVI, n= 21). One patient with HER2 positive breast cancer did not receive neoadjuvant or adjuvant Herceptin as she was lost to follow-up soon after initial medical oncologist visit.Lymphovascular Invasion in Breast Cancer Essay. The LVI group had no women who achieved pCR, as expected based on our definition of pCR, and in the no LVI group, n=34 (36%) patients achieved pCR (p<0.001). The LVI group also had significantly higher rates of mastectomy (p<0.001) and post-operative radiation therapy (p-0.006).
Table 1
Baseline Characteristics by Lymphovascular (LVI) Status
| Variable | LVI (n=74) | No LVI (n=92) | p-value* |
|---|---|---|---|
| Mean Age (SD), years | 52 (1.6) | 51 (1.1) | 0.72 |
| Race | |||
| Non-Hispanic White | 29 (39%) | 30 (33%) | 0.34 |
| Black | 10 (14%) | 24 (26%) | |
| Hispanic | 30 (41%) | 33 (36%) | |
| Other | 1 (1%) | 2 (2%) | |
| Unknown | 4 (5%) | 3 (3%) | |
| Type | |||
| Ductal Carcinoma | 60 (81%) | 77 (86%) | 0.33 |
| Lobular Carcinoma | 5 (7%) | 7 (8%) | |
| Other | 9 (12%) | 5 (6%) | |
| Size | |||
| 0-5cm | 55 (76%) | 74 (80%) | 0.53 |
| >5cm | 17 (24%) | 18 (20%) | |
| Grade | |||
| Low (I & II) | 25 (34%) | 29 (33%) | 0.911 |
| High (III) | 49 (66%) | 59 (67%) | |
| Subtype | |||
| Hormone Receptor+/HER2− | 37 (50%) | 35 (38%) | 0.29 |
| HER2 + | 22 (30%) | 36 (39%) | |
| Triple Negative | 15 (20%) | 21 (23%) | |
| Pathological Staging | |||
| pCR** | 0 (0%) | 34 (36%) | <0.001 |
| T+, N − | 9 (12%) | 29 (32%) | |
| Node + | 65 (88%) | 29 (32%) | |
| Surgery Type | |||
| Lumpectomy | 11 (15%) | 40 (44%) | <0.001 |
| Mastectomy | 63 (85%) | 51 (56%) | |
| Adjuvant Radiation | |||
| Yes | 70 (97%) | 74 (84%) | 0.006 |
| No | 2 (3%) | 14 (16%) | |
| Adjuvant Hormonal Therapy | |||
| Yes | 53 (75%) | 54 (68%) | 0.40 |
| No | 18 (25%) | 25 (32%) | |
| Neoadjuvant/Adjuvant Herceptin | |||
| Yes | 19 (27%) | 36 (52%) | 0.003 |
| No | 51 (73%) | 33 (48%) |
Survival Analysis
Median follow-up was 31 months (range 1.4-153 months). There were a total of 56 events with 50 of them being recurrence or progression of invasive breast cancer (13 local and 37 distant), 2 being new invasive primary cancers (1 colon and 1 laryngeal) and 4 being death from any cause without evidence of recurrence or progression. Of the 13 local recurrences, six were recurrences in the same breast, three in the lymph nodes, and four in the chest wall. Ten of these women received radiation therapy while two did not (data missing for last woman). There were 24 overall deaths from any cause.
On univariate analysis, presence of LVI was significantly associated with worse PFS (HR 3.37; 95% CI 1.87-6.06; p < 0.01) and OS (HR 4.35; 95% CI 1.61-11.79; p <0.01). Subtype (triple negative as compared to hormone receptor+/HER2- breast cancer) was also significantly associated with worse PFS (HR 2.00; 95% CI 1.06-3.75; p = 0.03) and OS (HR 4.23; 95% CI 1.47-12.17; p < 0.01), (Table 2.1 and 2.2). In addition to presence of LVI and subtype, the presence of lymph node involvement (nodal disease) at the time of definitive surgery (vs. pCR, HR 2.80; 95% CI 1.10-7.11; p = 0.03) was also significantly associated with worse PFS, although post-surgical nodal status itself was not overall significantly associated with either PFS or OS (Table 2.1 and 2.2). Age, size, grade and radiation therapy were not significantly associated with either PFS or OS. Lymphovascular Invasion in Breast Cancer Essay.
Table 2.1
Univariate analysis of predictors of progression-free survival (time from definitive surgery)
| No event
|
Event
|
|||||
|---|---|---|---|---|---|---|
| Characteristics | No. | % | No. | % | HR (95% CI) | P-value |
| Total patients | 110 | 66 | 56 | 34 | ||
| Age (continuous) | 1.00 (0.97, 1.02) | 0.6306 | ||||
| Age group | ||||||
| <50 years | 46 | 61 | 30 | 39 | 1 | – |
| 50+ years | 64 | 71 | 26 | 29 | 0.75 (0.44, 1.28) | 0.2911 |
| LVI | ||||||
| No | 75 | 82 | 17 | 18 | 1 | – |
| Yes | 35 | 47 | 39 | 53 | 3.37 (1.87, 6.06) | <0.0001* |
| Subtype | 0.0352* | |||||
| Hormone positive/HER2 | 51 | 71 | 21 | 29 | 1 | – |
| HER2 positive | 43 | 74 | 15 | 26 | 0.89 (0.45-1.77) | 0.7481 |
| TNBC | 16 | 44 | 20 | 56 | 2.00 (1.06-3.75) | 0.0314* |
| Post-surgical stage and nodal | 0.0610 | |||||
| pCR | 29 | 85 | 5 | 15 | 1 | – |
| T+, N negative | 29 | 76 | 9 | 24 | 1.76 (0.59, 5.26) | 0.3119 |
| N+, regardless of T | 52 | 55 | 42 | 45 | 2.80 (1.10, 7.11) | 0.0303* |
| Size (continuous) | 1.05 (0.92, 1.20) | 0.4745 | ||||
| Size | ||||||
| 0-5 cm | 83 | 64 | 46 | 36 | 1 | – |
| >5 cm | 27 | 77 | 8 | 23 | 0.74 (0.35, 1.57) | 0.4369 |
| Grade | ||||||
| low | 41 | 76 | 13 | 24 | 1 | – |
| High | 66 | 61 | 42 | 39 | 1.79 (0.96, 3.35) | 0.0682 |
Abbreviations: HR, Hazard ratio; CI, confidence interval; LVI: lymphovascular invasion; pCR: pathologic response; TNBC: Triple Negative Breast Cancer
Table 2.2
Univariate analysis of predictors of overall survival (time from definitive surgery)
| Alive
|
Dead
|
|||||
|---|---|---|---|---|---|---|
| Characteristics | No. | % | No. | % | HR (95% CI) | P-value |
| Total patients | 142 | 86 | 24 | 14 | ||
| Age (continuous) | 1.02 (0.99, 1.05) | 0.2757 | ||||
| Age group | ||||||
| <50 years | 66 | 87 | 10 | 13 | 1 | – |
| 50+ years | 76 | 84 | 14 | 16 | 1.29 (0.55, 3.01) | 0.5620 |
| LVI | ||||||
| No | 87 | 95 | 5 | 5 | 1 | – |
| Yes | 55 | 74 | 19 | 26 | 4.35 (1.61, 11.79) | 0.0039* |
| Subtype | 0.0898 | |||||
| Hormone positive/HER2 negative | 67 | 93 | 5 | 7 | 1 | – |
| HER2 positive | 51 | 88 | 7 | 12 | 1.52 (0.46-4.97) | 0.4927 |
| TNBC | 24 | 67 | 12 | 33 | 4.23 (1.47-12.17) | 0.0076* |
| Post-surgical stage and nodal status | 0.1434 | |||||
| pCR | 33 | 97 | 1 | 3 | 1 | – |
| T+, N negative | 35 | 92 | 3 | 8 | 2.97 (0.31, 28.59) | 0.3470 |
| N+, regardless of T | 74 | 79 | 20 | 21 | 5.89 (0.79, 44.13) | 0.0844 |
| Size (continuous) | 0.98 (0.79-1.22) | 0.8585 | ||||
| Size | ||||||
| 0-5 cm | 110 | 85 | 19 | 15 | 1 | – |
| >5 cm | 32 | 91 | 3 | 9 | 0.65 (0.19-2.18) | 0.4802 |
| Grade | ||||||
| low | 49 | 91 | 5 | 9 | 1 | – |
| High | 89 | 82 | 19 | 18 | 1.96 (0.72, 5.32) | 0.1854 |
Abbreviations: HR, Hazard ratio; CI, confidence interval; LVI: lymphovascular invasion; pCR: pathologic complete response; TNBC: Triple Negative Breast Cancer
On multivariate analysis, presence of LVI was an independent predictor for a worse PFS survival (HR 3.76, 2.07-6.83, p<0.01) and worse OS (HR 5.70, 2.08-15.64, p<0.01) after adjusting for subtype (Table 3). TNBC was an independent predictor of worse PFS (HR 2.59, 1.37-4.90, p<0.01) and OS (HR 6.06, 2.08-17.68, p<0.01) after adjusting for LVI.
A separate analysis using a cutoff of ≥1% for ER/PR positivity only affected the subtype of 3 women, changing them from TNBC to hormone receptor positive. On univariate analysis using the cutoff of ≥1%, TNBC, as compared to hormone receptor +/HER2- breast cancer, was significantly associated with worse PFS (p=0.05) and a trend towards worse OS (p=0.08). On multivariate analysis both presence of LVI (HR 3.88, 2.13-7.09, p<0.01) and TNBC, as compared to hormone receptor +/HER2- breast cancer, (HR 2.51, 1.31-4.80, p<0.01) were significantly associated with worse PFS. Presence of LVI (HR 5.85, 2.10-16.27, p<0.01) and TNBC, as compared to hormone receptor +/ HER2- breast cancer, (HR 4.41, 1.60-12.21, p<0.01) were also significant predictors of worse OS.
When stratified by triple negative status, those with no TNBC and no LVI had the most favorable PFS and OS. The presence of LVI was associated with a PFS and OS detriment to a similar extent as having TNBC. The presence of both TNBC and LVI was associated with the least favorable survival outcomes (Figure 2.1 and 2.2). Lymphovascular Invasion in Breast Cancer Essay.
