Breast Cancer

, Volume 19, Issue 3, pp 218–237 | Cite as

Possible clinical cure of metastatic breast cancer: lessons from our 30-year experience with oligometastatic breast cancer patients and literature review

  • Tadashi Kobayashi
  • Tamotsu Ichiba
  • Toshikazu Sakuyama
  • Yasuhiro Arakawa
  • Eijiroh Nagasaki
  • Keisuke Aiba
  • Hiroko Nogi
  • Kazumi Kawase
  • Hiroshi Takeyama
  • Yasuo Toriumi
  • Ken Uchida
  • Masao Kobayashi
  • Chihiro Kanehira
  • Masafumi Suzuki
  • Naomi Ando
  • Kazuhiko Natori
  • Yasunobu Kuraishi
Special Feature From improved survival to potential cure in patients with metastatic breast cancer

Abstract

Background

Metastatic breast cancer (MBC) is generally incurable. However, 10–20-year relapse-free survival of MBC is approximately 2%, implying that at least a small subset of MBC patients achieve prolonged survival. We therefore analyzed long-term outcome in a particular subset, i.e., oligometastatic breast cancer (OMBC).

Methods

Data of OMBC subjects (N = 75) treated in our institution from April 1980 to March 2010 were retrospectively analyzed. OMBC was identified as: one or 2 organs involved with metastatic lesions (excluding the primary lesion resectable by surgery), fewer than 5 lesions per metastasized organ, and lesion diameter less than 5 cm. Patients were generally treated with systemic chemotherapy first, and those who achieved complete response (CR) or partial response (PR) were further treated, if applicable, with local therapy (surgical or radiation therapy) to maintain CR or to induce no evidence of clinical disease (NED), with additional systemic therapy.

Results

Median follow-up duration was 103 (6–329) months. Single or 2 organs were involved in, respectively, 44 (59%) and 31 (41%) cases with metastatic lesions, 48% of which were visceral. In cases where effects of systemic therapy, possibly in combination with other treatments, were evaluated (N = 68), CR or PR was achieved in 33 (48.5%) or 32 (47.1%), respectively, with overall response rate (ORR: CR + PR) of 95.6% (N = 65). In cases receiving multidisciplinary treatment (N = 75), CR or NED (CR/NED), or PR was induced in 48 (64.0%) or 23 (30.7%) cases, respectively, with ORR (CR/NED + PR) of 94.7% (N = 71). CR rates (60.5%) with systemic therapy and CR/NED rates (79.5%) with multidisciplinary treatment were significantly better in subjects with a single involved organ than in those with two involved organs (P = 0.047 and 0.002, systemic only or multidisciplinary treatments, respectively).

Medians estimated by Kaplan–Meier method were: overall survival (OS) of 185.0 months and relapse-free interval (RFI) of 48.0 months. Estimated outcomes were: OS rates (OSR) of 59.2% at 10 years and 34.1% at 20 years, and relapse-free rates (RFR) of 27.4% at 10 years and 20 years. No disease progression was observed after 101.0 months as RFR. Cases with single organ involvement (N = 44) showed significantly better outcomes (OSR of 73% at 10 years and 52% at 20 years, RFR of 42% at 10 years and 20 years). Those who received local therapies (N = 35) also showed better prognosis: OSR of 82% at 10 years and 53% at 20 years, RFR of 38% at 10 years and 20 years. Three cases (4%) survived for their lifetime without relapse after achieving CR or NED, our definition of clinical cure.

Multivariate analysis revealed factors favoring better prognosis as: none for OS, and single organ involvement with metastasis, administration of local treatment, and shorter disease-free interval (DFI) (P = 0.030, 0.039, and 0.042, respectively) for RFR. Outcomes in OMBC in literature were OSR of 35–73% at 10 years and 26–52% at 20 years, and RFR of 27–42% at 10 years and 26–42% at 20 years.

Conclusions

The present analyses clearly indicate that OMBC is a distinct subgroup with long-term prognosis superior to MBC, with reasonable provability for clinical cure. Further prospective studies to better characterize OMBC are warranted to improve prognosis in MBC.

Keywords

Oligometastatic breast cancer Metastatic breast cancer Relapse-free survival Cure Clinical cure 

Introduction

Metastatic breast cancer (MBC) encompasses both primary breast cancers with distant metastases and those recurrent after surgical intervention. Unlike early-stage breast cancers, cure is rarely achieved in patients with MBC [1], and therefore current treatment for MBC is focused mainly on prolonging patient life and improving and maintaining quality of life (QOL). Median survival for MBC is variably reported but generally short, e.g., 8–24 months [1], 18–24 months [1, 2, 3], or as long as 2–4 years [4, 5]. Data on long-term survival beyond 3–5 years are limited [1, 2, 3], but 20-year survivals are reported as low as 1–3% [1, 4, 6]. However, development of new approaches in the last decade, using new hormone therapy formulations, chemotherapy agents, and drugs targeting specific molecules, brought hope for improved survival of MBC [7, 8]. A systematic review of results from various randomized trials on therapy regimens for MBC, including 370 trials with a total of 54,189 patients treated between 1973 and 2007, was performed, and survival data of 26,031 patients were obtained. A meta-analysis in this study indeed demonstrated that transition of systemic treatment regimes has stepwisely achieved significant improvement in survival rate of MBC over the last 30 years [9]. The improved efficacy of systemic therapy would ultimately lead to clinical cure of MBC, through increasing rate of complete response (CR) and prolonging no evidence of clinical disease (NED) following local treatments.

On the other hand, definition for “cure” of the breast cancers has yet been unanimously defined. Some suggest cure of breast cancer as a condition where cancer cells are eradicated, permitting a normal lifespan without threat of recurrence [3, 10] or without cancer-related complaints [11], whereas others consider that all cancer cells do not have to be destroyed in “cure,” but rather that disease must be rendered harmless (without clinically significant adverse effects) for prolonged periods [2]. In the present article, we define cure as clinical cure, in which systemic therapy has induced complete response (CR) or local therapy maintained no evidence of clinical disease (NED), i.e., sustained relapse-free interval (RFI) and no recurrence of cancer after CR/NED induction during the entire lifespan of the patient [12].

Factors that affect prognosis of MBC include: number of recurrence sites, tumor cell numbers, patient age and performance status (PS), disease-free interval (DFI) after surgical intervention, and tumor biology [grade, estrogen receptor status, human epidermal growth factor receptor type 2 (HER2) status] [3, 13]. Long-term survivors are usually young and have excellent PS with limited metastatic lesions [4]. Also, CR is more efficiently achieved in MBC with low tumor burden and good PS, and in those whose metastatic lesions are predominantly in soft tissues. Furthermore, survival periods for those in whom CR is established are significantly longer than those without CR [1, 14, 15]. In particular, MBC with only a few metastatic lesions is categorized as oligometastatic breast cancer (OMBC). In general, one or more organs are involved by a single metastatic lesion in OMBC [2, 11, 13, 16]. OMBC is a new paradigm proposed by Hellman in 1995 [16]. Due to its relatively limited nature, oligometastases either de novo or following systemic treatment could be removed by local therapy. In cases with more advanced lesions with possible subclinical systemic spreading, addition of systemic therapy would be further required. Therefore, the paradigm proposes that surgical and/or radiation therapies targeting solitary oligometastatic lesions could potentially cure oligometastases either alone or in combination with systemic therapy. To date, oligometastases denote lesions with limited metastases, solitary metastasis, isolated metastases, or minimal metastases. However, OMBC has not yet been widely recognized since its proposal in 1995, and despite many reports that suggest benefits of aggressive multidisciplinary treatment to induce long-term CR or cure [1], little data are available regarding clinical outcome, particularly for long-term observations, of OMBC following therapeutic interventions. OMBC is often surgically excised or treated with radiation, and consequent conditions without lesions are defined as stage IV-NED (no evidence of clinical disease). Two approaches are possible for treatment strategies in achieving long-lasting CR/NED and ultimate cure of OMBC. One is multidisciplinary treatment that first performs local therapy to remove clinically detectable lesions to establish disease-free status, i.e., stage IV-NED, after which postsurgical systemic treatment similar to adjuvant therapy in the case of primary breast cancer is administered. Outcomes from this approach in the longest and largest-scale study for 30 years conducted in M.D. Anderson Cancer Center (MDACC) were reported [17]. This approach stresses the characteristics of OMBC as a local disease. In contrast, the other approach emphasizes a systemic nature of breast cancer and therefore treats OMBC first with systemic therapies (chemo-, hormone, and molecular-targeted therapies), followed by local therapy targeting remaining lesions, mainly in responders to the initial systemic treatment, to achieve prolonged CR and subsequent clinical cure. We have adopted the latter approach in treating breast cancer patents in our institution since 1980. In this multidisciplinary approach, the systemic therapy rather resembles neoadjuvant therapy for de novo primary breast cancer. In the present article, we retrospectively analyze our clinical experience in the past 30 years. To our knowledge, the present article is the first to date reporting therapeutic outcome, particularly for the long term, by the systemic therapeutic strategy in OMBC, along with a systematic review of previous literature.

The primary purpose of the present analyses is to assess the long-term maintenance rate of CR/NED, an equivalent to clinical cure, in patients with OMBC. Secondly, we aim to evaluate factors that affect prognosis of OMBC. We also review literature on long-term survival rates in MBC and therapeutic outcomes of OMBC that have achieved long-term CR/NED, along with our experience, to address issues that would benefit our future approach to establish clinical cure in MBC.

Patients and methods

Patient selection

We performed retrospective analyses of cases of OMBC selected from the MBC patients treated mainly with chemotherapy-based systemic treatment as front-line therapy in our institution during the last 30 years between April 1980 and March 2010.

Patients who met all 3 following criteria as a modified, milder definition were considered as having OMBC: number of organs involved with metastatic lesions other than those with primary lesions (for which curative surgery was considered possible) of 2 or less; number of metastatic lesions per organ of 5 or less (in lungs or bones that were too small or unclear for detection by diagnostic imaging, approximately 10 or less); lesion diameter of 5 cm or less. Patients were excluded from the present analyses if: the patient had previously received intensive chemotherapy, such as those whose regimen included substantial dose and/or intensity of anthracyclines or taxanes to their metastatic lesions prior to study enrollment; the lesion was a recurrence within 1 year after adjuvant or neoadjuvant chemotherapy including anthracyclines or taxanes; patients presenting pulmonary lymphangitis carcinomatosis, symptomatic brain metastasis, dysfunction of critical organs such as bone marrow, heart, liver, or kidney, simultaneous active cancers of separate origin, or any other serious health problems. Patients were fully informed regarding their therapeutic decisions, and each patient’s consent was obtained and recorded prior to initiating treatment. For those demonstrating sensitivity to hormone therapy, the general recommendation for hormone therapy as initial systemic treatment for OMBC was explained, and only those who preferred to receive chemotherapy prior to hormone treatment were treated with chemotherapy as initial treatment, since an algorithm for treatment of recurrent breast cancer was reported by Hortobagyi in 1998 [18].

Treatments and evaluation of responses

In general, eligible patients received systemic chemotherapy first, and responders who achieved CR or partial response (PR) were, if applicable, further treated with local therapy (surgery or radiation) to sustain CR and to induce NED by removing the remaining tumor mass. In addition, systemic therapy (chemotherapy and hormone or molecular-targeted therapy, if applicable) was administered. Anthracycline-based regimens such as ACFV [doxorubicin (DOX), cyclophosphamide (CPM), tegafur, and vincristine (VCR)] were the front-line chemotherapies between 1980 and 1997, and taxane with or without anthracycline-based regimens such as AT [DOX, docetaxel (DOC)] were frequently used since 1998. The ACFV regimen consisted of DOX 40 mg/m2 i.v., CPM 500 mg/m2 i.v., and VCR 1.4 mg/m2 (maximum 2.0 mg/body) i.v. at day 1, and repeated every 3 weeks, along with tegafur 800 mg/body p.o. daily until white blood cell (WBC) counts dropped below 2,000/mm3. When cumulative dose of DOX exceeded 400 mg/m2, regimen was switched to CMF (CPM, methotrexate, fluorouracil) for maximum of 2 years in CR cases, or until disease progression was observed or side-effects became intolerable in non-CR cases. AT regimen included DOX 50 mg/m2 i.v. and DOC 60 mg/m2 i.v. at day 1 followed by every 3-week administration of the combination. DOX was discontinued after total dose of DOX exceeded 400 mg/m2 and changed to a regimen mainly with DOC, similar to that described for ACFV.

Prior and during the treatment, all patients underwent evaluation with complete medical history, physical examination, baseline blood tests, and imaging evaluations [radiography, bone scintigraphy, computed tomography scan, magnetic resonance imaging (MRI), and ultrasonography, if necessary and available]. Effects of the treatment were generally monitored by imaging analyses at every 3 months for lesions detected at diagnosis of OMBC or every 6 months without detectable lesions before the treatment.

Effects of the treatment were assessed by analyses of maximum response, according to either the criteria of the World Health Organization (WHO) [19] or the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 [20] since its announcement in 2004. Responses in bone metastases were evaluated using the methods reported by MDACC [14, 15], with CR as clear evidence of complete bone recalcification with attainment of near-normal bone architecture or normalization of scan, and PR as radiological evidence of sclerosis in lytic lesions or marked improvement of bone scan. In recent years, MRI was performed when available, and the imaging information was taken into account in evaluation of bone metastases. Responses in pleural fluids were determined as: CR for radiological demonstration of complete disappearance of pleural fluid, and PR for 50% or more decrease. For study inclusion, pathological diagnosis of the primary lesions had to be obtained, whereas tissue or cellular pathology of the metastatic lesions was preferred but not mandatory.

Variables

Information regarding patient age, DFI, PS, involved organs and their number, status of estrogen receptor (ER), progesterone receptor (PgR), and HER2, Ki67 status, and previous treatments prior to the present study periods was obtained from medical records. Immunohistochemical (IHC) staining was performed for ER, PgR, HER2, and Ki67. ER and PgR positivity were defined as any positive nuclear staining (≥1%), and HER2 positivity was defined as IHC score 3+ or fluorescence in situ hybridization (FISH) with amplification ratio ≥2.0. The cutoff point for Ki67 index was set as 13.25%, with below 14% defined as low, and 14% or higher defined as high expression [21]. Intrinsic breast cancer subtypes were classified according to a gene expression profile-validated IHC surrogate panel [22] as follows: luminal A (ER positive, low Ki67, and HER2 negative), luminal B (ER positive, high Ki67, and HER2 negative), HER2-like (any ER, any Ki67, and HER2 positive), and basal-like (ER negative, any Ki67, and HER2 negative).

Statistical analyses

The characteristics of the patients with assessable data were compared with χ2 test or Wilcoxon rank-sum tests. Overall survival (OS) was defined as duration from initiation of treatment to last visit or death. Progression-free interval (PFI) was defined as duration from initiation of treatment to the point when disease progression was detected. Complete response (CR) achieved by a systemic therapy or no evidence of clinical disease (NED) after a local therapy was considered relapse-free, and the duration between induction of relapse-free status and the point of relapse detection was defined as the relapse-free interval (RFI); survival time after induction of relapse-free status without relapse was defined as relapse-free survival (RFS). Unrelated death other than from breast cancer was considered as censored in evaluation of PFI and RFI. Survival curves were determined by the Kaplan–Meier method, and analyzed using the log-rank test. A multivariate analysis was performed by Cox regression and included the following variables: age, DFI, PS, number of involved organs, types of involved organs, liver metastasis, hormone receptor status, HER2 status, Ki67 status, intrinsic subtype, administration of local therapy, and chemotherapy regimens. Differences were considered statistically significant for P < 0.05. All P values were calculated for two-sided analyses.

Results

Analyses of OMBC patients in our institution in the last 30 years

Patient characteristics

There were 75 OMBC cases with sufficient records, and the patient characteristics at diagnosis are presented in Table 1. Performance status was good (PS 0 or 1) in the majority of subjects (92%). The number of organs involved with metastatic lesions was 1 in 44 cases (59%) and 2 in 31 cases (41%). Visceral metastases were found in approximately half of cases (48%). Metastases in liver, known as the worst prognosis group, were found in 10 patients. No brain metastasis was found at time of OMBC diagnosis. Ki67 levels were low in 42 cases (56%) and high in 18 cases (24%), though we encountered more cases with negative Ki67 staining by IHC in cases whose samples were preserved for prolonged periods from their acquisition. Intrinsic subtypes were luminal A in 26 cases (35%), luminal B in 7 cases (9%), HER2-like in 13 cases (17%), and basal-like in 18 cases (24%). Adjuvant or neoadjuvant therapy prior to relapse detection was performed in 30 cases (40%), which include anthracycline and/or taxane-based regimens in 16 cases (21%) and non-anthracycline and/or taxane-based regimens (CMF, fluorouracil, mitomycin C) in 14 cases (19%). For the metastatic lesions, 3 patients (4%) received chemotherapy prior to the present study periods, whereas no systemic treatments were previously performed in other 65 cases (87%).
Table 1

Characteristics of patients with oligometastatic breast cancer prior to treatment

 

No. of patients

No. of evaluable patients

75

Median age (years)

48 (28–69)a

Median DFI (months)

25.3 (0–168)a

PS

 0

52 (69)

 1

17 (23)

 2

2 (3)

 Unknown

4 (5)

No. of involved organs

 1

44 (59%)

 2

31 (41%)

Involved organs

 Viscera

36 (48%)

 Soft part

41 (55%)

 Bone

29 (39%)

Hormone receptor status

 ER and/or PgR positive

48 (64%)

 ER and PgR negative

24 (32%)

 Unknown

3 (4%)

HER2 status

 Positiveb

13 (17%)

 Negative

55 (73%)

 Unknown

7 (9%)

Ki67 level

 Low (<14%)

42 (56%)

 High (≥14%)

18 (24%)

 Unknown

15 (20%)

Intrinsic subtype by IHC

 Luminal A

26 (35%)

 Luminal B

7 (9%)

 HER2-like

13 (17%)

 Basal-like

18 (24%)

 Unknown

11 (15%)

Previous treatment

 Breast surgery

61 (81%)

 Adjuvant/neoadjuvant setting

 

  Chemotherapy

30 (40%)

   Anthracycline and/or taxane-based

16 (21%)

   Non-anthracycline and/or taxane-based

14 (19%)

  HER2-targeting therapy

2 (3%)

  Hormonal therapy

23 (31%)

  No adjuvant/neoadjuvant therapy

30 (40%)

  Unknown

4 (5%)

 Metastatic setting

  Chemotherapy

3 (4%)

   Taxane ± anthracycline-based

2 (3%)

   Non-anthracycline and/or taxane-based

1 (1%)

  HER2-targeting

1 (1%)

  Hormonal therapy

5 (7%)

  No systemic therapy

65 (87%)

  Unknown

1 (1%)

DFI disease-free interval, ER estrogen receptor, HER2 human epidermal growth factor receptor type 2, IHC immunohistochemical assays, No. number, PgR progesterone receptor, PS performance status [Eastern Cooperative Oncology Group (ECOG)]

aRange

bHER2 positive: Hercep Test™ score 3(+) or FISH amplified

Treatments administered

Systemic chemotherapy was performed as an initial treatment for OMBC in 66 cases (88%), including 63 cases (83%) with chemotherapy only and 3 cases (4%) with simultaneous treatment of both chemo- and radiation therapy, as an initial treatment. Others at first received local treatment by either radiation therapy (5 cases, 7%) or surgical excision (4 cases, 5%), followed by a systemic treatment. Chemotherapy regimens utilized in the study subjects included anthracycline-based regimens in 23 cases (30.7%), taxane with or without anthracycline-based regimens in 49 cases (65.3%), and molecular-targeted regimens in 3 cases (4.0%). Among the anthracycline-based regimens, ACFV regimen was most frequently used (15 cases). Among the taxane with or without anthracycline-based regimens, AT regimen was the most common (40 cases). In 23 cases administered anthracycline-based regimens against OMBC, adjuvant or neoadjuvant chemotherapy prior to relapse was performed in 4 cases (17.4%); regimens included non-anthracycline and/or taxane-based regimens (CMF, fluorouracil, mitomycin C) in 3 cases (13.0%) and anthracycline and/or taxane-based regimens in 1 case (4.3%). Among 49 cases who received taxane with or without anthracycline-based regimens for OMBC, 23 cases (46.9%) received adjuvant or neoadjuvant chemotherapy, including non-anthracycline and/or taxane-based regimens (9 cases, 18.4%) and anthracycline and/or taxane-based regimens (14 cases, 28.6%). Patients whose OMBC was treated with taxane with or without anthracycline-based regimens had more frequently received adjuvant/neoadjuvant therapy for their primary lesions, compared with those whose OMBC had been treated with anthracycline-based regimens. Among those who had received adjuvant or neoadjuvant therapies to their primary lesions, agents with more potent antitumor effects were more frequently used in those whose treatment for OMBC was taxane-based compared with those with anthracycline-based regimens.

Response to systemic or multidisciplinary treatments in each subgroup

Table 2 presents overall responses in all 75 subjects treated either by systemic therapy only (chemotherapies except 1 case with hormone therapy) or by multidisciplinary treatment in combination with local therapies. In 68 cases for which isolated effects of systemic therapy only were evaluated, overall response rates (ORR: CR + PR) were 65 cases [95.6%, 95% confidence interval (CI) 86.8–98.9%], with CR in 33 cases (48.5%, 95% CI 36.4–60.9%) and PR in 32 cases (47.1%, 95% CI 35.0–59.5%). The overall effects of multidisciplinary treatments were evaluated in all the OMBC cases (N = 75), with CR or NED (CR/NED), and PR achieved in 48 cases (64.0%, 95% CI 52.0–74.5%), and 23 cases (30.7%, 95% CI 20.8–42.5%), respectively, with ORR (CR/NED + PR) of 71 cases (94.7%, 95% CI 86.2–98.3%). When CR or CR/NED rates were compared in each subgroup, those with only one organ involved with metastatic lesions showed significantly higher CR or CR/NED rates compared with those with 2 involved organs, in either systemic therapy only groups (P = 0.047) or those who received multidisciplinary treatments (P = 0.002). Among metastatic patients with single organ involvement, CR was achieved in 60.5% of patients treated with systemic therapy and in 79.5% of those who received multidisciplinary treatments. Patients with low Ki67 levels tended to show higher CR or CR/NED rates with either systemic (P = 0.055) or multidisciplinary treatments (P = 0.09). Among patients who received any local therapy, those whose approaches were multidisciplinary demonstrated higher CR/NED rates (P = 0.003) than those treated with chemotherapy as solo treatment. CR or CR/NED rates were higher in patients who received anthracycline-based regimens for their OMBC (P = 0.010 in systemic therapy only, P = 0.064 in multidisciplinary treatment group) compared with those who received taxane with or without anthracycline-based regimens. Other factors such as patient age, DFI, status of hormone receptors and HER2, intrinsic subtype, and presence of liver metastases did not significantly affect rates for CR or CR/NED.
Table 2

Response by therapeutic approach in patient subgroups

 

Response to systemic therapy

Response to multidisciplinary therapy

No. evaluable

CR

PR

CR + PR

P (CR rate)

No. evaluable

CR/NED

PR

CR/NED + PR

P (CR/NED rate)

Total no. of patients

68

33 (49)

32 (47)

65 (96)

 

75

48 (64)

23 (31)

71 (95)

 

Age (years)

    

NS

    

NS

 <48

29

12 (41)

16 (55)

28 (97)

 

33

20 (61)

12 (36)

32 (97)

 

 ≥48

39

21 (54)

16 (41)

37 (95)

 

42

28 (67)

11 (26)

39 (93)

 

DFI (months)

    

NS

    

NS

 <25.3

31

15 (48)

15 (48)

30 (97)

 

34

24 (71)

9 (26)

33 (97)

 

 ≥25.3

31

16 (52)

13 (42)

29 (94)

 

34

22 (65)

10 (29)

32 (94)

 

No. of involved organs

    

0.047

    

0.002

 1

38

23 (61)

14 (37)

37 (97)

 

44

35 (80)

8 (18)

43 (98)

 

 2

30

10 (33)

18 (60)

28 (93)

 

31

13 (42)

15 (48)

28 (90)

 

Hormone receptor status

    

NS

    

NS

 ER and PgR positive

24

11 (46)

13 (54)

24 (100)

 

28

16 (57)

11 (39)

27 (96)

 

 ER or PgR positive

19

10 (53)

7 (37)

17 (89)

 

20

14 (70)

4 (20)

18 (90)

 

 ER and PgR negative

23

10 (43)

12 (52)

22 (96)

 

24

15 (63)

 

23 (96)

 

HER2 status

    

NS

     

 Positive

13

5 (38)

6 (46)

11 (85)

 

13

8 (62)

8 (33)

11 (85)

 

 Negative

49

23 (47)

25 (51)

48 (98)

 

55

34 (62)

3 (23)

53 (96)

 

Ki67 level

    

0.055

  

19 (35)

 

0.090

 Low (<14%)

37

2 (59)

13 (35)

35 (95)

 

42

30 (71)

9 (21)

39 (93)

 

 High (≥14%)

18

5 (28)

12 (67)

17 (94)

 

18

8 (44)

9 (50)

17 (94)

 

Intrinsic subtype by IHC

    

NS

    

NS

 Luminal A

21

13 (62)

8 (38)

21 (100)

 

26

18 (69)

7 (27)

25 (96)

 

 Luminal B

7

1 (14)

6 (86)

7 (100)

 

7

3 (43)

4 (57)

7 (100)

 

 HER2-like

13

5 (38)

6 (46)

11 (85)

 

13

8 (62)

3 (23)

11 (85)

 

 Basal-like

17

8 (47)

8 (47)

16 (94)

 

18

11 (61)

6 (33)

17 (94)

 

Local therapy

    

NS

    

0.003

 (−)

40

19 (48)

18 (45)

37 (93)

 

40

19 (48)

18 (45)

37 (93)

 

 (+)

28

14 (50)

14 (50)

28 (100)

 

35

29 (83)

5 (14)

34 (97)

 

Liver metastases

    

NS

    

NS

 (−)

58

29 (50)

27 (47)

56 (97)

 

65

43 (66)

19 (29)

62 (95)

 

 (+)

10

4 (40)

5 (50)

9 (90)

 

10

5 (50)

4 (40)

9 (90)

 

Chemotherapy regimen

    

0.010

     

 Anthracycline-based

20

15 (75)

5 (25)

20 (100)

 

23

19 (83)

3 (13)

22 (96)

0.064

 Taxane ± anthracycline-based

46

17 (37)

27 (59)

44 (96)

 

49

28 (57)

19 (39)

47 (96)

 

 Molecular-targeted

2

1 (50)

0

1 (50)

 

3

2 (67)

0 (0)

2 (67)

 

Values in parentheses indicate percentage

CR complete response, ER estrogen receptor, HER2 human epidermal growth factor receptor type 2, IHC immunohistochemical assays, NED no evidence of clinical disease, No. number, NS not statistically significant, PgR progesterone receptor, PR partial response

Overall survival (OS), progression-free interval (PFI), and relapse-free interval (RFI)

Median follow-up duration was 103 (6–329) months. Figure 1 shows OS, PFI, and RFI estimated by the Kaplan–Meier method for all study subjects. The RFI curve starts with all the patients who have achieved CCR/NED after multidisciplinary therapy (N = 75, 64% of all the study subjects), and the RFI is shown as percentage of the patients remained CCR/NED in the total study subjects. The estimated medians were OS of 185.0 months, PFI of 68.5 months, and RFI of 48.0 months. The estimated overall survival rate (OSR) was 79.2% at 5 years (95% CI 69.6–90.0%, 45 cases), 59.2% at 10 years (95% CI 46.9–74.7%, 16 cases), 51.2% at 15 years (95% CI 37.6–69.7%, 10 cases), and 34.1% at 20 years (95% CI 19.6–59.5%, 4 cases); the progression-free rate (PFR) was 56.8% at 5 years (95% CI 46.0–70.2%, 37 cases), 32.8% at 10 years (95% CI 22.3–48.1%, 10 cases), and 29.1% at 15 years and 20 years (95% CI 18.6–45.6%; 15 years: 6 cases; 20 years: 3 cases); the relapse-free rate (RFR) was 45.0% at 5 years (95% CI: 34.6-58.6%, 27 cases), and 27.4% at 10, 15, and 20 years (95% CI: 17.9-42.0%; 10 years: 8 cases; 15 years: 4 cases; 20 years: 3 cases). Among those whose PFR or RFR was longer than 128.0 and 101.0 months, respectively, no case with disease progression was observed. Median OS in cases with single organ involvement with metastatic lesions was 292 months with OSR of 73% at 10 years and 52% at 20 years, median RFI was 95 months, and RFR was 42% at 10 and 20 years, representing the best prognostic subgroup. Patients who received local therapy also showed good prognosis, with OSR of 82% at 10 years and 53% at 20 years, and RFR of 38% at 10 years and 20 years. OS in this subgroup had not reached median. By the time the current analyses were finalized, there were 3 cases (4%) that met our definition of clinical cure, and those subjects remained clinically relapse free for their entire survival periods, dying of traumatic intracranial hemorrhage at 85 years old, presumed acute cardiovascular disease at 64 years old, and an accident at 47 years old.
Fig. 1

Estimated overall survival, progression-free interval, and relapse-free interval by multidisciplinary treatment

OS in various response groups is shown in Fig. 2. In cases where CR/NED was induced, OS was significantly longer than in those who achieved PR or stable disease (SD) (P < 0.0001). Estimated median OS in CR/NED cases was 192.2 months, with 60-month OSR of 92.4% (95% CI 84.5–100%), 120-month OSR of 79.6% (95% CI 67.0–94.6%), 180-month OSR of 68.9% (95% CI 52.8–89.8%), and 240-month OSR of 45.9% (95% CI 27.0–78.2%); approximately 80% and 70% of CR/NED cases survived for 10 and 15 years, respectively, and about half of those cases were anticipated to survive 20 years after initial diagnosis of OMBC.
Fig. 2

Estimated overall survival by response to multidisciplinary treatment

Results of univariate analysis of OS, PFI, and RFI are shown in Table 3 by each factor. Factors that showed statistically significant benefits on OS were: single organ involvement by metastatic lesions (P = 0.0063), receipt of local therapies (P = 0.0063), absence of metastasis in liver (P = 0.0025), and anthracycline-based chemotherapy regimens (P = 0.0245). Statistically favorable factors for PFI were the same as those for OS except chemotherapy regimes, i.e., single organ involvement by metastatic lesion (P < 0.0001), receipt of local therapies (P = 0.0027), and absence of metastasis in liver (P = 0.0142). Significantly beneficial factors for RFI were also consistent with those for PFI: single organ involvement by metastatic lesions (P < 0.0001), receipt of local therapies (P = 0.0050), and absence of metastasis in liver (P = 0.0116). Age, DFI, hormone receptors and HER2 status, Ki67 levels, or intrinsic subtype did not demonstrate significant influences on OS, PFI, or CCR/NED.
Table 3

Main results of univariate analysis for estimated overall survival, progression-free interval, and relapse-free interval remained

 

No. evaluable

Overall survival

Progression-free interval

Relapse-free interval remaineda

Median (months)

5 years (%)

10 years (%)

15 years (%)

20 years (%)

P

Median (months)

5 years (%)

10 years (%)

15 years (%)

20 years (%)

P

Median (months)

5 years (%)

10 years (%)

15 years (%)

20 years (%)

P

All patients

75

185

79

59

51

34

 

69

57

33

29

29

 

48

45

27

27

27

 

No. of involved organs

      

0.0063

     

<0.0001

     

<0.0001

 1

44

292

87

73

61

52

 

128

74

50

45

45

 

95

63

42

42

42

 

 2

31

102

69

35

35

 

38

25

 

NA

22

 

Local therapy

      

0.0063

     

0.0027

     

0.0050

 (−)

40

102

71

42

38

23

 

34

38

20

20

20

 

NA

29

18

18

18

 

 (+)

35

NR

88

82

70

53

 

98

80

48

39

39

 

96

64

38

38

38

 

Liver metastases

      

0.0025

     

0.0142

     

0.0116

 (−)

65

187

80

66

61

41

 

83

61

38

34

34

 

52

50

32

32

32

 

 (+)

10

70

75

19

 

45

25

 

4

13

 

Chemotherapy regimen

      

0.0245

     

NS

     

NS

 Anthracycline-based

23

192

96

76

65

43

             

 Taxane ± anthracycline-based

49

NR

71

50

NR

NR

             

No statistical significance was shown for age, disease-free interval, hormone receptor status, HER2 status, Ki67 level, or intrinsic subtype

CR complete response, HER2 human epidermal growth factor receptor type 2, NED no evidence of clinical disease, NA not applicable, No. number, NR not reached, NS not statistically significant,

aEstimated percentile in all evaluable patients

Results of multivariate analysis are presented in Table 4. The anthracycline-based chemotherapy regimen demonstrated more favorable effects on OS, though the difference did not reach statistical significance (P = 0.097). Single organ involvement with metastatic lesions showed statistically significant benefit on PFI (P = 0.0023). Shorter DFI (P = 0.042), single organ involvement with metastatic lesions (P = 0.030), and administration of a local therapy (P = 0.039) showed significantly better effects on RFI, whereas negative hormone receptors (P = 0.086) and low Ki67 levels (P = 0.070) showed preferable trends toward better RFI despite lack of statistical significance.
Table 4

Main results of multivariate analysis

 

Hazard ratio

95% CI

P

Overall survival

 Chemotherapy regimen

   

  Anthracycline-based

1

  

  Taxane ± anthracycline-based

9.35

0.665–132

0.097

Progression-free interval

 No. of involved organs

  1

1

  

  2

3.18

1.18–8.58

0.023

Relapse-free interval

 DFI (months)

1.01

1.00–1.023

0.042

 No. of involved organs

  1

1

  

  2

2.68

1.10–6.55

0.030

 Hormone receptor status

  ER and PgR negative

1

  

  ER and/or PgR positive

1.79

0.920–3.483

0.086

 Ki67 level

  Low (<14%)

1

  

  High (≥14%)

3.49

0.901–13.508

0.070

 Local therapy

  (−)

1

  

  (+)

0.39

0.157–0.951

0.039

DFI disease-free interval, ER estrogen receptor, No. number, NED no evidence of clinical disease, PgR progesterone receptor

Review of literature on OMBC

Current status of MBC outcomes

At present, MBC is generally incurable. Despite ample reports on therapeutic outcomes of MBC, results from observation for over 10 years are rare, and therefore little is known regarding OS and RFR (CR/NED maintenance rate) in order to assess the possibility of achieving clinical cure in MBC. We summarize findings from publications to date on prognosis of MBC based on long-term observations in Table 5. Though such publications are extremely limited, OS for MBC has been reported as 12.2–22.5% at 5 years, 3.8–5.3% at 10 years, or 2.7% at 15 years. Long-term RFR (CR/NED maintenance rate), which one could consider as near clinical cure, has been reported as 3.1–3.2% at 5 years, 1.9–3.4% for over 10 years, or 2–5% in general [3]. Furthermore, subpopulation of MBC who have achieved CR by chemotherapy could remain CR for over 20 years [6, 14, 23].
Table 5

Summary of long-term outcomes of metastatic breast cancer in literature

Author (reference)

Study period

Treatment setting

Treatment modality

No. patients

OS

PFS

CCR/NED

Median (months)

5 years (%)

10 years (%)

15 years (%)

Median (months)

5 years (%)

10 years (%)

15 years (%)

Greenberg [6] and Rahman [15]

1973–1982

Front-line CT

DOX-based CT ± local therapy

1,581

21.3

12.2

3.8

2.7

11.5

4.3

2.7

2.5

3.1% at >5 years

1.9% at >10 years

Yamamoto [53]

1988–1993

Front-line

Various systemic Tx

279

28.0

22.5

5.3

 

17.1

   

3.2% at 5 years

Güth [11]

1990–1999

Front-line

Various (HT, CT, R, S)

149

 

13.7

      

3.4% at 9–14 years

CCR continuing complete response, CT chemotherapy, DOX doxorubicin, HT hormonal therapy, NED no evidence of clinical disease, OS overall survival, PFS progression-free survival, R radiotherapy, S surgery, Tx therapy

Reports by Greenberg and Rahman et al. from MDACC were the first to describe long-term prognosis of MBC with sustained CR and have refined a standard for current understanding on long-term outcome in MBC treated with chemotherapy [6, 15]. More recently, Güth et al. [11] reported results from a nonselective population-based cohort study on long-term prognosis and their characteristics in MBC. In their study, 5 out of 149 MBC patients (3.4%) remained with no clinical evidence of cancer relapse for 9–14 years. Their results were encouraging, suggesting that, though not many, a few MBC cases do survive for prolonged periods or even potentially achieve clinical cure, although the absolute necessity for including chemotherapy in treating every MBC patients was not fully supported in this particular study, since 4 out of 5 of those long-term survivors in that study had not received chemotherapy. The commentary on this article by Babiera et al. [24] also stressed that we must continue to learn not only from those who have succumbed to the disease but also from those who succeeded in escaping from their fate with MBC.

Theories supporting multidisciplinary approach for OMBC and the Swenerton Score

Revolution in understanding of breast cancer biology, natural history, therapeutic approaches, and evaluation of prognostic factors has modified our strategy for breast cancer treatment, either de novo or metastatic, and drastically improved survival. There have been three major paradigms for biology of breast cancer. First, in 1894, the Halsted theory defined breast cancer as a local disease that spreads in an orderly fashion and eventually becomes systemic, therefore proposing radical mastectomy as essential to cure the disease [25, 26]. The second paradigm, proposed by Fisher et al. in 1980, on the other hand, considered overt breast cancer as a systemic disease even at inception, therefore suggesting that therapies targeting local or regional lesions would not affect survival [27]. As the Fisher theory became more widely accepted than that of Halsted, importance of systemic therapies was underscored, and such treatments have been increasingly applied. However, subsequent evidence demonstrated that control over local lesions might also affect patient outcomes in MBC. Based on the two ostensibly contradictory theories and cumulative evidence, a third paradigm was proposed by Hellman et al. in 1994 [28], integrating the two previous hypotheses. The Hellman theory, also known as a spectrum paradigm, hypothesizes that breast cancer comprises a biological spectrum extending from purely localized to systemic nature, but also including many intermediate stages from the point of their first detection.

Subsequently, in 1995, Hellman proposed another theory, describing a novel concept, OMBC, as a characteristic subset of MBC [16]. In principle, the new theory presumes that likelihood of metastasis, as well as the number of involved organs and the location of the metastases, reflect the nature of the tumor. It also reiterates the importance of local therapy, either with or without combination of systemic therapies in metastatic or relapsing breast cancer to achieve better prognosis. Patients with oligometastases, either de novo or following systemic treatment, should reflect their relatively “local” state of the tumor and therefore ablation could cure these lesions, whereas more advanced, i.e., systemic in nature, disease would require more aggressive and effective systemic approach. Newer surgical or radiation therapies may further be required for curative treatment of such oligometastases.

Similarly, three major hypotheses on tumor cell kinetics have been proposed. The oldest is the Skipper–Schabel–Wilcox model (Log-kill model) reported in 1964. In this model, the authors hypothesized, using the L1210 leukemia cell lines, that tumor cell doubling time is constant regardless of cancer size, and therefore a set dosage of chemotherapeutic agent should kill tumor cells at a constant ratio [29]. According to this hypothesis, antitumor agents have to be administered up to the maximally tolerable levels, or treatments ought to be started while tumor cell mass is small enough for the host to tolerate an amount of antitumor agent necessary to effectively eliminate entire tumor cell populations. Subsequently, the Godie–Coldman hypothesis was proposed in 1979. In this hypothesis, authors noted a possibility for sudden spontaneous mutation that renders initially drug-sensitive tumor cells, which presumably account for the majority of the tumor mass in micrometastases, as drug-resistant after several cell cycles; therefore, delay in systemic therapy could result in a major disadvantage to patient survival [30]. The third hypothesis by Norton and Simon considers, in human breast cancers, that tumor cell proliferation follows a Gompertzian phenomenon and decelerates, while reaching a “plateau phase” as the tumor enlarges. Consequently, fast-growing, smaller tumors regress more rapidly in response to an antitumor agent compared with larger tumors, but also regrow faster (the Norton–Simon hypothesis) [31]. Plausibility of this hypothesis was demonstrated in a study with paclitaxel dose-dense therapy. Though efficacy and validity of those three hypotheses have not been proven in every tumor type or for all chemotherapy regimens, it appears to be commonly recognized that antitumor agents exert more efficient regression in smaller tumors than in those that have larger growth fraction and shorter doubling time.

The “small is sensitive” concept was supported by data of a study on MBC treated with cytotoxic chemotherapy by Swenerton et al. [14]. In this study, authors evaluated influences of estimated quantitative tumor burden, instead of number of organs involved, in combination with other characteristics of the host, tumor, and therapeutic approaches, and assessed predictive and prognostic factors for responses to chemotherapy and consequent survival in 619 MBC cases treated with FAC regimen (5-fluorouracil, adriamycin, and cyclophosphamide) or its modified version. The extent of metastatic lesions was evaluated by prospective review of the data from radiological images and clinical records using a scoring system [Swenerton Score (SS)]. The following 12 anatomical sites were considered: ipsilateral breast, contralateral breast, lymph nodes, skin/chest wall, lungs, pleura, liver, mediastinum, abdominal and pelvic cavities, bones, bone marrow, and central nervous system. A value was assigned to describe the extent of disease at each site as follows: 0 = no disease, 1 = strong suspicion of involvement but insufficient laboratory or clinical information to define further, 2 = minimal involvement, 5 = moderate involvement, and up to 10 as extensive involvement. The total burden of metastatic disease was the sum of the scores for all known disease sites. Both responses (P = 0.01) and survival (P < 0.01) showed highly significant correlations with the evaluation of total tumor burden by this scoring system. Not only was the overall response rate (ORR) clearly related to the estimated tumor burden, but the association was even more marked in cases that achieved CR. Patients with smaller tumor burden (SS <5) achieved CR in 38%, whereas the CR rate in those with larger tumor loads (SS >20) was only 7%. The difference in survival distributions among the various response categories was statistically significant (P < 0.01). Patients achieving CR had a definite survival advantage over patients in PR (P = 0.04). These findings suggest that the Swenerton Score is a more sensitive measurement of tumor burden than those using the number of sites with metastatic lesions as a parameter. Swenerton’s study sends a critical message that early diagnosis and timely institution of combination chemotherapy for MBC, while the relative tumor burden is low, could be key to achieving best possible outcome. However, the Swenerton Score is not practical for clinical application due to the huge efforts required in its calculation, and therefore it is rarely utilized. As another independent predictive factor that reflects tumor burden, circulating tumor cell (CTC) numbers are being evaluated. Cristofanilli et al. suggested that CTC numbers have superior and independent prognostic value for tumor burden. However, this study did not evaluate CTC numbers as a predictive factor for efficacy of thermotherapy in MBC [32].

As discussed above, the spectrum paradigm and concept of oligometastases proposed by Hellman are ratified both by the logical hypotheses for tumor cell kinetics and by results from the Swenerton Score study. At individual cellular levels, each breast cancer encompasses a spectrum of local and systemic natures, and as the disease progresses, the systemic nature of the cancer dominates. Since clinical observations also indicate that smaller tumors are more susceptible to chemotherapy, multidisciplinary approach with early and aggressive systemic therapy combined with local treatment to OMBC should be considered as front-line treatment, particularly in those who show sufficient response to initial systemic therapies, to achieve greatest therapeutic benefits.

Reports on therapeutic outcomes of OMBC

Reports on therapeutic outcomes of OMBC are limited, the majority focusing on local treatment rather than curative attempt with multidisciplinary treatments. Table 6 presents a summary of such limited studies that intended cure of MBC, by multidisciplinary approaches utilizing systemic and/or local treatments. Among those studies, 4 (Boner, Blumenshein, Nieto, Hanrahan) initially performed local therapy targeting the tumor, followed by adjuvant-type therapy after induction of stage IV-NED. This approach emphasizes the relatively local nature of OMBC.
Table 6

Summary of outcome of oligometastatic breast cancer in literature

Author (reference)

Study period

Disease status

Study design and main treatment modality

Median (range) F/U duration (months)

No. patients

OS

PFSI

RFSI

Median (months)

5 years (%)

10 years (%)

>10 years (%)

Median (months)

5 years (%)

10 years (%)

>10 years (%)

Median (months)

5 years (%)

10 years (%)

>10 years (%)

Borner [33]

1982–1991

OMBC/stage IV-NED

Phase III (RCT)

75.6

167

            
   

 Adj. TAM

  

NR

74

      

82*1

59

  
   

 Observation

  

NR

76

      

26*1

36

  

Blumenschein [34]

1986–1996

OMBC/stage IV-NED

Retrospective

44

59

132

85a

      

58

53a

  
   

 S-CT ± R ± HT

              
   

 CT-R ± S ± HT

              

Nieto [35]

1991–1998

OMBC/stage IV-NED

Prospective

62

60

80

62

      

52

52

  
   

 S-HDC ± R ± HT

(4-108)

             

Hanrahan [17]

1974–2004

OMBC/stage IV-NED

Retrospective phase II

 

285

            
 

1967–1976

 

S and/or R (control)

267b

62

 

36

16

12c

     

7

4

3c

 

1974–1992

 

S ± R-DOX-based CT ± HT

212.5b

259

87

56

42

26d

    

42

41

34

26d

 

1998–2004

 

S ± R-DOC-based CT ± HT

45

26

NR

59

       

34

  

Rahman [15]

1973–1982

MBC

Prospective

>171.6

1,581

            
   

 Front-line Tx: CT

              
   

 No. of involved organs

              
   

  1

  

27

   

14

       
   

  2

  

23

   

12

       
   

  ≥3

  

18

   

10

       
   

 Swenerton Score

              
   

  ≤10

  

27

   

15

       
   

  11–20

  

21

   

11

       
   

  >20

  

15.5

   

9

       

Current study, 2011

1980–2010

OMBC

Retrospective

103 (6–329)

75

185

79

59

51c, 34d

69

57

33

29c,d

48

45

27

27c,d

   

CT ± S and/or R ± HT

              
   

No. of involved organs

              
   

 1

 

44

292

87

73

61c, 52d

128

74

50

45c,d

95

63

42

42c,d

   

 2

 

31

102

69

35

35c

38

35

   

22

  

Adj. adjuvant, CT chemotherapy, DOC docetaxel, DOX doxorubicin, F/U follow-up, HDC high-dose chemotherapy, HT hormonal therapy, MBC metastatic breast cancer, NED no evidence of clinical disease, No. number, NR not reached, OMBC oligometastatic breast cancer, OS overall survival, PFSI progression-free survival or interval, R radiotherapy, RCT randomized controlled trial, RFSI relapse-free survival or interval, S surgery, Tx therapy

aAt 44 months (3.7 years), b living patients, c at 15 years, d at 20 years

*1p = 0.007

Borner et al. [33] report data from the only randomized controlled trial (RCT) to date with patients of OMBC. In OMBC patients who developed isolated locoregional recurrence after mastectomy, absence of remote metastases was verified and locoregional lesions were surgically excised after irradiation to induce stage IV-NED, macroscopically determined as total removal of the recurrent lesions. Subjects were then randomly allocated either to receive an adjuvant-type therapy with tamoxifen (TAM) or not. Analyses of the follow-up data indicated that, in hormone-sensitive subjects, systemic administration of TAM significantly suppressed progression of the disease.

Blumenschein et al. [34] described outcomes for 59 OMBC cases with remote metastasis and/or relapse. Recurring lesions that are easily resectable, such as locoregional recurrence or metastases in the lung or liver, were first surgically removed to achieve stage IV-NED, followed by chemotherapy and, if applicable, radiation therapy to the site of relapse. The results from this study suggested a desirable outcome and potential cure with multidisciplinary treatment group in OMBC as a small subset of MBC, and that early diagnosis for MBC is of benefit.

Nieto et al. [35] reported outcome of selected 60 OMBC cases treated with multidisciplinary treatments combining a local therapy and high-dose chemotherapy with autologous hematopoietic stem-cell transplantation (HDC). Subjects in this study were limited to those who met at least one of the following criteria: metastatic lesion was surgically removable prior to HDC or was within a single irradiation field of curative intent, and bone marrow tumor cell infiltration was less than 5% by microscopic evaluations. Cases with liver or brain metastases, those that received chemotherapy for their metastatic lesions prior to the present study periods, or relapse within a previous irradiation field were excluded. Median observation period was 62 months. Median OS and 5-year OSR were 80 months and 62%, and median RFS and 5-year RFS rates were 52 months and 52%, respectively. Multivariate analysis showed that cases that involved single organ had significantly better RFS (P = 0.03) compared with those whose metastatic lesions involved 2 or 3 organs. These results for long-term prognosis of OMBC are encouraging and imply a possibility to re-evaluate the current tenet, if larger-scale prospective randomized studies validate their findings, that early detection of relapsing cancer is of no benefit.

In an editorial comment to the article by Nieto et al., the editor Hortobagyi introduced data from a clinical trial evaluating efficacy of adjuvant-type systemic therapy following local therapy on OMBC since 1974 at MDACC, to which the editor belongs. Taken together with data of the Nieto study, Hortobagyi suggested that 3–30% of selected MBC patients with distant metastases and those who achieve long-term disease-free status by multidisciplinary treatments are probably curable [4]. Subjects in the study by Nieto et al. indeed represent a subgroup of patients whose outcome would be affected by choice of therapeutic approach. Patients who are asymptomatic and hormone receptor positive are those expected to have most favorable prognosis, and therefore, according to the currently most common practice standard, are likely to initially receive palliative hormonal therapy. In contrast, data from the Nieto study suggest that this subgroup of patients would rather most benefit from more intensive, multidisciplinary approach. The editorial comment therefore emphasized the importance of large-scale controlled clinical trials to verify the hypothesis and also reiterates Nieto’s conclusion suggesting that an intensive monitoring strategy to detect relapsing lesions after mastectomy is essential.

Hanrahan et al. [17] summarized their 30-year experience of isolated recurrence cases with 4 phase II trials at MDACC. In this study, the subjects first received local therapy (surgery and/or radiotherapy) with curative intent, and efficacy of adjuvant-type chemotherapy in subjects who achieved stage IV-NED was evaluated. Doxorubicin-based regimens as adjuvant-type chemotherapy were performed in 259 out of 285 cases. Median observation periods until surviving subjects’ last visits were 212.5 months. Median OS time was 87 months with OSR of 56, 42, and 26% at 5, 10, and 20 years, respectively, and median RFS time of 42 months with RFS rates of 41, 34, and 26% at 5, 10, and 20 years, respectively. There were 28 patients (10.8%) who remained disease free for more than 20 years.

Despite several historical biases, this is the study to date with largest scale and longest observation period, in which effects of adjuvant-type chemotherapy in OMBC patients who achieved stage IV-NED by a local therapy were evaluated. Authors also performed comparative analyses with archival control patients treated only with local therapy at their institution and found that patients who received an adjuvant-type chemotherapy after the induction of stage IV-NED showed higher OS and RFS rates [36]. At present, data based on a phase III randomized control trial evaluating efficacy of adjuvant-type chemotherapy in stage IV-NED breast cancer patients are not yet available. Nonetheless, the result from MDACC clearly suggests an importance of adjuvant-type chemotherapy in managing stage IV breast cancer patients.

A report in the Cochrane Library summarized current understanding on efficacy of systemic treatments against locoregional recurrence in stage IV-NED breast cancer cases after receiving curative local treatment [37]. Unfortunately, 3 out of the 4 RCTs included in that comprehensive analysis, other than the previously mentioned Borner study, were of small scale with sample sizes less than 20, and therefore the review had to conclude that evidence supporting efficacy of systemic therapy following local therapy against locoregional recurrence is insufficient.

Rahman et al. also reported long-term outcome of the same patient group that Greenberg et al. had reported [6, 15]. The analyses did not solely focus on OMBC or multidisciplinary approach with local therapy of curative intent. Nevertheless, the study warrants mention as it addresses many aspects that we intend to stress in this review article, as: (1) it was a rare report that included cases presumed as OMBC, (2) it was a clinical trial that utilized systemic chemotherapy as an initial treatment for relapsing tumor, (3) outcomes for up to 5 years were shown despite lacking details of local treatments, and (4) it showed that patients with less organ involvement with metastatic lesions and with lower Swenerton Score demonstrated better CR rates, as well as 5-year OS and PFS, indicating that OMBC with lower tumor burden represents a subgroup with relatively good prognosis.

We believe that the present assessment of experience with OMBC patients in our institution for the past 30 years is the first to consider OMBC as a systemic disease and to describe corresponding outcomes in response to multidisciplinary strategy, first with systemic chemotherapy, followed by local therapy in a selected subject population who responded to the initial systemic treatments.

Comparison of the data from various studies is challenging, as criteria for subject selection and specific therapeutic approaches are not identical. Nonetheless, overall prognosis for OMBC are OSR of 56–87, 35–73, and 26–25%, and RFR of 22–63, 27–42, and 26–42%, at 5, 10, and 20 years, respectively, though reports on outcome over 10 years are very limited (Table 6). These data suggest that, though still challenging, prognosis for patients with OMBC is more promising than that for patients with MBC in total (see Table 5 and discussion in the previous section).

Benefits of local and systemic treatment for OMBC

At present, it is not fully understood how or when to integrate such local management into standard systemic therapies for MBC or which subpopulations of patients would most benefit from such treatments. Local therapy, other than as a palliative means, is not generally recommended for early-stage MBC patients in current clinical practice. However, such approach may be worth consideration in a limited population of OMBC that demonstrates good response to systemic therapy [2, 13]. No data from RCT assessing efficacy of local therapy for OMBC are currently available. Discussion regarding outcomes of metastatic lesions in various organs can be found in other articles of this Special Feature. Unfortunately, reports on OMBC outcomes treated with local therapy are oftentimes biased by various factors such as patient selection or leading times. Based on results from nonrandomized comparative studies on local therapy or observational studies in patients who received local therapies, overall outcome for OMBC appears promising, though some investigators argue that these results showing preferable outcomes might be incorrect due to patient selection biases [39]. In addition, difference in tumoricidal effects of systemic and local therapy is of consideration. Chemotherapy could effectively eliminate cancer cells in a tumor burden of <1 million cells, whereas surgical debulking procedure can easily remove a focus of cancer up to an estimated 50 billion cells. Every 7 Gy irradiation would kill approximately 1 logarithm cells in radiosensitive tumors, i.e., 56 Gy irradiation eliminating every cancer cell in a metastasis with 100 million cells [34]. On the other hand, therapies targeting local lesions are not effective in eliminating cancer cells that could be systemically spread but might be subclinical. Therefore, we should carefully examine characteristics of each therapeutic approach, and data from prospective studies on optimal combination of systemic and local therapies should be collected to establish therapeutic strategy that is maximally tumoricidal. Recent advances in research on cancer stem cell (CSC) biology have revealed possible mechanisms by which CSC could affect therapeutic efficacy. Biological characteristics of CSCs may be distinct in either primary or metastatic lesions or in circulation. CSCs in a metastatic lesion may differentiate to tumor cells, which may cause a second metastasis via circulation. These possibilities also stress the importance of locally targeting CSCs.

Interestingly, 30–40% of clinically diagnosed OMBC patients treated first with local therapies and achieving stage IV-NED demonstrate widespread metastases within 3 months after the local therapy, and eventually, 50–80% progress to MBC within 2 years. These observations indicate that the subpopulation of patients diagnosed as OMBC could actually have other lesions that are not clinically detectable but equivalent rather to MBC, which cannot be controlled with local treatment only. As a result, overall 5-year OS rates in OMBC are 4–36% [1]. The largest study so far on outcomes of stage IV-NED OMBC patients, conducted at MDACC as mentioned earlier in our assessment of the previously published study results, was not a RCT. Hortobagyi, a lead investigator of this study, ponders that, considering the extremely high incidence of additional metastases when treated with regional treatment only, control arm was not ethically acceptable [4]. RCTs on efficacy of systemic treatment in stage IV-NED patients to date are also only small scale and have not sufficiently proven the benefit of systemic approach [37]. Accurate selection of “pure” OMBC by newer diagnostic means and yet-to-be identified markers would allow us to determine exact efficacy and plausibility of these two approaches, either solo or in combination. Whether local or systemic therapy should be the first to be administered in treatment of OMBC is another important aspect that has not been clarified.

Guidelines for treatment of OMBC

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Breast Cancer version 2 (2011) recommends to initially perform a local therapy (surgical resection and/or radiation therapy), with consideration of subsequent systemic therapies for locoregional recurrence (breast, chest wall, axillary, supraclavicular, and internal mammary node recurrence) [38]. Efficacy of chemotherapy following the local therapies on isolated local and/or regional ipsilateral recurrence is being evaluated prospectively by an international multicenter project (the BIG 1-01/IBCSG 27-02/NSABP B-37 studies) [38, 40].

The international guideline for management of MBC: Can MBC be cured? by the European School of Oncology-Metastatic Breast Cancer (ESO-MBC) Task Force, is another important guideline, based on the discussion at the European Breast Cancer Conference (EBCC)-6, April 2008, Berlin [2]. In particular, the guidelines focus on current understanding and therapeutic approaches for OMBC with one or only a few organs involved with metastatic lesions, since these form a distinctive subset of MBC patients who are “potentially curable” and would most benefit from multidisciplinary treatment. As shown in the outline (Table 7), the guidelines conclude, “The presented data, overall, seem to suggest the possibility of a curative multidisciplinary therapeutic approach for at least a fraction of patients with limited MBC. Based on the available data, the ESO-MBC Task Force retains its original recommendation statement (2007): A small but very important subset of MBC patients, for example, those with a solitary metastatic lesion, can achieve complete remission and a long-term survival. A more aggressive and multidisciplinary approach should be considered for these selected patients. A clinical trial addressing this specific situation is needed” [41].
Table 7

Outline of international guidelines for metastatic breast cancer: Can metastatic breast cancer be cured? (2010)

Identification of MBC patients suitable for curative treatment

Gene expression profiling may identify the highest probability of therapeutic benefit (potentially leading to cure), and advances in pharmacogenetics may allow selection of the therapeutic options with the higher therapeutic efficacy for the individual patient. Improved diagnostic tools will improve the identification of truly solitary metastatic lesions susceptible to effective local treatment.

Definition of cure and appropriate endpoints

“Cure” does not necessarily mean destroying every cancer cell, but rather rendering the disease harmless (without clinically significant adverse effects) for prolonged periods. Importantly, the ultimate goal in MBC management is to prolong duration of life while maintaining good quality of life. New endpoints must be defined to assess this global definition of cure.

The role of systemic treatment

An increasing number of randomized clinical trials document statistically significant improvements in disease control with modern chemotherapy in MBC. In addition, a small but recognizable subset of patients achieves long-term remission.

“Adjuvant” systemic therapy after local treatment

Available data suggest that, despite important differences in patient characteristics and selection bias, at 5 years after local treatment for a locally recurrent or metastatic lesion followed by adjuvant systemic treatment, 36–52% of patients remain alive and without evidence of relapse. The utility of chemotherapy after locoregional treatment for isolated locoregional recurrence (i.e., not associated with distant metastasis) is still an open question being currently investigated in a joint study by the International Breast Cancer Study Group (IBSCG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP), under the umbrella of the Breast International Group (BIG).

The role of local treatment

Available data demonstrate favorable results in a subset of patients undergoing “radical” local therapy for metastatic disease. Selection bias and the retrospective nature of available data do not allow for generalization of the results, and the use of such approaches must be individualized.

 Surgery for primary tumor in the presence of metastatic disease

There is a bulk of retrospective data suggesting the importance of local treatment of primary tumor and strongly recommending that well-conducted randomized trials be performed in this setting. One such trial is being developed under the joint effort of Breast International Group and the North American Intergroup. While waiting for data from these studies, surgery for breast primary tumor can be considered as a relatively inexpensive and low-morbidity treatment which can offer rapid local control and has potential for survival benefit, provided it is performed optimally.

 Surgery for lung metastases

The largest dataset comes from the International Registry of Lung Metastases and presents results of lung metastasectomy in 467 breast cancer patients. Complete resection was possible in 84% of patients and led to median survival of 37 months (5-year OS of 38%, 10-year OS of 22%). Pulmonary resection in MBC patients, apart from its potential therapeutic value, is also an important diagnostic tool, especially in patients with a suspected first recurrence. The proportion of lesions proved not to be breast cancer metastases in various series ranges from 7% to 66%.

 Surgery for liver metastases

In various series of hepatic resection for breast cancer metastases, the reported median survival ranged from 14.5 to 63 months and the 5-year survival from 14% to 61%, in general, comparing well with nonsurgically treated patients. Most of the reported series, however, describe extremely selected patients. Effective local control can be achieved by radiofrequency ablation in solitary lesions less than 3 cm in diameter. This therapy provides promising survival rates in patients with no visceral extrahepatic disease or with single bone metastases.

Discussion

Cure for MBC is practically impossible to achieve with our current therapeutic tactics. However, OMBC, a subgroup of MBC, demonstrates relatively favorable prognosis. In the present study, we analyzed outcomes of OMBC from the 30-year experience of our own institution and other study results reported in literature, intending to gain perspective on the possibility of clinical cure for MBC.

First, we aimed to attest whether prolonged relapse-free condition (CR/NED maintenance) can be sufficiently assumed as clinical cure of OMBC, by evaluating long-term outcome of OMBC patients in our institution. One-third of the OMBC patients treated with multidisciplinary approach in our institution were expected to survive over 20 years, and one-fourth of the entire subject population analyzed were supposed to remain relapse free, based on the estimated OS and CR/NED maintenance rates, respectively. None of those who achieved CR/NED developed progressive disease after 101 months. Patients with a single organ involved with metastasis showed markedly better prognosis. These data indicate, despite various biases intrinsic to a retrospective analysis, that OMBC represents a small but particular subgroup of MBC, in which prolonged relapse-free interval/survival (CR/NED maintenance) and subsequent clinical cure are not incidental but a plausible treatment goal by aggressive application of neoadjuvant chemotherapy-type multidisciplinary treatment. The second aim of the present analysis of OMBC outcomes in our institution is to elucidate possible factors that affect OMBC prognosis. We identified such factors by multivariate analyses as single organ involvement with metastatic lesions for both PFI and RFI, and administration of local therapy and shorter DFI for RFI. Anthracycline-based chemotherapy regimen for OS, and negative hormone receptors and low Ki67 index for RFI also showed trends for favorable prognosis though lacked statistical significance. These data verify our empirical understanding and rationale that single organ involvement by metastatic lesions is a characteristic for a MBC subgroup with favorable prognosis. Association of shorter DFI with better OMBC prognosis may reflect faster tumor cell proliferation that renders cells more susceptible to chemotherapy. The present assessment encompasses patients from over 30 years, when available choices of agents for systemic therapy were also changing. Therefore, patient outcomes cannot simply be compared. Nonetheless, patients treated with anthracycline-based regimens for their OMBC demonstrated better outcome than those treated with taxane with or without anthracycline-based regimens. We speculate that the former group of patients showed greater sensitivity for chemotherapy after their relapse, since: (1) they had less frequently received adjuvant/neoadjuvant chemotherapy for the primary lesions, and (2) their regimen for adjuvant/neoadjuvant therapy, if received, was less potent, preserving remaining potential for cancer cells to be targeted with a newly administered tumoricidal agent. Relapse following more potent adjuvant/neoadjuvant therapy might also reflect more malignant biology of cancer cells, which could be harder to eliminate. Ironically, recent data suggest that adjuvant/neoadjuvant chemotherapy for the primary lesion with more potent antitumor effects would reduce efficacy of the chemotherapy after relapses [2, 15, 42]. Our data also agreed with others suggesting that chemotherapy is more effective on hormone receptor-negative than hormone receptor-positive tumors. Ki67 is a marker for cellular proliferative potential, and high Ki67 index has been associated with greater sensitivity to chemotherapy [3]; therefore, the present result was unexpected. We frequently experienced negative Ki67 staining in archived tissue samples. The negative staining in preserved old specimens is a limitation of the retrospective analysis and may have underestimated the effect of Ki67 on OMBC prognosis in our study. Dosage of chemotherapy agents we used in the present study was relatively low compared with those recommended by several more recent guidelines (NCCN clinical practice guidelines). Therefore, we cannot exclude a possibility that higher dose regimen might have resulted in higher rate for cure. Though some studies suggest dose-dependent increase of tumoricidal effects [43, 44], others suggest that the most efficient antitumor effects may not be observed at the highest possible dose [45, 46]. As discussed above, biological heterogeneity of tumor cells might limit the dose-responsiveness of antitumor agents, which might be overcome by combination of newer, non-cross-resistant agents. Thirdly, we performed a systemic review of literature on the long-term outcome of OMBC, in search of a clue to envision possible clinical cure for MBC. As there are not many reports from studies on OMBC prognosis, we included data from our own institution in the systemic review. Comparison of the results from different studies in literature is challenged by various biases, such as differences in subjects’ background and therapeutic choice in each clinical study. Among those, lead-time bias needs particular attention. However, if, as is generally recognized at present, early detection and treatment of MBC do not prolong OS in MBC, lead-time bias should be negligible. Nevertheless, overall outcome for OMBC was markedly superior to those for the entire MBC populations (Tables 5, 6). These data strongly suggest that OMBC is a specific subgroup, in which clinical cure is conceivable.

In the long-lasting battle against breast cancer, recent advances in systemic and radiation therapies and supportive means for unfavorable effects of these treatment, as well as novel diagnostic techniques for early detection of metastatic or microinvasive lesions, are immensely accelerating. Those advances would show best and prompt benefit by targeting OMBC, rather than dealing with the entire MBC population. When improved clinical outcome is proven in OMBC, means of evaluation after curative surgery for early breast cancer must be restructured to better identify this subgroup. Biomarkers that determine biological characteristics for OMBC must be identified to enable selection of the subgroup with better prognosis, and provision of more appropriate treatment on a molecular basis will improve the outcome in OMBC, resulting in better prognosis of the entire MBC population. Integration of findings in the above-mentioned various areas will help us obtain better insights into treatments and outcome of MBC.

As discussed in our evaluation of previous reports, clinical cure is no longer beyond hope, at least in OMBC, and 10 or even 20 years of long-term relapse-free survival/interval (CR/NED maintenance rates) can be achieved at relatively high incidence. Then, what level of proof for clinical cure in OMBC or MBC would reasonably justify curative intent in every breast cancer? In acute myeloid leukemia (AML), a malignant tumor that we can currently anticipate to achieve cure with a highest probability, long-term complete remission rates in adults are 20–30%, except for acute promyelocytic leukemia whose prognosis is exceptionally good [47, 48, 49]. These numbers appear similar to those we observed for RFSI in patients with OMBC. However, even in an era when cytosine arabinoside and daunorubicin, core agents in the current chemotherapy regimens, brought hope for cure of AML (1968–1974), renowned hematologists such as Crosby or Boggs were skeptical about aggressive chemotherapy and suggested that supportive and/or palliative treatments without performing chemotherapies would be sufficient [50, 51, 52], with their famous statement: “With the therapeutic agents that we have today, there is no hope for cure and an idea that cure is just around the corner is simply an optimistic illusion” [52]. Current advances in treatment of AML clearly show that history has answered the question of whether or not intensive approaches including chemotherapy should be pursued to achieve cure. This historical evidence also indicates that it is improbable that we will find a correct answer while in the midst of controversy.

Cumulative, though limited, data on long-term prognosis in OMBC discussed herein clearly shed light on possible clinical cure in MBC, which we consider, to date, to be deemed fatal. As Dr. Wood commented at the “Can metastatic breast cancer be cured?” session in EBCC-6, April 2008 in Berlin, physicians and patients should set their mutual goal to achieve cure in treating breast cancer. If a physician in charge considers a cure as out of scope, sufficiently aggressive treatment that would potentially cure the disease would never be chosen, despite patient’s desire for a cure-oriented therapy, neglecting a possibility to achieve clinical cure. Therefore, in order to accumulate sufficient information to estimate outcomes and factors that determine the outcomes in MBC, it is essential, for both physicians and the patients with OMBC, to discuss their pros and cons and to make a best suitable choice from available therapeutic options. These options should take multidisciplinary approaches, and even rather aggressive ones that may not be highly provable to date to achieve clinical cure should not be overly discouraged.

Conclusions

The long-term outcome of OMBC in our institution for over 30 years was OSR of 59.2% at 10 years and 34.1% at 20 years, and RFR of 27.4% at 10 and 20 years. Those whose metastatic lesions involved only one organ represented a subgroup with excellent prognosis (OSR of 73% at 10 years and 52% at 20 years, RFR of 42% at 10 and 20 years). There were 3 cases (4%) that we consider clinical cure, and more cases should be observed in the future. We also reviewed literature on OMBC outcomes and found that OSR is 35–73% at 10 years and 26–52% at 20 years, and RFR is 27–42% at 10 years and 26–42% at 20 years. Though more information should be compiled, current data indicate that long-term prognosis in OMBC is distinct from that in the entire population of MBC, in which relapse-free survival rate (RFS rate) for 10–20 years is as low as 1.9–3.4% or 2–5%. As we assemble more data by long-term observations of multicenter prospective studies and from results of phase II and III trials, we anticipate confirmation of long-term prognosis for OMBC and verification of factors that affect prognosis, enabling identification of subgroups in MBC and to provide personalized and multidisciplinary care, leading to improved overall prognosis for MBC. To accomplish this impending task, cooperative efforts beyond a single institution and an individual physician’s lifetime career are imperative.

Notes

Acknowledgments

First and foremost, we acknowledge the courage and vision of the patients who participated in our clinical studies that enabled us to reach our present understanding of breast cancer biology. We would also like to thank all the physicians, nurses, pharmacists, and other staff members of the participating hospitals and universities for their genuine and continual efforts to support our study. We appreciate the considerable support provided by Ms. Akiko Akahori in her administrative work and data collection in preparing the current manuscript, and Mss. Michiko Kasai and Kana Tamura for their pathological expertise. The lead author is most grateful for 30 years’ mentoring and assistance for a long-lasting journey in breast cancer clinical practice and studies in medical oncology by Dr. Makoto Ogawa, President Emeritus, Aichi Cancer Center. Also, the author would not be present as a physician without Dr. Masakazu Abe, the former Dean of the Jikei University School of Medicine, whose dedication and thoughtful approach to medicine has always led us.

Conflict of interest

Dr. Keisuke Aiba has received honoraria paid by a company as compensation (Ono Pharmaceutical Co.). Dr. Ken Uchida has received research funding from a company (Daiichi-Sankyo Pharma, clinical research on Sonazoid).

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Copyright information

© The Japanese Breast Cancer Society 2012

Authors and Affiliations

  • Tadashi Kobayashi
    • 1
  • Tamotsu Ichiba
    • 1
  • Toshikazu Sakuyama
    • 1
  • Yasuhiro Arakawa
    • 1
  • Eijiroh Nagasaki
    • 1
  • Keisuke Aiba
    • 1
  • Hiroko Nogi
    • 2
  • Kazumi Kawase
    • 2
  • Hiroshi Takeyama
    • 2
  • Yasuo Toriumi
    • 2
  • Ken Uchida
    • 2
  • Masao Kobayashi
    • 3
  • Chihiro Kanehira
    • 3
  • Masafumi Suzuki
    • 4
  • Naomi Ando
    • 5
  • Kazuhiko Natori
    • 6
  • Yasunobu Kuraishi
    • 6
  1. 1.Department of Clinical Oncology and HematologyThe Jikei University School of MedicineTokyoJapan
  2. 2.Department of Breast and Endocrine SurgeryThe Jikei University School of MedicineTokyoJapan
  3. 3.Department of Therapeutic RadiologyThe Jikei University School of MedicineTokyoJapan
  4. 4.Department of PathologyThe Jikei University School of MedicineTokyoJapan
  5. 5.Department of PharmacologyThe Jikei University HospitalTokyoJapan
  6. 6.Department of Hematology and OncologyToho University Omori Medical CenterTokyoJapan

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