Metastatic Presentations of Previously Treated Early-Stage Breast Cancer Patients and Association With Survival

Journal Pre-proof Metastatic Presentations of Previously Treated Early Stage Breast Cancer Patients and Association with Survival Najla Itani, Nicole Grogan, Sarah Mott, Sneha Phadke PII:

S1526-8209(19)30735-9

DOI:

https://doi.org/10.1016/j.clbc.2019.11.004

Reference:

CLBC 1059

To appear in:

Clinical Breast Cancer

Received Date: 26 April 2019 Revised Date:

31 October 2019

Accepted Date: 11 November 2019

Please cite this article as: Itani N, Grogan N, Mott S, Phadke S, Metastatic Presentations of Previously Treated Early Stage Breast Cancer Patients and Association with Survival, Clinical Breast Cancer (2019), doi: https://doi.org/10.1016/j.clbc.2019.11.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 The Author(s). Published by Elsevier Inc.

Metastatic Presentations of Previously Treated Early Stage Breast Cancer Patients and Association with Survival

Running Title: Metastatic Presentations of Recurrent Breast Cancer Authors: Najla Itani1, Nicole Grogan1, Sarah Mott2, Sneha Phadke1 1

University of Iowa Hospitals and Clinics 200 Hawkins Drive Iowa City, IA 52242

2

Holden Comprehensive Cancer Center 200 Hawkins Drive Iowa City, IA 52242

Keywords: breast cancer, recurrence, metastasis, symptoms, survival Main manuscript word count: 2,146, Tables: 2, Figures: 3

Corresponding Author:

Sneha Phadke 200 Hawkins Drive, C21GH Iowa City, IA 52242 (T) 319-384-9502 (F) 319-353-8383 [email protected] Funding: This work was supported in part by the Holden Comprehensive Cancer Center Population Research and Biostatistics Cores (P30 CA086862).

Conflicts of Interest Page: Conflict of Interest Statement: The authors declare no potential conflicts of interest.

Microabstract: Fear of cancer recurrence is common among breast cancer survivors. The aim of our study was to investigate methods of diagnosing recurrence and their association with survival. We found that metastatic diagnoses were most commonly made by patientreported symptoms and that there was no difference in survival by diagnostic method, which hopefully eases the anxiety experienced by breast cancer patients.

Abstract: Background: Breast cancer (BC) patients on surveillance often suffer from a fear of recurrence. Given that routine imaging is not recommended, recognizing metastatic disease early requires a knowledge of recurrence patterns. The aim of this study was to analyze the most common presentations of metastatic disease. Patients: A retrospective review was conducted of patients that were initially diagnosed with early stage BC and later developed metastatic disease. Data collected included method of metastatic disease diagnosis, types of symptoms at diagnosis, and survival. Chi-squared tests, logistic and Cox regression models were used. Results: We found that metastatic diagnoses were made from reported symptoms in 77.6% of patients, clinical exam in 3.2%, and 7.8% incidentally on imaging. Among those with symptoms, musculoskeletal pain was the most common (33.7%) and more frequently noted at scheduled (48.9%) compared to acute care visits (26.0%, p<0.01). Receptor status was associated with nervous system (NS) symptoms at metastasis (p=0.01), with higher odds of NS symptoms in triple negative (TN) (OR=3.02) compared to ER/PR+, HER2- cases. On multivariable analysis, initial stage (p=0.03), receptor status (p<0.01), age (p<0.01), and time to recurrence (p<0.01) were significantly associated with 10-year survival after metastatic diagnosis whereas the presence of symptoms was not (p=0.27). Discussion: Providers of BC patients on surveillance should modify their threshold of suspicion for recurrence depending on characteristics of the initial diagnosis and symptoms subsequently reported. Conclusion: In this retrospective study, patients who presented with symptoms did not have a shorter survival compared with those who were diagnosed in other ways.

Introduction: There have been great strides made in adjuvant therapy for early stage breast cancer (BC) in the last few decades, fortunately leading to significantly fewer cases of metastatic disease. However, 25-40% of patients still develop metastatic BC, even after standard multimodality therapy1. Patients on surveillance often suffer from a fear of recurrence, especially after the initial therapy is completed and the frequency of oncology clinic visits tapers2. A common question encountered in practice is “How do I know if the cancer is back?”. This can be a difficult question to answer, given that patients can present with metastatic BC in several ways, and routine surveillance imaging of the body (other than the breasts) is not recommended3-5. Moreover, survivorship care is increasingly being transferred to advanced practice providers in dedicated survivorship clinics or to primary care providers. Thus, the ability to recognize metastatic disease early requires adequate knowledge of recurrence patterns. The aims of this study were to analyze the most common ways in which patients with previously treated BC present with metastatic disease and to investigate if there are differences in overall survival by manner of presentation. Materials and Methods: Patient Selection Any patient at the Holden Comprehensive Cancer Center that had been initially diagnosed with stage I through III BC from January 1, 2000 through December 31, 2017, and later developed metastatic disease was included. The cohort was created using TriNetX, a global health research network that provides access to a network of inhouse clinical data. Three separate database searches were conducted, given the difficulty of creating a single search that would capture all eligibility criteria. These searches or “groups” eventually comprised the final cohort: 1) Any female patient, 18 years or older, with a diagnosis of BC who received denosumab or zoledronic acid. 2) Any female patient, 18 years or older, with a diagnosis of BC who had a CT scan or PET scan followed by chemotherapy. 3) All male patients diagnosed with BC in the above stated time frame, given the rarity of male BC. The above groups were merged and overlap was taken into account. After obtaining IRB approval, each patient’s chart was retrospectively reviewed for eligibility. Finally, additional eligible patients identified from the BC clinic were added to the cohort if not initially listed in the above groups. Patients with incomplete information regarding their

metastatic presentation were excluded. Data on vital status was obtained from Iowa Cancer Registry. Figure 1 is a flow diagram of subject selection. Data Collection Active data collection took place from January 26, 2018 through July 15, 2018. Using a standardized review form, data was collected on demographic variables as well as the details of the initial and subsequent metastatic BC diagnoses. To assess for potential differences and inconsistencies in data collection, an initial set of 20 patient charts was reviewed by 3 of the investigators (SP, NI, NG) and modifications to the methodology were made thereafter. This procedure was repeated with another 20 charts to ensure that the modifications were successful. Throughout the data collection period, answers to any data item that were felt to be debatable or uncertain were reviewed by the PI (SP). We were particularly interested in 1) how the metastatic recurrence was discovered (symptoms, exam finding, or other method of detection) and whether this differed among receptor subtypes, 2) if the patient had a symptom, where and when they presented (to an oncology clinic at a pre-scheduled follow-up or acute care visit, an emergency department, urgent care, or to primary care) and 3) overall survival, stratified by manner of metastatic presentation. Statistical Analysis The association between characteristics at initial diagnosis and presence of symptoms at metastatic presentation was evaluated using Firth-penalized logistic regression models. Cox regression models were utilized to assess factors associated with time to recurrence (TTR) and overall survival (OS). Time was calculated from initial diagnosis to metastatic recurrence for TTR and from metastatic recurrence to death due to any cause for OS. Estimated effects of predictors are reported as odds ratios (OR) or hazard ratios (HR) along with 95% confidence intervals. All statistical testing was twosided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Results: A total of 2,028 patients were identified via the database search method and 365 patients were subsequently deemed eligible for analysis on chart review. An additional 6 patients were added from the breast cancer clinic as they had not been identified via database search. Therefore, a total of 371 patients comprised the final cohort. Female patients comprised 96.5% of the cohort. With regard to the initial cancer diagnosis, the majority of patients had stage II or stage III disease (80.6%, Table 1).

Patients with triple negative (TN) and hormone positive disease accounted for 19.0% and 74.1% of the cohort, respectively. While most metastatic diagnoses were made as a result of reported symptoms (77.6%), 3.2% were made with clinical exam findings and 4.1% by abnormal lab results. Diagnoses made incidentally via imaging done for other reasons accounted for 7.8% of the cohort. A total of six patients (1.6%) had a locoregional recurrence diagnosed initially, with metastatic findings discovered on subsequent staging scans. A similar proportion of patients presenting with symptoms was noted at scheduled versus acute care visits (49.1% and 50.9%, respectively). Among those with symptoms, 40.4% had a clinical encounter with a non-oncologic provider. Musculoskeletal pain was the most common symptom (33.7%), and more frequently noted at scheduled visits (48.9%) compared to acute care visits (26.0%, p<0.01). Figure 2 depicts the subtypes of symptoms that were analyzed and the frequency with which they occurred. Neither initial stage nor receptor status was associated with the presence of symptoms at metastatic diagnosis (p=0.58 and 0.68, respectively). Upon further analysis of specific types of symptoms, metastatic bone pain was not associated with any particular receptor subtype (p=0.12). However, receptor status was associated with nervous system (NS) symptoms at metastatic diagnosis (p=0.01), with higher odds of NS symptoms in TN (OR=3.02 95% CI 1.05-8.44) compared to ER/PR+, HER2- cases. HER2+ cases were not found to have a higher odds of NS symptoms compared to ER/PR+, HER2- cases (ER/PR+ HER2+: OR=3.52, 95% CI 0.88-12.29; ER/PRHER2+: OR=3.82, 95% CI 0.79-14.97). Initial stage and receptor status were associated with TTR (both p<0.01). Those with stage III disease (versus stage I, HR=1.69, 95% CI 1.24-2.31) and TNBC (versus ER/PR+, HER2-, HR=2.52, 95% CI 1.90-3.35) had the shortest TTR. On multivariable analysis, initial stage, receptor status, age, and TTR were significantly associated with 10-year survival after metastatic diagnosis (Table 2, Figure 3) whereas the presence of symptoms at metastatic diagnosis was not (HR=1.21, 95% CI 0.86-1.70). Discussion: The aim of this study was to analyze the most common ways in which patients with previously treated BC present with metastatic disease in order to better understand the patterns of recurrence and impact on survival. Although several studies have explored how the various molecular subtypes of BC recur and the risk factors that predict recurrence, this is the first study to our knowledge that specifically explores the different presentations of symptoms at metastasis6-11.

The proportion of patients in our study with TN and HER2+ disease was greater than typically reported in surveillance databases12, which likely reflects the increased recurrence rates that occur in patients with both receptor subtypes. As expected, most metastatic recurrences occurred in those with a higher stage and grade at initial diagnosis, with patients with stage II and III cancers accounting for 80.6% of the cohort. With regard to the diagnosis of metastatic recurrence, patients most commonly presented with a symptom that triggered further evaluation (77.6%). Pandya and colleagues made a similar conclusion in their retrospective study of the earliest indicators of BC recurrence, finding that 54.3% of patients that relapsed presented with symptoms or with an abnormality detected on self-examination3. Of note, a patient detected breast abnormality was considered a symptom in our data analysis instead of a separate means by which the recurrence was diagnosed. Additionally, Pandya and colleagues included patients with both metastatic presentations and locoregional recurrences. As a result, a significant proportion of recurrences were found by physical examination by the clinician (19.4%), which could account for the differences in cumulative percentages compared to our study. Analogous findings were noted in a retrospective review by Dewar and colleagues, whereby 92 metastatic recurrences were reported and only 1 was asymptomatic with the remainder of patients experiencing symptoms upon relapse13. In addition, more patients with metastatic symptoms presented at acute care visits. Although we found that the overall number of patients with symptoms presenting at acute care visits and scheduled visits was comparable, those with non-musculoskeletal complaints were more frequently reported with the former. This may reflect the severity of non-musculoskeletal symptoms that involve the cardiac, pulmonary, and nervous systems. Historically, studies have shown that hormone positive BC most commonly metastasizes to bone, and brain metastasis is more common in TN and HER2+ cancers7,14,15. Despite that, we found that metastatic bone pain was not associated with any particular receptor subtype. This may reflect the common finding of asymptomatic bony metastasis. In other words, although the site of metastasis may be associated with a specific receptor subtype, this does not always translate into the presence of symptoms. In contrast, receptor subtype was associated with NS symptoms at metastatic diagnosis, with higher odds of symptoms in TN relative to ER/PR+, HER2disease. This suggests that it may be relatively more common to have symptoms associated with NS metastasis versus bone metastasis. Only a small percentage of metastatic diagnoses in our study were found incidentally on imaging done for other reasons (7.8%) and even fewer by clinical exam (3.2%). However, in our study 80.8% of patients were found to have evidence of metastatic disease during the clinical encounter itself (history/review of systems or physical exam). Thus, theoretically the clinical encounter would suffice in detecting a metastatic

recurrence in a majority of patients. Interestingly, a significant portion of patients presenting with symptoms (at scheduled or acute care visits) had a clinical encounter with a non-oncologic provider. Similarly, in a study performed in England, Grunfeld and colleagues found that almost half of patients with recurrences first presented to their general practitioners16. While oncologists may be well aware of symptoms that should prompt further evaluation of recurrent cancer, other types of providers may not. Hopefully our study offers such providers guidance, to modify their threshold of suspicion for recurrence depending on the characteristics of the initial diagnosis and symptoms subsequently reported. This is particularly important because one of the aims of survivorship care is to identify disease relapse early before the patient suffers from significant morbidity17. In a prospective study on the patterns of breast cancer relapse, Elder and colleagues found that the location of metastatic disease impacted survival with bony metastases having the most favorable prognosis18. Similarly, Pogoda and colleagues found that the location of metastasis was associated with survival in triple negative BC patients19. A recently published study by Klar and colleagues showed that the presence of visceral metastasis and/or brain metastasis was negatively associated with long-term survival of patients with metastatic breast cancer, as was triple negative receptor status20. In these studies, the presence or absence of symptoms in relation to location of metastasis was not examined. Our data showed that in the event that a patient experiences symptoms upon metastatic recurrence, the overall survival is not impacted. The location of metastatic disease appears to be a more significant predictor of survival than symptoms. There were several study limitations that were potentially unavoidable. The determination of how a patient’s BC recurrence was first found (i.e. a symptom, incidentally on imaging, etc.) has not been described or standardized in the literature. We were therefore obliged to deduce such information by reviewing the clinicians’ notes in depth in addition to the reason documented for ordering particular radiologic images. At this time, no cancer surveillance mechanism in the United States systemically collects data on cancer recurrence, therefore, some creativity was required to identify data elements that could be collected from TriNetX and were reflective of those patients who had experienced recurrence. Consequently, some patients who would have fit the criteria may have been missed. Lastly, we acknowledge that this study may be underpowered to detect a statistically significant difference in survival, irrespective of whether this difference would prove to be clinically significant. Conclusion: Overall, we expect that our results will ease the anxiety of BC patients that are on surveillance as most recurrences will be diagnosed by reporting symptoms, and patients

can be proactively involved in that regard. Moreover, they can be reassured by our findings, which showed that patients did not have a shorter survival as a result of presenting with metastatic symptoms. Further research on breast cancer recurrence could potentially be performed using the database we have created, to inform guidelines on improving survivorship care.

Clinical Practice Points: Current clinical guidelines do not support the use of routine surveillance imaging in follow-up care of breast cancer patients, who often suffer from anxiety related to the possibility of cancer recurrence. Previous studies have shown that breast cancer recurrence is usually discovered as a result of symptoms. Our study aimed to investigate methods of diagnosing recurrence, whether the method of metastatic diagnosis resulted in a difference in survival, and whether certain breast cancer subtypes were associated with differences in symptomatology. Consistent with previous literature, we found that most patients present with symptoms at metastatic diagnosis. We also found that having symptoms at diagnosis is not associated with 10-year survival. Patients with triple negative breast cancer were more likely to have nervous system symptoms at the time of metastatic diagnosis, consistent with the fact that these patients have a higher chance of brain metastasis. Our findings will hopefully ease the minds of patients who are anxious about waiting until the onset of symptoms to obtain imaging. These results support the use of symptom-directed imaging and not surveillance imaging in the follow-care of breast cancer patients. Additionally, our results provide guidance for providers for when to have a lower threshold to obtain symptom-directed imaging, based on baseline clinicopathologic factors.

References: 1. Guarneri V, Conte P. Metastatic breast cancer: therapeutic options according to molecular subtypes and prior adjuvant therapy. The Oncologist. 2009; 14:645-656. 2. Khatcheressian JL, Hurley P, Bantug E, Esserman LJ, Grunfeld E, Halberg F, et al. Breast cancer follow up and management after primary treatment: American Society of Clinical Oncology clinic practice guideline update. Journal of Clinical Oncology. 2013 March; 31(7):961-965. 3. Pandya KJ, McFadden ET, Kalish LA, Tormey DC, Taylor SG 4th, Falkson G. A retrospective study of earliest indicators of recurrence in patients on Eastern Cooperative Oncology Group adjuvant chemotherapy trials for breast cancer. Cancer. 1985; 55:202-205. 4. Podoloff DA, Advani RH, Allred C, Benson AB 3rd, Brown E, Burstein HJ, et al. NCCN task force report: positron emission tomography (PET)/computed tomography (CT) scanning in cancer. J Natl Compr Canc Netw. 2007;5 Suppl 1:1-1. 5. Rosselli Del Turco M, Palli D, Cariddi A, Ciatto S, Pacini P, Distante V. Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA. 1994 May 25; 271(20): 1593-1597. 6. San-Gang W, Sun JY, Yang LC, Tag LY, Wang X, Chen XT, et al. Patterns of distant metastatic in Chinese women according to breast cancer subtypes. Oncotarget. 2016 Jul 26; 7(30):47975-47984. 7. Metzger-Filho O, Sun Z, Viale G, Price KN, Crivellari D, Snyder RD, et al. Patterns of recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. J Clin Oncol. 2013 Sep 1; 31(25): 3083-3091. 8. Wu Q, Li J, Zhu S, Wu J, Chen C, Liu Q, et al. Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study. Oncotarget. 2017 Apr 25; 8(17):27990-27996. 9. Kaplan MA, Arslan UY, Isikdogan A, Dane F, Oksuzoglu B, Inanc M, et al. Biological subtypes and distant relapse pattern in breast cancer patients after curative surgery. Breast Care. 2016; 11:248-252. 10. Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 2010 Apr 1. 28(10):1684-1691.

11. Geurts YM, Witteveen A, Bretveld R, Poortmans PM, Sonke GS, Strobbe LJA, et al. Patterns and predictors of first and subsequent recurrence in women with early breast cancer. Breast Caner Res Treat. 2017. 165:709-720. 12. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014 May; 106(5): dju055. 13. Dewar JA, Kerr GR. Value of routine follow up of women treated for early carcinoma of the breast. BMJ. 1985 Nov 23; 291:1464-1467. 14. Lee SJ, Park S, Ahn HK, Yi JH, Cho EY, Sun JM, et al. Implications of bone-only metastases in breast cancer: favorable preference with excellent outcomes of hormone receptor positive breast cancer. Cancer Res Treat. 2011 June; 43(2):89-95. 15. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010; 28:3271-3277. 16. Grunfeld E, Mant D, Yudkin P, Adewuyi-Dalton R, Cole D, Steward J, et al. Routine follow up of breast cancer in primary care: randomized trial. BMJ. 1996 Sep 14; 313:665-9. 17. Institute of Medicine and National Research Council. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington DC: The National Academies Press. 2006. https://doi.org/10.17226/11468. 18. Elder EE, Kennedy CW, Gluch L, Carmalt HL, Janu NC, Joseph MG, et al. Patterns of breast cancer relapse. EJSO. 2006; 32:922-927. 19. Pogoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013 March; 30(1):388. 20. Klar N, Rosenzweig M, Diergaarde B, Brufsky A. Features Associated with LongTerm Survival in Patients with Metastatic Breast Cancer. Clinical Breast Cancer. published online Feb 2019.

Table 1: Diagnostic Characteristics of Initial and Metastatic Diagnoses N = 371

%

I

65

19.3

II

150

44.7

III

121

35.9

Missing

35

-

ER/PR(-) HER2 (+)

23

6.8

ER/PR (+) HER2 (-)

216

64.3

ER/PR (+) HER2 (+)

33

9.8

Triple negative

64

19

Missing

35

-

Initial Stage

Initial receptor status

How metastatic diagnosis was first suspected Symptoms

287

77.6

Clinical exam by physician

12

3.2

Screening breast imaging in which local recurrence was found prompting systemic imaging Screening chest x-ray

6

1.6

6

1.6

Incidental on imaging

29

7.8

Lab only

15

4.1

Other

15

4.1

Missing

1

-

Table 2: Multivariable analysis for 10-year overall survival Covariate Initial Stage I II III Initial Receptor ER/PR(-) HER2(+) ER/PR (+) HER2 (-) ER/PR (+) HER2 (+) Triple negative Received chemotherapy after initial diagnosis Did not receive chemotherapy Received endocrine therapy after initial diagnosis Did not receive endocrine therapy > 60 years old at metastatic diagnosis <60 years old Presence of symptoms at metastatic diagnosis Other means of diagnosis Time to recurrence <5 years >5 years

N

Hazard Ratio

95% CI

P-value

54 132 111

Reference 1.67 1.83

1.10-2.54 1.15-2.91

0.03

20 187 30 61

0.45 0.35 0.24 Reference

0.25-0.81 0.22-0.55 0.13-0.45 -

225

1.12

73

Reference

180

1.03

118

Reference

123

1.66

175 239

Reference 1.21

59

Reference

188 167

1.62 Reference

Figure 1: Subject selection flow diagram

<0.01

0.76-1.64

0.58

0.70-1.52

0.88

1.23-2.25

<0.01

0.86-1.70

0.27

1.20-2.20 -

<0.01

Figure 2: Symptoms Reported at Metastatic Diagnosis

4.2% 10.5%

Breast-related

9.8%

Musculoskeletal 32%

Cardiopulmonary Nervous System

8.7%

Gastrointestinal Combination of symptoms

22.7%

Figure 3: 10-year overall survival by TTR