Differences between palpable and nonpalpable tumors in early-stage, hormone receptor-positive breast cancer

Accepted Manuscript Differences between palpable and nonpalpable tumors in early-stage, hormone receptor-positive breast cancer Stephanie L. Warren, MD, Neal Bhutiani, MD, Steven C. Agle, MD, MPH, Robert C.G. Martin, II, MD, PhD, Kelly M. McMasters, MD, PhD, Nicolas Ajkay, MD PII:

S0002-9610(17)31373-9

DOI:

10.1016/j.amjsurg.2018.02.020

Reference:

AJS 12809

To appear in:

The American Journal of Surgery

Received Date: 6 October 2017 Revised Date:

4 January 2018

Accepted Date: 6 February 2018

Please cite this article as: Warren SL, Bhutiani N, Agle SC, Martin II RCG, McMasters KM, Ajkay N, Differences between palpable and nonpalpable tumors in early-stage, hormone receptor-positive breast cancer, The American Journal of Surgery (2018), doi: 10.1016/j.amjsurg.2018.02.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Abstract

Background: We compared characteristics and outcomes of palpable versus

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nonpalpable, hormone-sensitive, early-stage breast cancers.

Methods: Patients from the North American Fareston vs. Tamoxifen Adjuvant (NAFTA) trial were divided into palpable (n=513) and nonpalpable (n=1063) tumor groups.

and overall survival (OS) were analyzed.

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Differences in pathological features, loco-regional therapy, disease-free survival (DFS)

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Results: Patients with palpable tumors were older, had larger tumors, and higher rates of lymph-node involvement. The tumors were more likely to be poorly differentiated, of high nuclear grade, and display lymphovascular invasion. After mean followup of 59 months, DFS and OS were significantly lower for palpable than nonpalpable tumors

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(DFS 93.5% vs. 98.4%, p<0.001, OS 88.5% vs. 95.6%, p<0.001). Controlling for age, size and nodal status, palpability was an independent factor for DFS (OR=2.56; 95%CI, 1.37-4.79, p=0.003) and OS (OR=2.12; 95%CI, 1.38-3.28, p<0.001).

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Conclusions: In a group of hormone-sensitive, mostly postmenopausal early-stage breast cancer patients, palpable tumors were more likely to have more aggressive

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features and metastatic potential, which translated in to a higher incidence of breast cancer-related events and worse overall survival.

ACCEPTED MANUSCRIPT Warren, et al. 1 Differences between palpable and nonpalpable tumors in early-stage, hormone receptorpositive breast cancer Authors: Stephanie L. Warren, MD1; Neal Bhutiani, MD1; Steven C. Agle, MD, MPH2;

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Robert C.G. Martin, II, MD, PhD1; Kelly M. McMasters, MD, PhD1; Nicolas Ajkay, MD1

1

Department of Surgery, Division of Surgical Oncology University of Louisville School of

Medicine, Louisville, KY

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2

Department of Surgery, Division of Surgical Oncology, University of Texas Medical

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Branch, Galveston, TX

Running Head: Palpable vs. nonpalpable breast cancer

Corresponding Author: Nicolas Ajkay, MD, 315 East Broadway (M10), Louisville, KY

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Disclosures: none

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40202, phone (502) 629-3355, [email protected]

ACCEPTED MANUSCRIPT Warren, et al. 2 Abstract Background: We compared characteristics and outcomes of palpable versus nonpalpable, hormone-sensitive, early-stage breast cancers.

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Methods: Patients from the North American Fareston vs. Tamoxifen Adjuvant (NAFTA) trial were divided into palpable (n=513) and nonpalpable (n=1063) tumor groups.

Differences in pathological features, loco-regional therapy, disease-free survival (DFS)

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and overall survival (OS) were analyzed.

Results: Patients with palpable tumors were older, had larger tumors, and higher rates of

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lymph-node involvement. The tumors were more likely to be poorly differentiated, of high nuclear grade, and display lymphovascular invasion. After mean follow up of 59 months, DFS and OS were significantly lower for palpable than nonpalpable tumors (DFS 93.5% vs. 98.4%, p<0.001, OS 88.5% vs. 95.6%, p<0.001). Controlling for age, size and nodal status, palpability was an independent factor for DFS (OR=2.56; 95%CI, 1.37-4.79,

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p=0.003) and OS (OR=2.12; 95%CI, 1.38-3.28, p<0.001).

Conclusions: In a group of hormone-sensitive, mostly postmenopausal early-stage breast cancer patients, palpable tumors were more likely to have more aggressive

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features and metastatic potential, which translated in to a higher incidence of breast

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cancer-related events and worse overall survival.

ACCEPTED MANUSCRIPT Warren, et al. 3

Introduction Several studies have shown that palpable tumors have different clinical and

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pathological characteristics compared to nonpalpable tumors.1-8 Most of these studies have shown that palpability is a predictor of nodal involvement, independent of tumor size. However, few studies have shown that palpability, independent of size, also

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confers an effect on survival.8

Improvements in breast cancer survival have been attributed in part to the widespread use of screening mammography, which detects cancers before they become

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clinically apparent.9 Randomized clinical trials of screening mammography have shown improved survival in the screening groups,10-16 with the notable exception of the Canadian Screening trial, with its recent 25 year follow-up showing a lack of survival advantage in the 40 to 59 age group.17 Additionally, the advantages of clinical breast

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examination as a screening modality have recently been questioned.18 The goal of our study was to further evaluate the different characteristics, as well as the outcomes, between palpable versus nonpalpable early stage breast cancers in a

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homogenous group of hormone receptor-positive and mostly postmenopausal breast cancer patients. Our hypothesis is that even in a group of patients with biologically

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similar tumors, palpability will still be a predictor of worse outcomes. Methods

The North American Fareston (toremifene) vs. Tamoxifen Adjuvant (NAFTA)

trial19 was a prospective multicenter study to evaluate differences in long-term outcomes between two selective estrogen receptor modulators. Ninety-three academic and private institutions in the United States enrolled patients from July of 1998 to December 2002. Patients were randomized to receive 20 mg of Tamoxifen or 60 mg of toremifene (Fareston) for 5 years as adjuvant therapy. The Institutional Review Board of all

ACCEPTED MANUSCRIPT Warren, et al. 4 participating institutions approved the study and informed consent was signed by each patient prior to enrollment. 19 Patient population included peri- or postmenopausal women with stage I-II

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hormone receptor-positive breast cancer (estrogen receptor-positive and/or progesterone receptor-positive). Patients were required to undergo definitive surgery for the primary tumor, as well as axillary lymph node staging by sentinel lymph node (SLN)

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biopsy and/or axillary lymph node dissection. Data of clinical and pathological factors

was prospectively collected. Decisions of the type of breast surgical treatment, method

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of axillary evaluation, and adjuvant radiation therapy were at the discretion of the treating physicians. Cytotoxic chemotherapy was not indicated for postmenopausal patients with hormone positive breast cancer at the beginning of the trial, but as indications for chemotherapy changed during the enrollment period, a small proportion of patients receiving chemotherapy where included close to the end of the study. The trial showed

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no difference in overall survival (OS) or disease free survival (DFS) between the two groups (tamoxifen vs. toremifene) at 59 months of follow up.19 For this post hoc analysis, patients from the NAFTA trial were divided into

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palpable tumor and nonpalpable tumor groups. Patients with incomplete data were excluded. The relationship between tumor palpability and clinicopathological features

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was analyzed. Univariate analysis was conducted to identify the differences in pathological features and locoregional therapy using chi-square test. Kaplan–Meier analysis was used to study disease free survival (DFS) and overall survival (OS). Cox regression analysis was performed to identify independent predictors for DFS and OS. All statistical analyses were performed using SPSS version 22 (Armonk, NY). Results 1813 patients were analyzed from the original database. 237 patients were excluded due to one or more missing data points (96 patients missing tumor size, 1

ACCEPTED MANUSCRIPT Warren, et al. 5 missing palpability description, 85 missing stage, 53 missing histologic grade, and 2 missing estrogen receptor status). After exclusions, a total of 1576 patients were evaluated (Table 1). Palpability was documented for all patients. Patients were divided

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into palpable tumor (n=513) and nonpalpable tumor (n=1063) groups. On univariate analysis of clinical characteristics, patients with palpable tumors were older (69.1±10.0 years palpable vs. 67.1±9.6 years nonpalpable, p<0.001), had

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larger tumors (1.73±1.07 cm palpable vs. 1.29±0.85 cm nonpalpable, p<0.001), and had higher rates of sentinel node positivity (13.0% palpable vs. 5.3% nonpalpable, p<0.001)

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and lymph node involvement (14.6% palpable vs. 7.2% nonpalpable, p<0.001). These differences also resulted in a significant difference in staging for both groups with a higher percentage of stage I patients in the nonpalpable group (84.2% nonpalpable vs. 67.5% palpable, p<0.001). The majority of patients were postmenopausal in both groups (95.2% nonpalpable vs. 95.1% palpable, p=1.00). There was no significant difference

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between groups in regards to ER and PR positivity (p=0.04).

On pathological characteristics, palpable tumors were more likely to be poorly differentiated (18.3% palpable vs. 13.4% nonpalpable, p=0.02), exhibit high nuclear

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grade (12.7% palpable vs. 8.0% nonpalpable, p=0.02), display lymphovascular invasion (8.6% palpable vs. 4.1% nonpalpable, p=0.002), and more likely to demonstrate

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extracapsular nodal extension (1.8% palpable vs. 0.4% nonpalpable, p=0.01). Breast conserving therapy was less likely in patients with palpable tumors than

for those with nonpalpable cancers (63.2% palpable vs. 72.3% nonpalpable, p<0.001) and were less likely to undergo SLN biopsy (54.7% nonpalpable vs. 46.6% palpable, p=0.002). The advent and institution of SLN staging as an acceptable method of axillary lymph node staging occurred during the NAFTA trial and so it was not yet universal. All patients in the trial were required to undergo nodal staging by SLN biopsy and/or axillary

ACCEPTED MANUSCRIPT Warren, et al. 6 lymph node dissection.19 Finally, patients with palpable tumors were less likely to receive radiation therapy (53.0% palpable vs. 59.6% nonpalpable, p=0.01). After a mean follow up of 59 months, Kaplan-Meier (K-M) analysis demonstrated

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that DFS was significantly lower for palpable than nonpalpable tumors (93.5% vs. 98.4% respectively, p<0.001) (Figure 1). Similarly, OS was lower for palpable than for

nonpalpable tumors (88.5% vs. 95.6% respectively, p<0.001) (Figure 2). Additional K-M

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analysis demonstrated that these differences persisted in subgroup stage analysis. For stage I, OS and DFS were significantly lower for palpable than for nonpalpable tumors

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(OS, 92% vs. 95.8%, p,0.001; DFS, 95.6% vs. 98.8%, p=0.0016, respectively) (Figures 3 and 4). Similarly, significant differences were found for stage II (OS, 81.8% vs. 94.2%, p,0.0034; DFS, 89.9% vs. 95.5%, p=0.0038, respectively) (Figures 5 and 6). On multivariate Cox regression analysis, controlling for age, tumor size and nodal status, palpability was an independent factor for DFS (odds ratio [OR] =2.56; 95%

p<0.001). Discussion

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confidence interval (CI) 1.37-4.79, p=0.003) and OS (OR=2.12; 95% CI 1.38-3.28,

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The purpose of our study was to evaluate differences in characteristics and outcomes of patients with palpable vs. nonpalpable breast cancers. In a group of

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hormone-sensitive, mostly postmenopausal early stage breast cancer patients, palpable tumors were more likely to have more aggressive features and metastatic potential, which translated in to a higher incidence of breast cancer-related events and worse overall survival. Other studies have also shown palpable tumors to have increased nodal positivity independent of tumor size.1-7 The relationship between palpability and lymph node metastasis is not completely understood. Chao et al. examined palpability as an independent risk factor for nodal metastasis using a large database of 3192 patients who underwent SLN biopsy.7 The incidence of positive axillary metastasis was

ACCEPTED MANUSCRIPT Warren, et al. 7 significantly higher in patients with palpable vs. nonpalpable tumors, independent of tumor size (43% vs. 23%, p=0.0001). In addition, the SLN identification rate was significantly different between palpable and nonpalpable tumors (95% vs. 91%,

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p<0.0001). They hypothesized that palpable tumors may be associated with an increased rate of nodal metastasis because they are closer to the skin and its rich network of dermal lymphatics.

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Although most of the above referenced studies found tumor palpability to be an

independent risk factor for lymph node metastasis, unlike our study, they either found no

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difference in survival or did not evaluate survival. Skinner et al. evaluated the characteristics between palpable and nonpalpable tumors in a group of 1258 patients with T1 breast cancer and an average age of 53 years.6 They found no difference between palpable and nonpalpable tumors in terms of receptor positivity or Her-2/neu status. However, at every tumor size, palpable tumors were twice as likely to be node-

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positive as nonpalpable tumors. Women with nonpalpable tumors had better 8-year breast cancer-specific survival (BCSS) than women with palpable tumors, however this did not reach significance when controlling for tumor size. Silverstein et al. evaluated

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palpability as a predictor of axillary nodal positivity in 1891 patients with invasive cancer.3 For T1b, T1c, and T2 lesions, nodal positivity was significantly higher for

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palpable vs. nonpalpable lesions of the same size. They also found that nonpalpable tumors were more likely to be estrogen and progesterone receptor positive. The 8-year BCSS was significantly better for nonpalpable vs. palpable tumors (91% vs. 79%, p<0.0001). However, subgroup analysis by T category and palpability did not have sufficient statistical power to detect a survival difference. Even for node-negative patients, palpability was a poor prognostic factor, associated with decreased survival (88% palpable vs. 94% nonpalpable, p=0.006).

ACCEPTED MANUSCRIPT Warren, et al. 8 Our study’s findings of improved outcomes with nonpalpable tumors seem to indirectly support the benefits of subclinical detection. This is especially relevant in light of emerging data and current changes in guidelines regarding breast cancer screening. 20-22

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. There have been eight randomized controlled trials evaluating screening

mammography.10-17 All found a reduction in breast cancer mortality when cancers are

detected at a preclinical stage, except for the Canadian National Breast Screening Study

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(CNBSS).17

The CNBSS did not find a reduction in breast cancer-specific mortality for women

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aged 40-59.17 However, it did find longer survival in women with nonpalpable versus palpable tumors in the screening arm (hazard ratio = 0.58, 95% CI, 0.41-0.82, p<0.0001). At 25 years, survival for woman with nonpalpable breast cancers was 79% versus 66.3% (mammography arm) and 62.8% (control arm) for those with palpable breast cancers. Seventy fewer palpable cancers were found in the screening arm versus

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the control arm (454 vs. 524), suggesting that some women that presented in a preclinical state through early detection, may have presented with a palpable cancer if randomized to the control arm. This large-scale study with long follow up also confirms

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that palpable tumors have a worse prognosis. The CNBSS also found an excess of 106 patients detected in the mammography

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arm vs. the control arm, for an overdiagnosis rate of 22%. Overdiagnosis refers to the detection of cancer that would have not become clinically apparent during that person’s lifetime, due its lack of potential to progress clinically, or the patient’s death before it becomes clinically relevant.23 Other estimates of overdiagnosis range from less than 5%24,25 to more than 50%.21,26,27 Brouckaert et al. evaluated prognostic variables in 1610 patients with screendetected breast cancer.8 On univariate analysis, tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-

ACCEPTED MANUSCRIPT Warren, et al. 9 specific death. On multivariate analysis, palpability, phenotype, and nodal status remained independent prognostic factors of worse outcomes. They noted that palpability differed by breast cancer phenotype. They concluded that palpability should be

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considered as a prognostic variable in prognostic models for screen-detected breast cancers. This is supported by our study’s findings of palpability as an independent

predictor of poor prognosis. The excellent DFS and OS of the nonpalpable group in our study could be explained by the higher percentage of low histologic grade, a surrogate

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for luminal A phenotype28. It could also suggest that some cancers in the nonpalpable

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group have a less clinically aggressive or indolent tumor biology. These patients may benefit from less aggressive local and systemic therapies.

If palpability is a useful prognostic indicator, then what is the role of clinical breast examination (CBE) in breast cancer screening? Overall, there is limited evidence regarding the efficacy of CBE in screening, which is why many organizational guidelines,

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including the ACS and USPSTF, no longer recommend CBE.21,22 Provencher et al. found that CBE alone was responsible for diagnosing invasive cancer in about 9% of patients, as well as found that tumors diagnosed by CBE alone were likely to be more

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aggressive.18 Chiarelli et al. found that the sensitivity of referrals was higher from centers that also offered CBE, however the false-positive rate was also higher.29

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The role of routine CBE as part of primary breast cancer screening remains unclear. Perhaps we should focus on the role of CBE in screen-detected cancers. Palpability has been shown in our study and others to be an important prognostic indicator. As we continue to try to determine which cancers we are overdiagnosing and overtreating, maybe in the future, palpability should be part of a risk-stratification algorithm. The algorithm could help determine which lesions have a low risk of malignant potential versus those with a high risk.

ACCEPTED MANUSCRIPT Warren, et al. 10 The limitations of our study are the relatively short follow-up period of 59 months, since it is well known that hormone receptor-positive breast cancer patients can have late recurrences beyond 5 years. 30 Nevertheless, the majority of recurrences would be

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expected during this time period. Also, other prognostic histological and molecular factors that are currently used in clinical practice to predict risk or benefit from adjuvant therapies were not collected in this trial.28 Furthermore, it is unclear whether the findings

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in this study are generalizable to other populations of women with breast cancer, i.e.,

younger patients and hormone receptor-negative tumors. More contemporary datasets

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with longer follow up are required to further validate our findings. Conclusion

Multiple studies have shown that palpable tumors have different inherent characteristics compared to nonpalpable tumors. The biology underlying these differences is not completely understood. Our study has shown that palpable tumors

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confer a worse prognosis, independent of tumor size, nodal status and patient’s age. Further genomic and molecular studies could confirm the theory that palpability is a surrogate for tumor biology variability. Additional studies could also better define the

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clinicopathological characteristics associated with palpability and help determine the role of palpability as a prognostic indicator.

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Funding Sources: This research did not receive any support from funding agencies in the public, commercial, or not-for-profit sectors.

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Legends:

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Figure 1. Disease free survival for palpable vs. nonpalpable breast cancer. Figure 2. Overall survival for palpable vs. nonpalpable breast cancer. Figure 3. Disease free survival for palpable vs. nonpalpable stage I breast cancer. Figure 4. Overall survival for palpable vs. nonpalpable stage I breast cancer. Figure 5. Disease free survival for palpable vs. nonpalpable stage II breast cancer. Figure 6. Overall survival for palpable vs. nonpalpable stage I breast cancer.

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ACCEPTED MANUSCRIPT Warren, et al. 15

Nonpalpable (n=1063)

Palpable (n=513)

P value

Age (years) Size (cm) Stage 1 2 Histologic Grade Low Intermediate High Unknown Nuclear Grade Low Intermediate High Unknown Hormone receptor status ER+/PR+ ER+/PRER-/PR+ ER+/PR unknown Extracapsular Nodal Extension

67.1, +/-9.6 1.29, +/-0.85

69.1, +/-10.0 1.73, +/-1.07

<0.001 <0.001

895 (84.2%) 168 (15.8%)

346 (67.5%) 167 (32.5%)

<0.001

330 (31.0%) 471 (44.3%) 142 (13.4%) 120 (11.3%)

131 (25.5%) 232 (45.2%) 94 (18.3%) 56 (10.9%)

0.02

No Yes Lymphovascular invasion No Yes Unknown Axillary node status

90 (17.5%) 183 (35.7%) 65 (12.7%) 175 (34.1%)

0.02

421 (82.1%) 83 (16.2%) 6 (1.2%) 3 (0.6%)

0.04

1059 (99.6%) 4 (0.4%)

504 (98.2%) 9 (1.8%)

0.01

716 (67.4%) 44 (4.1%) 303 (28.5%)

328 (63.9%) 44 (8.6%) 141 (27.5%)

0.002

986 (92.8%) 77 (7.2%)

438 (85.4%) 75 (14.6%)

<0.001

581 (54.7%) 482 (45.3%)

239 (46.6%) 274 (53.4%)

0.003

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895 (84.2%) 147 (13.8%) 9 (0.8%) 12 (1.1%)

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Negative Positive Sentinel Lymph Node performed Yes No

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219 (20.6%) 403 (37.9%) 85 (8.0%) 356 (33.5%)

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Characteristics

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Table 1. Characteristics of palpable vs. nonpalpable breast cancer

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31 (5.3%) 550 (94.7%)

31 (13.0%) 208 (87.0%)

<0.001

Yes No Radiation Therapy Yes No

769 (72.3%) 294 (27.7%)

324 (63.2%) 189 (36.8%)

<0.001

634 (59.6%) 429 (40.4%)

272 (53.0%) 241 (47.0%)

0.01

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Positive Negative Breast Conservation

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Sentinel Lymph Node status

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*Categorical variables expressed as n (%). Continuous variables expressed as mean, standard deviation. ER: Estrogen receptor, PR: progesterone receptor, +: positive, -: negative.

ACCEPTED MANUSCRIPT Warren, et al. 17

CAPTIONS Figure 1. Kaplan-Meier curve demonstrating differences in disease free survival (DFS) among patients with nonpalpable (blue) and palpable (green) primary hormone receptorpositive breast tumors.

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Figure 2. Kaplan-Meier curve demonstrating differences in overall survival (OS) among patients with nonpalpable (blue) and palpable (green) primary hormone receptor-positive breast tumors.

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Highlights •

Palpable vs. non-palpable tumors were compared in a group of hormone-sensitive, early-stage breast cancers. Palpability was an independent factor for worse disease-free survival and overall

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survival.

Non-palpable breast cancers have better short-term outcomes than non-palpable

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tumors.

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