Abstract
Introduction
The risk factors of breast cancer overlap with those of peripheral arterial disease (PAD), with increasing prevalence. In addition, there is under-utilization of risk factor modification measures in patients with PAD.
Materials and Methods
Electronic medical records of breast cancer patients with ICD 9/10 codes for PAD spanning 10 years from June 1, 2009 to June 1, 2019 were reviewed.
Results
248 patients, 98% women, with median age of 75, and median follow up of 76 months were included. PAD risk factors were identified as smoking (44%), obesity (38%), hyperlipidemia (68%), hypertension (HTN) (74%) and diabetes (42%). Overall, survival was significantly impacted by smoking (p = 0.0301) and HTN (p = 0.0052). In Cox proportion hazard ratio regression, HTN (overall death HR 3.1784 95% CI 1.0291–6.7490 p = 0.0070, cancer-related death HR 2.6354 95% CI 1.0291–6.7490 p = 0.0434) and Smoking (overall death HR 1.7452 95% CI 1.0707–2.8444 p = 0.0255, cancer-related death HR 2.7432 95% CI 1.4190–5.3030 p = 0.0027) were predictors of overall death and cancer-related death.
48% of all patients were on statin and 54% of all patients were on antiplatelet therapies. 62% of current smokers were offered a smoking cessation program, 27% of obese patients were offered a nutrition consult, 42% of diabetic patients had blood glucose controlled, and 54% of HTN patients had Blood Pressure (BP) controlled.
Conclusion
Smoking and HTN are risk factors associated with decreased survival and predictive of overall death and cancer-related death. In this population, risk factor modification was under-utilized.
MicroAbstract
Peripheral arterial disease and breast cancer have overlapping risk factors. Single-arm retrospective study with 248 patients, 98% women, median age of 75, and median follow up of 76 months was performed. Survival was impacted by smoking (p = 0.0301) and HTN (p = 0.0052). HTN and Smoking were also predictors of overall and cancer-related death. Risk factor modification was underutilized.
Introduction
Over 200 million people have been diagnosed with peripheral arterial disease (PAD) with an age-adjusted prevalence of 12%.1 The risk factors of PAD are advanced age, smoking, diabetes, hypertension (HTN), hyperlipidemia (HLP), obesity, and sedentary lifestyle which overlap with risk factors for cancer. Because of the overlapping risks, PAD patients have an increased risk of developing cancer. A prospective study with 6,172 PAD patients demonstrated a 19% higher risk of developing cancer compared to the general population.2 Another study with 6,600 patients with lower limb arterial thrombosis, demonstrated a 2.5% rate of diagnosis of cancer in a 6 month period and 17.9% after 20 years, with increased all-cause mortality after diagnosis of colon, lung, bladder, and breast cancer.3
In addition, cancer patients may be at risk of developing PAD due to cancer therapies. External beam radiation and certain chemotherapy drugs such as Tyrosine kinase inhibitors (TKIs) targeting Bcr-Abl nilotinib and ponatinib, cisplatin-based drugs, and interferon-α may cause PAD by damaging the endothelium.4 Furthermore, cancer treatment may cause risk factors of PAD, as in the case of Bevacizumab, a drug inhibiting the vascular endothelial grown factor (VEGF) signaling pathway carrying a 70% risk of developing hypertension.5
Although the prevalence of breast cancer patients with PAD is not well established, the risk factors of breast cancer (advanced age, HLP, obesity, sedentary lifestyle) closely overlap those of PAD, and the prevalence of these risk factors is rising.2,7 In a study with 59,673 breast cancer patients evaluating co-morbidities and risk factors, PAD impacted both breast cancer-specific and overall survival.6 We examine the impact of risk factors on outcome of breast cancer patients with PAD. In addition, given the propensity of under-utilization of risk factor modification measures in patients with PAD compared to patients with other forms of cardiovascular disease, we also examine the rate of use of risk factor modification.8,9,10
Materials and Methods
Institutional Review Board approved this single-arm retrospective study spanning 10 years from June 1, 2009 to June 1, 2019. Database review was performed utilizing the ICD-9: 443.9 and ICD-10 173.9 codes for Peripheral Arterial Disease and Peripheral Vascular Disease, respectively, of patients seen at our institution with a diagnosis of Breast cancer. Patients with diagnoses of additional cancers were excluded from the study. Electronic medical records – including physician notes, medication lists, ICD9/10 codes, and death notifications – were reviewed to obtain demographics, risk factors, use of risk factor modifications, and mortality. Risk factors included HTN, HLP, Smoking (both previous and current grouped as Smoking), DM, and obesity. Risk factor modification analysis included assessing the use of antiplatelet therapy and statins, nutrition consult referral for obese patients, smoking cessation referral, Glucose control for DM patients, and BP control for HTN patients, was also obtained from the electronic medical records – including assessing medication lists, referral orders, labs, and outpatient vital signs documentation. Glucose control was determined by Hgba1c (controlled is <7), fasting glucose (controlled is <126 mg/dL), or random glucose (< 200 mg/dL) over last 3 months recorded. Blood pressure control was determined by a BP of <140/90 over the last 5 outpatient clinic visits. LDL levels were not considered specifically as societal guidelines encourage all patients to be on statins (LDL-lowering medication). Antiplatelet and statin therapy compliance and smoking abstinence in patients with smoking cessation referral was inconsistently documented in the electronic medical record therefore assessment of these factors was not included in this study.
Risk factor-specific survival and risk-factor modification-specific survival were calculated using Kaplan-Meier estimates. DM and HLP demonstrated significant impact on survival in later months, therefore additional analysis was made for these two factors assessing survival after 200 months. Smoking and HTN both demonstrated impact on survival therefore the effect of medical optimization (use of statin, antiplatelet and previous smoker rather than current smoker in Smoking patients and use of statin, antiplatelet and HTN control for HTN patients) on the survival of Smoking and HTN patients was also assessed. Overall death and cancer-related death predictors were calculated with Cox proportional hazard ratio regression. Odds of cancer death vs. competing risk of other-related death were calculated utilizing odds ratios and logistic regression. MedCalc Statistical Software version 19.2.1 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2020) was used for analysis. Significance was set at p = <0.05.
Results
Out of 5,237 patients with any cancer seen at our institution between the study period, 248 patients were eligible for inclusion. 98% were women, with median age of 75. Median follow up was 76 months. 23 patients (9.3%) had Stage 0 disease (Ductal Carcinoma in Situ), 114 (46.0%) had Stage 1 disease, 66 (26.6%) had Stage 2 disease, 10 (4.0%) had Stage 3 disease, and 35(14.1%) had Stage 4 (metastatic) disease. 137 patients had no lymph node involvement or metastatic disease and 111 patients had lymph node involvement and/or metastatic disease. See Demographics in Table 1.
Table 1.
Demographics and clinical factors of patients included in our study.
| Total patients, n | 248 |
| Mean Age ± SD, years | 73 ± 11 |
| Median Age | 75 |
| Female, % | 98 |
| White, % | 77 |
| Black, % | 14 |
| Asian, % | 2 |
| Smoking, % | 44 |
| Obesity, % | 38 |
| HLP, % | 68 |
| HTN, % | 74 |
| DM, % | 42 |
| Stage 0, % | 9 |
| Stage 1, % | 46 |
| Stage 2, % | 27 |
| Stage 3, % | 4 |
| Stage 4, % | 14 |
| Pts on anti-platelet therapy, % | 54 |
| Pts on statin, % | 48 |
| DM pts, controlled, % | 42 |
| HTN pts, controlled, % | 54 |
| Obese pts, nutrition offered, % | 27 |
| Smokers, cessation offered, % | 62 |
| Cancer deaths, n | 39 |
| Noncancer deaths, n | 27 |
| Mean ± SD Follow up, months | 108 ± 102 |
| Median Follow up, months | 76 |
PAD risk factors were identified as smoking (44%), obesity (38%), hyperlipidemia (68%), hypertension (74%) and diabetes (42%). Overall, survival was significantly impacted by smoking (p = 0.0301) and HTN (p = 0.0052) (Figure 1). The other risk factors including obesity, hyperlipidemia, and diabetes did not impact survival as shown in Figure 1. However, two additional risk factors – hyperlipidemia (p = 0.0153) and diabetes (p = 0.0409) become significant after 200 months (Figure 1 cc and Figure 1 ee).
Figure 1 a.
Effect of Obesity on overall survival
Figure 1 cc.
Effect of Hyperlipidemia on overall survival after 200 months
Figure 1 ee.
Effect on Diabetes on overall survival after 200 months.
48% of all patients were on a statin and 54% of all patients were on antiplatelet therapy. 62% of current smokers were offered a smoking cessation program. 27% of obese patients were offered a nutrition consult. 42% of diabetic patients had blood glucose controlled. 54% of HTN patients had BP controlled. (See Figure 2).
Figure 2.
Bar graph demonstrating % of patients with risk factor modification
In the follow up period, 66 patients died. 39 patients died from cancer-related causes and 27 died from other causes. In Cox proportion hazard ratio regression, HTN (overall death HR 3.1784 95% CI 1.0291–6.7490 p = 0.0070, cancer-related death HR 2.6354 95% CI 1.0291–6.7490 p = 0.0434) and Smoking (overall death HR 1.7452 95% CI 1.0707–2.8444 p = 0.0255, cancer-related death HR 2.7432 95% CI 1.4190–5.3030 p = 0.0027) were predictors of overall death and cancer-related death Table 2 and 3). Risk factor modification did not have a significant impact on survival in our cohort (Kaplan-Meier curves not demonstrated). Medical optimization in Smokers and HTN patients did show a nonsignificant trend in improved survival (Figure 3a and 3b).
Table 2.
Cox proportional-hazard ratio demonstrates HTN and Smoking as predictors of overall death. Other variables (DM, HLP, and Obesity) not included in the model due to P > 0.05.
| Variable | β | standard error | P | hazard ratio exp(β) | 95% CI of exp(β) |
|---|---|---|---|---|---|
| HTN | 1.1564 | 0.4286 | 0.0070 | 3.1784 | 1.3722 to 7.3621 |
| Smoking | 0.5569 | 0.2492 | 0.0255 | 1.7452 | 1.0707 to 2.8444 |
Table 3.
Cox proportional-hazard ratio demonstrates HTN and Smoking as predictors of cancer death. Other variables (DM, HLP, and Obesity) not included in the model due to P > 0.05.
| Variable | β | standard error | P | hazard ratio exp(β) | 95% CI of exp(β) |
|---|---|---|---|---|---|
| HTN | 0.9690 | 0.4798 | 0.0434 | 2.6354 | 1.0291 to 6.7490 |
| Smoking | 1.0091 | 0.3363 | 0.0027 | 2.7432 | 1.4190 to 5.3030 |
Figure 3a.
Effect on survival with medical optimization in Smokers.
Figure 3b.
Effect on survival with medical optimization in HTN patients.
Out of 66 deaths, where 39 deaths were from cancer-related reasons, logistic regression analysis and odds ratios were used to assess the impact of PAD risk factors and lymph node status/metastases on cancer-related death vs. competing risk of other cause of death. Only lymph node involvement and metastases (OR 3.2353 95% CI 1.0050–10.4148, p = 0.0490) were indicative of cancer death vs other cause of death (Table 4).
Table 4.
Odds ratio of risk factors and Lymph node status/metastasis to determine cause of death (cancer-related death vs. other-related death).
| Odds ratio | 95% CI | P | |
|---|---|---|---|
| HTN | 0.2615 | 0.02878 to 2.3769 | 0.2336 |
| Smoking | 2.2321 | 0.8194 to 6.0807 | 0.1163 |
| Obesity | 0.4364 | 0.1497 to 1.2718 | 0.1286 |
| HLP | 0.3913 | 0.1109 to 1.3807 | 0.1447 |
| DM | 0.4092 | 0.1493 to 1.1219 | 0.0825 |
| LN involvement or metastases | 3.2353 | 1.0050 to 10.4148 | 0.0490 |
Discussion
This study highlights the impact of overlapping risk factors on survival in breast cancer patients with PAD and demonstrates the poor utilization of risk factor modification in this at-risk cohort which is concerning. Of note, there are knowledge gaps and poor awareness about PAD and its risk factors in women – the gender that is also largely affected by breast cancer – with studies demonstrating greater functional impairment and lower management rates in women with PAD compared to counterparts.11,12 In our study, HTN and smoking, two prominent risk factors of PAD, impacted overall survival and breast cancer-specific survival in this cohort of breast cancer patients with PAD. In a meta-analysis of 13 prospective studies, hypertension was associated with a 7% higher risk of developing breast cancer.13 Suggestive mechanisms for this relationship involve blocking of apoptosis, adipose tissue related hypoxia and chronic inflammation promoting formation of reactive oxygen species.14 Moreover, a meta-analysis with 12 studies and 400,944 women diagnosed with primary invasive breast cancer demonstrated a hazard ratio (HR) for breast cancer associated death in former smokers of 1.02 (95% CI 0.93–1.12) and for current smokers 1.28 (95% CI 1.17–1.41) when compared to never smokers. For all-cause death, the HR for former smokers was 1.12 (95% CI 1.04–1.19), and for current smokers 1.52 (95% CI 1.32–1.76).15 In our study, other risk factors, namely DM and HLP, interestingly, became significant later in the patient’s life. Advances in breast cancer management has resulted in significant improvement in cancer survival in patients with breast cancer. In a recent article published in the Journal of American College of Cardiology, an initiative to manage cardiovascular risk factors in breast cancer patients acknowledges the competing causes of death in these patients given current greater breast cancer survival.16
In our cohort, risk-factor modification was alarmingly under-utilized. Society and task-force guidelines for PAD management extensively discuss risk factor modification.17 All PAD patients should be on anti-platelet therapy and on a statin. The patients with HTN, should have a BP < 140/90, and Blood glucose should be controlled in Diabetics with a goal of Hgba1c goal of < 7. Weight loss should be addressed, and physical exercise encouraged in overweight/obese patients or patients with sedentary lifestyle. Studies such as the landmark PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) study and the Reduction of Atherothrombosis for Continued Health (REACH) registry have shown the under-recognition of PAD and under-utilization of risk factor modification in PAD patients compared to patients with coronary artery disease or cerebrovascular disease.18,19 Smoking was the risk factor best addressed with 62% of smokers offered smoking cessation in our cohort. However, only 54% of patients were on antiplatelet therapy and less than half were on a statin. Less than half of diabetics had blood sugar under control, only 54% of patients had blood pressure controlled, and only 27% of obese patients were offered a nutrition consult. Our study only showed a trend towards improved survival when medical optimization (all applicable risk factor modifications combined) was used in Smokers and HTN patients, probably because of the study’s small size. However, multiple large randomized, retrospective, and case-controlled studies and registries have demonstrated that smoking cessation, the use of aspirin and statin, blood pressure control in hypertensives, blood sugar control in diabetics, and nutritional status and weight loss in obese patients significantly improve survival.20–28. Large studies are lacking regarding PAD risk factor modification in a cancer patient cohort.
Limitations of the study include retrospective study with inherent bias and relatively small size. PAD diagnosis was obtained from ICD 9/10 score rather than more definitive methods such as an Ankle Brachial index of < 0.9. Medical and smoking cessation compliance could not be ascertained due to inconsistent documentation. Lastly, causes of death other than cancer were not able to be obtained.
Conclusion
Breast cancer patients with PAD carry the typical risk factors of PAD seen in the general population including smoking, HTN, HLP, obesity, and DM. In our study, smoking and HTN are risk factors associated with decreased survival and predictive of overall and cancer-related death. In this population, risk factor modification was alarmingly under-utilized.
Figure 1 b.
Effect of Hypertension on survival
Figure 1 c.
Effect of Hyperlipidemia on overall survival
Figure 1 d.
Effect on smoking on overall survival.
Figure 1 e.
Effect of Diabetes on overall survival
Breast cancer and Peripheral arterial disease (PAD) have overlapping risk factors with prevalence that is rising. PAD risk factors are treated less often than other cardiovascular diseases such as coronary artery disease. In our study we demonstrated that risk factors in our breast cancer patients with PAD can affect survival, such as in the case of hypertension and smoking. Moreover, the risk factors in this population are not managed well with suboptimal utilization of risk factor modification measures. Larger studies are needed to assess the importance of risk factor modification in this population.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Footnotes
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Contributor Information
Yolanda Bryce, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Richard Bourguillon, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30310, USA.
Juan Camacho Vazquez, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Etay Ziv, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Daehee Kim, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Ernesto Santos, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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