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

Open AccessPublished:November 20, 2019DOI:https://doi.org/10.1016/j.clbc.2019.11.004

      Abstract

      Background

      Breast cancer (BC) patients undergoing surveillance often fear 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 and Methods

      A retrospective review was conducted of patients who were initially diagnosed with early-stage BC and who later developed metastatic disease. Data collected included method of metastatic disease diagnosis, types of symptoms at diagnosis, and survival. Chi-square tests as well as logistic and Cox regression models were used.

      Results

      Metastatic diagnoses were made from reported symptoms in 77.6% of patients, clinical examination in 3.2%, and 7.8% incidentally on imaging. Among those with symptoms, musculoskeletal pain was the most common (33.7%) and was more frequently noted at scheduled (48.9%) compared to acute-care visits (26.0%, P < .01). Receptor status was associated with nervous system symptoms at metastasis (P = .01), with higher odds of nervous system symptoms in triple-negative (odds ratio = 3.02) compared to estrogen receptor/progesterone receptor–positive, HER2- cases. On multivariable analysis, initial stage (P = .03), receptor status (P < .01), age (P < .01), and time to recurrence (P < .01) were significantly associated with 10-year survival after diagnosis of metastasis, whereas the presence of symptoms was not (P = .27). Providers of BC patients undergoing surveillance should modify their threshold of suspicion for recurrence depending on the characteristics of the initial diagnosis and the symptoms subsequently reported.

      Conclusion

      In this retrospective study, patients who presented with symptoms did not have shorter survival compared to those who were diagnosed in other ways.

      Keywords

      Introduction

      Great strides have 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% to 40% of patients still develop metastatic BC, even after receiving standard multimodal therapy.
      • Guarneri V.
      • Conte P.
      Metastatic breast cancer: therapeutic options according to molecular subtypes and prior adjuvant therapy.
      Patients undergoing surveillance often fear disease recurrence, especially after the initial therapy is completed and there are fewer oncology clinic visits.
      • Khatcheressian J.L.
      • Hurley P.
      • Bantug E.
      • et al.
      Breast cancer follow up and management after primary treatment: American Society of Clinical Oncology clinic practice guideline update.
      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 recommended.
      • Pandya K.J.
      • McFadden E.T.
      • Kalish L.A.
      • Tormey D.C.
      • Taylor 4th, S.G.
      • Falkson G.
      A retrospective study of earliest indicators of recurrence in patients on Eastern Cooperative Oncology Group adjuvant chemotherapy trials for breast cancer.
      • Podoloff D.A.
      • Advani R.H.
      • Allred C.
      • et al.
      NCCN task force report: positron emission tomography (PET)/computed tomography (CT) scanning in cancer.
      • 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.
      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 (OS) by manner of presentation.

      Patients and Methods

      Patient Selection

      Any patient at the Holden Comprehensive Cancer Center who had been initially diagnosed with stage I-III BC from January 1, 2000, through December 31, 2017, and then later developed metastatic disease was included. The patient cohort was created using TriNetX, a global health research network that provides access to a network of in-house 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 computed tomographic or positron emission tomographic 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 institutional review board 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. Patients with incomplete information regarding their metastatic presentation were excluded. Data on vital status were obtained from Iowa Cancer Registry. Figure 1 provides a flow diagram illustrating subject selection.

      Data Collection

      Active data collection took place from January 26, 2018, through July 15, 2018. Using a standardized review form, data were collected on demographic variables; also collected were the details of the initial and subsequent metastatic BC diagnoses. To look for potential differences and inconsistencies in data collection, an initial set of 20 patient charts was reviewed by 3 of the investigators (S.P., N.I., N.G.), and modifications to the methodology were implemented as appropriate. 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 considered debatable or uncertain were reviewed by the primary investigator (S.P.).
      We were particularly interested in the following: how the metastatic recurrence was discovered (symptoms, finding at examination, or other method of detection) and whether this differed among receptor subtypes; if patients had symptoms, where and when they sought care (to an oncology clinic at a prescheduled follow-up or acute-care visit, an emergency department, urgent care, or primary care); and OS, stratified by manner of metastatic presentation.

      Statistical Analysis

      The association between characteristics at initial diagnosis and presence of symptoms at metastatic presentation was evaluated by Firth-penalized logistic regression models. Cox regression models were utilized to assess factors associated with time to recurrence (TTR) and 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 (CIs). All statistical testing was 2 sided and was assessed for significance at the 5% level using SAS 9.4 (SAS Institute, Cary, NC).

      Results

      A total of 2028 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 BC clinic who had not been identified via the 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 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 examination findings and 4.1% by abnormal laboratory results. Diagnoses made incidentally via imaging done for other reasons accounted for 7.8% of the cohort. A total of 6 patients (1.6%) had a locoregional recurrence diagnosed initially, with metastatic findings discovered on subsequent staging scans.
      Table 1Diagnostic Characteristics of 371 Initial and Metastatic Diagnoses
      CharacteristicN (%)
      Initial Stage
       I65 (19.3)
       II150 (44.7)
       III121 (35.9)
       Missing35 (—)
      Initial Receptor Status
       ER/PR HER2+23 (6.8)
       ER/PR+ HER2216 (64.3)
       ER/PR+ HER2+33 (9.8)
       Triple negative64 (19)
       Missing35 (—)
      How Diagnosis of Metastasis Was First Suspected
       Symptoms287 (77.6)
       Clinical exam by physician12 (3.2)
       Screening breast imaging in which local recurrence was found, prompting systemic imaging6 (1.6)
       Screening chest X-ray6 (1.6)
       Incidental on imaging29 (7.8)
       Laboratory results only15 (4.1)
       Other15 (4.1)
       Missing1 (—)
      Abbreviations: ER = estrogen receptor; PR = progesterone receptor.
      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 nononcologic provider. Musculoskeletal pain was the most common symptom (33.7%); it was more frequently noted at scheduled visits (48.9%) compared to acute-care visits (26.0%, P < .01). Figure 2 depicts the subtypes of symptoms that were analyzed and the frequency with which they occurred.
      Figure thumbnail gr2
      Figure 2Symptoms Reported at Diagnosis of Metastasis
      Neither initial stage nor receptor status was associated with the presence of symptoms at diagnosis of metastasis (P = .58 and .68, respectively). Upon further analysis of specific types of symptoms, metastatic bone pain was not associated with any particular receptor subtype (P = .12). However, receptor status was associated with nervous system (NS) symptoms at diagnosis of metastasis (P = .01), with higher odds of NS symptoms in TN (OR = 3.02; 95% CI, 1.05-8.44) compared to estrogen receptor (ER)/progesterone receptor (PR)-positive, 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 and 95% CI, 0.88-12.29; ER/PR HER2+: OR = 3.82 and 95% CI, 0.79-14.97).
      Initial stage and receptor status were associated with TTR (both P < .01). Those with stage III disease (vs. stage I, HR = 1.69 and 95% CI, 1.24-2.31) and TN BC (vs. ER/PR+, HER2, HR = 2.52 and 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 diagnosis of metastasis (Table 2, Figure 3) whereas the presence of symptoms at diagnosis of metastasis was not (HR = 1.21, 95% CI, 0.86-1.70).
      Table 2Multivariable Analysis for 10-Year Overall Survival
      CovariateNHR95% CIP
      Initial Stage.03
      Statistically significant; level of significance 5% using 2-sided test.
       I54Reference
       II1321.671.10-2.54
       III1111.831.15-2.91
      Initial Receptor<.01
      Statistically significant; level of significance 5% using 2-sided test.
       ER/PR HER2+200.450.25-0.81
       ER/PR+ HER21870.350.22-0.55
       ER/PR+ HER2+300.240.13-0.45
       Triple negative61Reference
      Received Chemotherapy After Initial Diagnosis0.76-1.64.58
       Yes2251.12
       No73Reference
      Received Endocrine Therapy After Initial Diagnosis0.70-1.52.88
       Yes1801.03
       No118Reference
      Age at Diagnosis of Metastasis1.23-2.25<.01
      Statistically significant; level of significance 5% using 2-sided test.
       ≥60 y1231.66
       <60 y175Reference
      Mode of Diagnosis0.86-1.70.27
       Presence of symptoms at diagnosis of metastasis2391.21
       Other means of diagnosis59Reference
      Time to Recurrence1.20-2.20<.01
      Statistically significant; level of significance 5% using 2-sided test.
       <5 y1881.62
       ≥5 y167Reference
      Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; PR = progesterone receptor.
      a Statistically significant; level of significance 5% using 2-sided test.
      Figure thumbnail gr3
      Figure 3Ten-Year Overall Survival by TTR
      Abbreviation: TTR = time to recurrence.

      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 the impact on survival. Although several studies have explored how the various molecular subtypes of BC recur as well as the risk factors that predict recurrence, to our knowledge, this is the first study to specifically explore the different presentations of symptoms at metastasis.
      • San-Gang W.
      • Sun J.Y.
      • Yang L.C.
      • et al.
      Patterns of distant metastatic in Chinese women according to breast cancer subtypes.
      • Metzger-Filho O.
      • Sun Z.
      • Viale G.
      • 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.
      • Wu Q.
      • Li J.
      • Zhu S.
      • et al.
      Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study.
      • Kaplan M.A.
      • Arslan U.Y.
      • Isikdogan A.
      • et al.
      Biological subtypes and distant relapse pattern in breast cancer patients after curative surgery.
      • Voduc K.D.
      • Cheang M.C.
      • Tyldesley S.
      • Gelmon K.
      • Nielsen T.O.
      • Kennecke H.
      Breast cancer subtypes and the risk of local and regional relapse.
      • Geurts Y.M.
      • Witteveen A.
      • Bretveld R.
      • et al.
      Patterns and predictors of first and subsequent recurrence in women with early breast cancer.
      The proportion of patients in our study with TN and HER2+ disease was greater than typically reported in surveillance databases,
      • Howlader N.
      • Altekruse S.F.
      • Li C.I.
      • et al.
      US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status.
      which likely reflects the increased recurrence rates that occur in patients with both receptor subtypes. As expected, most metastatic recurrences occurred in those with disease of 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 et al
      • Pandya K.J.
      • McFadden E.T.
      • Kalish L.A.
      • Tormey D.C.
      • Taylor 4th, S.G.
      • Falkson G.
      A retrospective study of earliest indicators of recurrence in patients on Eastern Cooperative Oncology Group adjuvant chemotherapy trials for breast cancer.
      drew a similar conclusion in their retrospective study of the earliest indicators of BC recurrence, finding that 54.3% of patients who experienced relapse presented with symptoms or with an abnormality detected by self-examination. 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 et al 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 Kerr,
      • Dewar J.A.
      • Kerr G.R.
      Value of routine follow up of women treated for early carcinoma of the breast.
      whereby 92 metastatic recurrences were reported, only one of which was asymptomatic, with the remainder of patients experiencing symptoms at relapse. 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 nonmusculoskeletal complaints were more frequently reported with the former. This may reflect the severity of nonmusculoskeletal symptoms that involve the cardiac, pulmonary, and NSs.
      Historically, studies have shown that hormone-positive BC most commonly metastasizes to bone, and brain metastasis is more common in TN and HER2+ cancers.
      • Metzger-Filho O.
      • Sun Z.
      • Viale G.
      • 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.
      ,
      • Lee S.J.
      • Park S.
      • Ahn H.K.
      • et al.
      Implications of bone-only metastases in breast cancer: favorable preference with excellent outcomes of hormone receptor positive breast cancer.
      ,
      • Kennecke H.
      • Yerushalmi R.
      • Woods R.
      • et al.
      Metastatic behavior of breast cancer subtypes.
      Despite this, 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, however, receptor subtype was associated with NS symptoms at diagnosis of metastasis, with higher odds of symptoms in TN relative to ER/PR+, HER2 disease. 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 performed for other reasons (7.8%), and even fewer by clinical examination (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 examination). Thus, theoretically, the clinical encounter would suffice to detect a metastatic recurrence in most patients. Interestingly, a significant portion of patients presenting with symptoms (at scheduled or acute-care visits) had a clinical encounter with a nononcologic provider. Similarly, in a study performed in England, Grunfeld et al
      • Grunfeld E.
      • Mant D.
      • Yudkin P.
      • et al.
      Routine follow up of breast cancer in primary care: randomized trial.
      found that almost half of patients with recurrences first presented to their general practitioners. While oncologists may be well aware of symptoms that should prompt further evaluation of recurrent cancer, other types of providers may not. We hope our study offers such providers guidance, so that they might 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 experiences significant morbidity.
      Institute of Medicine; National Research Council
      From Cancer Patient to Cancer Survivor: Lost in Transition.
      In a prospective study on the patterns of BC relapse, Elder et al
      • Elder E.E.
      • Kennedy C.W.
      • Gluch L.
      • et al.
      Patterns of breast cancer relapse.
      found that the location of metastatic disease affected survival, with bony metastases having the most favorable prognosis. Similarly, Pogoda et al
      • Pogoda K.
      • Niwinska A.
      • Murawska M.
      • Pienkowski T.
      Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients.
      found that metastasis location was associated with survival in TN BC patients. Klar et al
      • Klar N.
      • Rosenzweig M.
      • Diergaarde B.
      • Brufsky A.
      Features associated with long-term survival in patients with metastatic breast cancer.
      showed that the presence of visceral metastasis and/or brain metastasis was negatively associated with long-term survival of patients with metastatic BC, as was TN receptor status. 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 at metastatic recurrence, OS is not affected. The location of metastatic disease appears to be a more significant predictor of survival than symptoms.
      Our study had several limitations that were potentially unavoidable. The determination of how a patient’s BC recurrence was first found (eg, via symptoms or incidentally on imaging) 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, so some creativity was required to identify data elements that could be collected from TriNetX that were reflective of those patients who had experienced recurrence. Consequently, some patients who would have fit the criteria may have been missed. Last, 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 who are undergoing 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 BC 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 BC patients, who often experience anxiety related to the possibility of cancer recurrence.
      • Previous studies have shown that BC recurrence is usually discovered as a result of symptoms.
      • Our study aimed to investigate methods of diagnosing recurrence, whether the method of diagnosis of metastasis resulted in a difference in survival, and whether certain BC subtypes were associated with differences in symptomatology.
      • Consistent with previous literature, we found that most patients present with symptoms at diagnosis of metastasis. We also found that having symptoms at diagnosis is not associated with 10-year survival.
      • Patients with TN BC were more likely to have NS symptoms at the time of diagnosis of metastasis, consistent with the fact that these patients have a higher chance of brain metastasis.
      • Our findings will, we hope, ease the minds of patients who are anxious about waiting until the onset of symptoms to obtain imaging.
      • Our results support the use of symptom-directed imaging and not surveillance imaging in the follow-care of BC 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.

      Disclosure

      The authors have stated that they have no conflict of interest.

      Acknowledgment

      Supported in part by the Holden Comprehensive Cancer Center Population Research and Biostatistics Cores ( P30 CA086862 ).

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