Clinical and pathological characterization of 158 consecutive and unselected oligometastatic breast cancers in a single institution

doi:10.21203/rs.3.rs-2191256/v1

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Research Article

Clinical and pathological characterization of 158 consecutive and unselected oligometastatic breast cancers in a single institution

https://doi.org/10.21203/rs.3.rs-2191256/v1

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published 15 Feb, 2023

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Purpose: Data about incidence, biological and clinical characteristics of oligometastatic breast cancer (OMBC) are scarce. However, these data are essential in determining optimal treatment strategy. Gaining knowledge of these elements means observing and describing large, recent, and consecutive series of OMBC in their natural history.

Methods: We collected data retrospectively at our institution from 998 consecutive patients diagnosed and treated with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis.

Results: Of 998 MBC, 15.8% were classified OMBC. Among these, 88% had one to three metastases, and 86.7% had only one organ involved. Bone metastases were present in 52.5% of cases, 20.9% had progression to lymph nodes, 14.6% to the liver, 13.3% to the brain, 8.2% to the lungs, and 3.8% had other metastases. 55.7% had HR+/HER2- OMBC, 25.3% had HER2+ OMBC, and 19% HR-/HER2- OMBC. The HR+/HER2- subtype statistically correlated with bone metastases (p=0.001), the HER2+ subtype with brain lesions (p=0.001), and the HR-/HER2- subtype with lymph node metastases (p=0.008). Visceral metastases were not statistically associated with any OMBC subtypes (p=0.186). OMBC-SBR grade III was proportionally higher than in the ESME series of 22,109 MBC (49.4% vs. 35.2%, p< 0.001).

Conclusion: OMBC is a heterogeneous entity whose incidence is higher than has commonly been published. Not an indolent disease, each subgroup, with its biological and anatomical characteristics, merits specific management.

Oligometastatic breast cancer

biology

incidence

metastatic diffusion

biomarkers

According to Hellman and Weichselbaum, some metastatic cancers do not develop diffuse metastases from the start but acquire this capacity gradually. There would therefore be an intermediate stage where metastatic spread would be limited to specific organs and the number of metastases would be low. These authors defined this stage as oligometastatic [1, 2].

If the benefits of curative strategies have been proven for several types of oligometastatic diseases (OMD) [2–5], the question remains controversial concerning oligometastatic breast cancer (OMBC). No randomized studies have thus far answered the question. Recently one phase IIR/III trial, including OMBC of various anatomical and biological characteristics, failed to establish the benefits of a curative strategy for OMBC [6].

To confirm, or refute, the benefits of intent-to-cure strategies, Hellman and Weichselbaum defined four milestones [1, 2]:

Epidemiology: “The importance of the oligometastatic state will be dependent on the size of the group of patients for whom it offers curative prospects”.
Biology: “This paradigm emphasizes the importance of markers specifically related to where in the spectrum of malignancy an individual cancer is located”.
Imaging: “[Its] effectiveness will be critically dependent on the specificity, sensitivity, precision, and accuracy of tumor imaging”.
Treatments: “New methods of surgery or radiation therapy may allow curative treatment of such oligometastases either alone or combined with systemic therapy and focal treatment”.

Today, several treatments are available with low toxicity and high efficiency: surgery, stereotactic body radiotherapy, intensity-modulated radiation therapy, percutaneous image-guided treatment [7–10]. Also available are imagery techniques with high sensitivity and specificity [11–13]. However, OMBC incidence remains uncertain: values in the literature are based on outdated studies [14] or come from highly selected series of OMBC [15]. Furthermore, data on OMD specific biomarkers are limited [9], and a recent review confirms that data on OMBC biology are also scarce [14]. It thus remains unclear whether a limited number of metastases at diagnosis reflects specific biology, early diagnosis of metastases, or both.

In order to determine the incidence and the clinical and biological characteristics of OMBC, data must be available from series respecting the following conditions: series must be consecutive; they must describe OMBC at the moment when the first metastases are seen, thus corresponding to synchronous and metachronous OMBC according to the ESTRO-ASTRO classification [5]; criteria pertaining to the number of organs and metastases must be consensual; the calculation method for metastases must be explicitly described. Finally, the feasibility of focal treatment must not enter into inclusion criteria, thereby avoiding a selection bias linked to practices and available resources of participating teams.

In a systematic review, Van Ommen et al. [15] selected eleven publications identifying OMBC prognostic factors. Since all of these series describe cohorts of highly selected, nonconsecutive patients, they cannot provide the information sought.

Since their work, other retrospective cohorts of OMBC have been published. One is a large, retrospective and consecutive cohort of 3,447 patients with synchronous MBC analyzed with inverse-sampling probability weighting collected in the Netherlands Cancer Registry (NCR) between January 2000 and December 2007 [16]. In this cohort, patients were considered to have OMBC (15.0%; 517/3,447) when the number of metastases was limited to five with no other inclusion or exclusion criteria.

Two other retrospective cohorts have more restrictive inclusion criteria. The first presents a cohort of 170 patients treated at the Chennai Oncology Cancer Institute (India) for OMBC [17]. Those with ≤ 5 metastases in total and metastases ≤ 5 cm were considered OMBC. Patients with OMBC who failed to receive any treatment or those with incomplete case records were excluded; their proportion is not specified. The second is a retrospective series of 50 patients treated from 2009 to 2014 at the National Cancer Center (China) for metachronous OMBC. The series included metachronous OMBC only; primary breast tumors had had to have been resected; metastatic disease had to be limited to a single organ; no more than three metastases, and no brain or lymph node metastases were possible for inclusion [18].

In the absence of publications strictly respecting our criteria, we undertook a retrospective study involving all consecutive patients with synchronous or metachronous MBC starting treatment at metastatic stage at our institution from January 2014 to December 2018. MBC was considered oligometastatic if there were one to five metastases at the time of diagnosis with no other inclusion or exclusion criteria. Our analysis focuses on the initial description of OMBC, providing a maximum of information on this subject. Our series was then compared with the Epidemiological Strategy and Medical Economics (ESME) cohort of MBC (22,109 patients treated in France for MBC between January 2008 and December 2016) [19] and the NCR cohort with its large number of OMBC cases [16].

2.1 Patient selection

We conducted a non-interventional, retrospective, and monocentric study to describe the clinical and pathological characteristics of all consecutive OMBC selected from the IUCT-O database between January 2014 and December 2018. This study was approved by our Multidisciplinary Breast Committee and our Institutional Board Committee (BEC-FO-0227).

Patient selection focused on females, aged > 18 years with newly diagnosed synchronous or metachronous OMBC. Patients were excluded whose treatment at metastatic stage had been initiated in another institution, who had exclusive unresectable local relapse or who had a history of second cancer.

2.2 Synchronous and metachronous OMBC definition

In our study, OMBC was defined as MBC with up to five distant metastases at the time of diagnosis not necessarily in the same organ. This included patients with synchronous OMBC (maximum six months interval between diagnosis of oligometastatic disease and primary cancer diagnosis) and metachronous OMBC (more than six months interval between diagnosis of oligometastatic disease and primary cancer diagnosis) according to ESTRO-ASTRO classification [5].

Organs were divided into brain, lung, liver, bone, lymph nodes, and others (skin, pancreas, and adrenal glands). Local relapse at the time of diagnosis included relapse in the breast, ipsilateral loco-regional lymph node infiltration, limited ipsilateral cutaneous breast or chest infiltration.

Definition and number of distant metastases were derived from Kelly et al. [20]. “For lesions in the brain, bone, lung, and liver, each radiologically identifiable lesion was considered one site of disease. For lesions in the lymph nodes, radiologic involvement of each echelon of the axillary, cervical or mediastinal lymphatics was considered a single site of disease, even if there were multiple nodes noted in a given echelon” [21, 22]. In the absence of a contralateral tumor in the breast, contralateral loco-regional lymph node invasion was considered as one metastasis. Leptomeningeal disease, malignant pleural or peritoneal effusions, and extensive cutaneous involvement were considered as diffuse disease.

2.3 Data collection

All data were collected at the time of diagnosis of the first metastases, prior to any treatment for this stage. HR and HER2 status was determined by metastatic biopsy, if available, otherwise by biopsy of local relapse or of the primary tumor. Standard guidelines were applied to any tumor analysis performed. Tumors were defined as hormone receptor positive (HR+) if estrogen receptor or progesterone receptor expression was > 10% (immunohistochemistry); (HER2) immunohistochemical (IHC) score 3 or IHC score 2 with a positive in situ hybridization (ISH) classified the cancer as HER2+. All cancers with an IHC score of 0, 1, or 2 with a negative ISH test were considered HER2-.

Surrogate intrinsic subtypes (SIS) were defined according to Harbeck et al.’s classification [23]: Luminal A (ER and/or PR > 10%, Scarf-Bloom-Richardson (SBR) Grade I or II and Ki-67 ≤ 15%, HER2 negative), luminal B (ER and/or PR > 10%, SBR Grade II or III and Ki-67 > 15%, HER2+/-), HER2 enriched (ER negative, PR negative, and HER2+) and triple negative (ER-/PR-/HER2-).

Imaging techniques applied for staging evaluation –Computed Tomography (CT) scan, bone scan, Positron Emission Tomography/Computed Tomography with ¹⁸fluorodeoxyglucose (¹⁸F-FDG-PET/CT), Whole-Body Resonance Magnetic Imaging (WB-MRI), liver, brain, or spinal MRI– were recorded. We then compared our cohort with the very large ESME cohort [19] and the NCR cohort —according to our literature review— the largest sample of synchronous OMBC to date with inclusion criteria similar to ours [16].

2.4 Review of the literature

The algorithms used for the literature review are presented in Appendix 2.

2.5 Objectives

Primary objective:

Describe the clinical and pathological characteristics of synchronous and metachronous OMBC.

Secondary objectives:

Estimate the incidence of synchronous and metachronous OMBC in our database.
Describe the clinical and pathological characteristics of OMBC according to synchronous/metachronous features.
Evaluate inconsistencies in clinical and pathological characteristics between our cohort and the NCR cohort.
Determine the specific pathological characteristics of OMBC by comparing our cohort with ESME data.

2.6 Statistical analysis

This cohort is a population-based registry, with individual data on all consecutive patients treated for MBC in our institution from January 2014 to December 2018. Population characteristics were described using the usual statistics. Continuous variables were summarized by median, range, and qualitative variables by frequency and percentage. Comparison between groups was performed using either Chi-square or Fisher’s exact test for qualitative variables and the Kruskall-Wallis test for continuous variables. All statistical tests were two-sided, with p-values < 0.05 considered statistically significant. Statistical analyses were conducted using STATA v16 (StataCorp, College Station, TX, USA) software.

3.1 Patient characteristics

We identified 1,229 patients in our database with unresectable local relapse, synchronous or metachronous MBC, from January 2014 to December 2018. Among them, 33 presented exclusive local relapse, 198 had initiated treatment for MBC in another institution, and 998 had MBC treated in our institution. Among the latter, 84.2% were considered polymetastatic during this period, and 15.8% presented one to five metastases (Fig. 1).

Among these 158 OMBC patients, medium age at diagnosis was 55 years [range 28–90]. Sixty-one were synchronous (38.6%) and 97, metachronous (61.4%). For the latter, median time to relapse was 60.4 months [range 6.0-482.2], and 28.1% had local relapse at the time of distant metastatic relapse. Patients with metachronous OMBC were older than those with the synchronous form (p = 0.003). There was no statistical difference between synchronous and metachronous OMBC for performance status (PS) (p = 0.713) or for menopausal status (p = 0.171). There was also no statistical difference in HR and HER2 status between synchronous and metachronous OMBC (p = 0.603) (Table 1).

Table 1

Baseline characteristics for the whole cohort and for synchronous and metachronous OMBC
	Total	Synchronous OMBC	Metachronous OMBC
	(N = 158)	(N = 61)	(N = 97)		p-value
Age at diagnosis of OMBC (y) (n = 158)					0.183
Median	55.0	51.0	58.0
(Range)	(28.0;90.0)	(28.0;90.0)	(38.0;87.0)
Age groups OMBC (y) (n = 158)					0.003
<45 years	27 (17.1%)	17 (27.9%)	10 (10.3%)
45–65 years	86 (54.4%)	24 (39.3%)	62 (63.9%)
>65 years	45 (28.5%)	20 (32.8%)	25 (25.8%)
Performance status (n = 155)					0.713
0–1	147 (94.8%)	57 (93.4%)	90 (95.7%)
>=2	8 (5.2%)	4 (6.6%)	4 (4.3%)
Menopausal status (n = 154)					0.171
No	58 (37.7%)	27 (44.3%)	31 (33.3%)
Yes	96 (62.3%)	34 (55.7%)	62 (66.7%)
Time to relapse (months) (n = 97) (metachronous OMBC only)					.
Median	NA	NA	60.4
Range			(6.0;487.2)
Local relapse
Metachronous OMBC only	NA	NA	27 (28.1%)
Histological subtypes (n = 157)					0.405
Invasive ductal carcinoma	131 (83.4%)	53 (88.3%)		78 (80.4%)
Others	26 (16.6%)	7 (11.7%)	19 (19.6%)
SBR Grade (n = 156)					0.091
I/II	79 (50.6%)	35 (59.3%)	44 (45.4%)
III	77 (49.4%)	24 (40.7%)	53 (54.6%)
Breast cancer subtype (n = 158)					0.603
RH+/HER2-	88 (55.7%)	37 (60.7%)	51 (52.6%)
HER2+	40 (25.3%)	14 (23.0%)	26 (26.8%)
HR-/HER2-	30 (19.0%)	10 (16.4%)	20 (20.6%)
Surrogate intrinsic subtypes (n = 156)					0.292
Luminal A	28 (17.9%)	14 (23.3%)	14 (14.6%)
Luminal B	78 (50.0%)	31 (51.7%)	47 (49.0%)
HER2	21 (13.5%)	5 (8.3%)	16 (16.7%)
TN	29 (18.6%)	10 (16.7%)	19 (19.8%)
HER2: human epidermal growth factor receptor 2; HR: Hormone receptor; OMBC: oligometastatic breast cancer; NA: not applicable; SIS: Surrogate Intrinsic Subtype;
Luminal A: ER and/or PR > 10%, SBR Grade I or SBR Grade II and Ki-67 ≤ 15%, HER2 negative; Luminal B: ER and/or PR > 10%, SBR Grade III or SBR Grade II and Ki-67 > 15%, HER2+/-; HER2e (HER2-enriched): ER negative, PR negative, and HER2+; TN (Triple Negative): HR-/HER2-

Sixty-six percent of patients underwent ¹⁸F-FDG-PET/CT or Whole-Body Magnetic Resonance Imaging (WB-MRI) for staging evaluation; others had a CT scan associated with a bone scan. Among patients with liver metastases, 52% had a liver MRI or WB-MRI, as did all patients with brain metastases, who underwent a brain MRI (data not shown).

One hundred thirty-seven (86.7%) patients had only one organ involved (brain, liver, lung, bone, lymph node or others), and 13.3% had two. None had more than two organs with metastases. One hundred and thirty-nine (88.0%) patients had only one to three metastases at diagnosis, whereas 19 (12.0%) had four or five distant metastases. Eighty-three (52.5%) patients had bone metastases, 36 (22.8%), had visceral metastases including 23 (14.6%) with liver metastases and 13 (8.2%) with lung metastases. Thirty-three (20.9%) had lymph node metastases, 21 (13.3%) had brain metastases, and six (3.8%) had metastases in other organs (Table 2).

Table 2

OMBC baseline characteristics for the whole cohort and for each pathological subgroup
		OMBC PATHOLOGICAL SUBGROUPS
	Total	HR-/HER2-	RH+/HER2-	HER2+
	(N = 158)	(N = 30)	(N = 88)	(N = 40)	p-value
Synchronous vs. metachronous OMBC					0.603
Synchronous	61 (38.6%)	10 (33.3%)	37 (42.0%)	14 (35.0%)
Metachronous	97 (61.4%)	20 (66.7%)	51 (58.0%)	26 (65.0%)
Time to relapse for metachronous OMBC (months) (n = 97)					< 0.001
Median	60.4	28.1	99.3	36.0
(Range)	(6.0;487.2)	(12.9;137.7)	(6.0;487.2)	(11.6;201.4)
Number of metastases					0.199
<=3	139 (88.0%)	28 (93.3%)	79 (89.8%)	32 (80.0%)
>3	19 (12.0%)	2 (6.7%)	9 (10.2%)	8 (20.0%)
Number of organs with metastases					0.694
1	137 (86.7%)	25 (83.3%)	78 (88.6%)	34 (85.0%)
2	21 (13.3%)	5 (16.7%)	10 (11.4%)	6 (15.0%)
>2	0	0	0	0
Bone metastases					0.001
Yes	83 (52.5%)	9 (30.0%)	57 (64.8%)	17 (42.5%)
No	75 (47.5%)	21 (70.0%)	31 (35.2%)	23 (57.5%)
Bone-only metastases					0.001
Yes	67 (42.4%)	6 (20.0%)	48 (54.5%)	13 (32.5%)
Non	91 (57.6%)	24 (80.0%)	40 (45.5%)	27 (67.5%)
Visceral metastases					0.186
Yes	36 (22.8%)	8 (26.7%)	15 (17.1%)	13 (32.5%)
No	122 (76.6%)	22 (73.3%)	73 (82.9%)	27 (67.5%)
- Liver metastases					0.379
Yes	23 (14.6%)	5 (16.7%)	10 (11.4%)	8 (20.0%)
No	135 (85.4%)	25 (83.3%)	78 (88.6%)	32 (80.0%)
- Lung metastases					0.352
Yes	13 (8.2%)	3 (10.0%)	5 (5.7%)	5 (12.5%)
No	145 (91.8%)	27 (90.0%)	83 (94.3%)	35 (87.5%)
Lymph node metastases					0.008
Yes	33 (20.9%)	12 (40.0%)	17 (19.3%)	4 (10.0%)
Non	125 (79.1%)	18 (60.0%)	71 (80.7%)	36 (90.0%)
Brain metastases					0.001
Yes	21 (13.3%)	4 (13.3%)	5 (5.7%)	12 (30.0%)
No	137 (86.7%)	26 (86.7%)	83 (94.3%)	28 (70.0%)
Other metastases (skin, pancreas, adrenal glands)					0.218
Yes	6 (3.8%)	2 (6.7%)	4 (4.5%)	0 (0.0%)
Non	152 (96.2%)	28 (93.3%)	84 (95.5%)	40 (100.0%)
HER2: human epidermal growth factor receptor 2; HR: Hormone receptor; OMBC: oligometastatic breast cancer;
*MBC: metastatic breast cancer
**OMBC: oligometastatic breast cancer

3.2 OMBC subtypes

HR and HER2 status was available for all patients, and SBR grade for 156 patients; 50.6% had SBR grade I or II, and 49.4% had SBR grade III, 55.7% had HR+/HER2- disease, 25.3% had HER2 + disease and 19.0% had HR-/HER2- disease (Table 1).

HR, HER2 status and SBR grade are not associated with the number of metastases (p = 0.199) or the number of organs involved (p = 0.694). HR+/HER2- OMBC showed significantly more bone metastases than HER2 + and HR-/HER2- disease, respectively 64.8%, 42.5% and 30.0% (p = 0.001). HER2 + OMBC presented significantly more brain metastases than HR-/HER2- and HR+/HER2- diseases, respectively 30%, 13.3% and 5.7% (p = 0.001). HR-/HER2- OMBC showed significantly more lymph node metastases than HR+/HER2- and HER2 + diseases, respectively 40.0%, 19.3% and 10.0% (p = 0.08). Lastly, visceral metastases were not statistically associated with any of the OMBC subtypes (p = 0.186) (Table 2).

HR, HER2 status and SBR grade together predicted median time to relapse in the case of metachronous OMBC (p < 0.001) (Table 1). Finally, there were no statistical differences for histological subtypes (p = 0.195), SBR grade (p = 0.091), HR and HER2 status (p = 0.603) between synchronous and metachronous OMBC (Table 1). Data are also available according to SIS subtypes (Appendix 1).

3.3 Comparison with the ESME cohort

We first compared our cohort with that of ESME [19] (22,109 MBC, Table 3). Our 158 OMBC patients had better PS (p < 0.001), fewer patients were menopausal at diagnosis (p = 0.002), and more patients had synchronous metastases (38.6% vs. 30.1%; p = 0.02).

Table 3

Comparison of baseline characteristics between the current cohort, the NCR cohort and the ESME cohort
	Current OMBC cohort	NCR OMBC cohort [20]	ESME OMBC cohort [26]
	(n = 158)	(n = 517)	(n = 22.109)	p-value
Age (years) at diagnosis of first metastasis	(n = 158)	(n = 517)	(n = 22.109)
Median	55.0	NA	NA
(Range)	(28.0;90.0)	NA	NA
Performance status (PS)	(n = 155)		(n = 8595)
0–1	147 (94.9%)	NA	6795 (79.0%)	< 0.001
2–4	8 (5.1%)	NA	1800 (20.9%)
Missing	3	NA	13,514
Menopausal status	(n = 154)	(n = 517)	(n = 22,109)	< 0.01
No	58 (37.7%)	202 (39.1%)	5921 (26.8%)
Yes	96 (62.3%)	315 (60.9%)	16,188 (73.2%)
Missing	4	0	0
Synchronous versus metachronous MBC	(N = 158)	(N = 517)	(N = 22.109)	0.02
Synchronous	61 (38.6%)	517 (100%)	6658 (30.1%)
Metachronous	97 (61.4%)	0 (0%)	15,451 (69.9%)
Time between initial diagnosis and MBC diagnosis (months) (among relapsed MBC patients)	(n = 97)		(n = 22,109)	0.02
Median	60.4	NA	66.9
(Range)	(6.0;487.2)	NA	NA
Histological subtype	(n = 157)		(n = 21,681)	p = 0.018
IDC	131 (83.4%)	NA	16.322 (75.3%)
Others	26 (16.6%)	NA	5359 (34.7%)
Missing	1		428
SBR grade	(n = 156)		(n = 18.373)	p = 0.001
I/II	79 (50.6%)	NA	11,851 (64.8%)
III	77 (49.4%)	NA	6422 (35.2%)
Missing	2		3826
Pathological subtypes	N = 158	(n = 480)	(n = 20,636)	< 0.001
		IUCT versus NCR < 0.001
		IUCT versus ESME 0.02
HR-/HER2-	30 (19.0%)	36 (7.5%)	2963 (14.4%)
HR+/HER2-	88 (55.7%)	315 (65.6%)	13,656 (66.1%)
HER2+	40 (25.3%)	129 (26.8%)	4017 (19.5%)
Missing	0	37	1473
Number of organs with metastases (OMBC only)	n = 158	n = 517		0.221
1	137(86.7%)	427 (82.6%)	NA
2	21 (13.3%)	90 (17.4%)	NA
Number of metastases (OMBC only)	N = 158	N = 612		0.270
1 to 3	139 (88.0%)	517 (84.4%)	NA
4 and 5	19 (12.0%)	95 (15.6%)	NA
Metastatic sites (OMBC only)
Lymph node metastases	33 (20.9%)	39 (7.5%)	NA	< 0.001
Bone metastases	83(52.5%)	289 (55.9%)	NA	0.456
Liver metastases	23 (14.6%)	176 (34.0%)	NA	0.001
Lung metastases	13 (8.2%)	54 (10.4%)	NA	0.415
Skin and others	6 (3.8%)	14 (2.7%)	NA	0.480
Brain metastases	21 (13.3%)	29 (5.6%)	NA	0.001
Note: all percentages have been recalculated excluding missing data
ESME: Epidemiological Strategy and Medical Economics; HER2: human epidermal growth factor receptor 2; HR: hormone receptor; IDC: invasive ductal carcinoma; MBC: metastatic breast cancer; NA: not available; NCR: Netherlands Cancer Registry; OMBC: oligometastatic breast cancer; SBR grade: Scarf-Bloom-Richardson grade.

The proportion of patients with invasive ductal carcinoma was significantly higher in our cohort (83.4% vs. 75.3%, p = 0.018). There was a larger proportion of HR-/HER2- (19% vs. 14.4%), HER2+ (25.3% vs. 19.5%), and a lower proportion of HR+/HER2- (55.7% vs. 66.1%) cancers (p < 0.02). The proportion of SBR grade III BC was also statistically higher in our cohort (49.4% vs. 35.2%; p < 0.001). No comparison was possible by SIS due to absence of data in the ESME cohort.

3.4 Comparison with the NCR cohort

Due to lacking data, it was also not possible to compare age at diagnosis, PS, SIS or SBR Grade between our cohort and that of the NCR. The incidence of patients with one to five metastases was 15.8% in our cohort compared with 17.3% in the NCR cohort (Table 3). The proportion of patients with only one organ affected in our cohort was consistent with the proportion in the NCR cohort (86.7% vs. 82.6%; p = 0.221). With our patients, the proportion with one to three metastases among those with one to five metastases was consistent with the same proportion in the NCR cohort, respectively 88% and 84.4 (p = 0.270).

There were significantly more patients with distant lymph node metastases (20.9% vs. 7.5%; p < 0.001) and brain metastases (13.3% vs. 5.6%; p = 0.001) and fewer patients with liver metastases (14.6% vs. 34.0%; p < 0.001) in our cohort compared to the NCR study. The proportion of patients with bone metastases was equal in each cohort (52.5% vs 55.9%; p = 0.456). Ours included significantly more HR-/HER2- OMBC (19.0% vs. 7.5%) and fewer HR+/HER2- OMBC (55.7% vs. 65.6%); finally, HER2 + OMBC frequency was similar in both cohorts (25.3% vs. 26.8%) (p < 0.001).

Our study offers original data concerning OMBC incidence, optimal thresholds for OMBC definition and considerations regarding OMBC biology and anatomy. In this cohort, incidence is significantly higher than the 1–10% frequently proposed. The latter value is obsolete, as has been previously shown [14]. Our result is closer to more recent data: 17.3% for synchronous OMBC [16], 23.1% for synchronous and metachronous OMBC [17], 16.9% and 21.9% for metachronous OMBC [24, 25] and 31% for HR + metachronous OMBC [20]. This result confirms that a specific therapeutic strategy for OMBC, where possible, is not anecdotal but concerns a substantial proportion of MBC.

We must keep in mind, moreover, that the very concept of OMBC is based on a specific biological profile. Limited metastatic extension is merely the phenotypic consequence. As long as OMBC specific biomarkers remain unknown, anatomy is the sole indicator that can be used to define OMBC. Therefore, a defining threshold number of organs and metastases must necessarily lead to identifying a subgroup of patients with a homogeneous biological profile. In some publications on OMBC [26–28] and MBC [29–31], involvement of a single organ is associated with better outcome, but this has not been consistently observed [16, 17]. Other authors provide no information on this point [32–35]. Given this context, should we consider that one of the biological characteristics of OMBC is, firstly, its spread to a single organ? And consequently, should we then include this property in the anatomical definition of OMBC? Such is the position taken by Weichselbaum and Hellman [1, 2]. It should be noted that this characteristic also concords with the « seed and soil » theory [36–38] as well as with the contemporary view of metastatic diffusion physiology, where successive genomic alterations lead progressively to polymetastatic diffusion [39–41].

The proportion of patients with one to three metastases is a majority in both our cohort and NCR data, respectively 88.0%, and 84.4%. A key result of Steenbrugeen et al. is that overall survival is significantly better for OMBC with one to three metastases than for MBC with more than five metastases, whereas overall survival for patients with four to five metastases does not differ from patients with more than five metastases [16]. Therefore, three metastases as an upper threshold is clinically significant. Consequently, it may be more consistent to apply this threshold in defining OMBC than the value of five applied by ESO-ESMO and ESTRO-ASTRO in defining OMD [11, 42].

In our study, the proportion of aggressive BC is higher than in the ESME MBC cohort. The same observation can be made for other cohorts: Selvarajan et al. report 77% of patients with SBR Grade III and 94% with Ki67 > 20% [17]. Lan et al. cite 48% of patients with triple negative or HER2 + OMBC [18]. These results are somewhat counterintuitive, since OMBC is traditionally described as an indolent disease [11, 27, 43, 44]. The argument that its indolent nature could explain the observed prolonged survival must therefore be rethought.

Finally, OMBC appears to be a heterogeneous entity, both clinically and biologically. As such, it seems difficult to imagine that different subgroups would benefit from the same therapeutic strategy. This consideration questions the design of clinical trials including different subgroups of OMBC.

Nevertheless, we found major discrepancies in the pathological and anatomical features of OMBC in comparing our cohort with that of the NCR. We therefore enlarged our analysis to two other retrospective, non-consecutive series cited above [17, 18]. On a first level, inclusion criteria vary widely from one series to the other: number and nature of organs invaded, number and maximum diameters of metastases, feasibility of focal treatments, inclusion of synchronous and/or metachronous disease. Other factors also influence the number and location of observed metastases and thus the distribution of pathological subtypes: metastasis screening procedures and calculation methods. All of these biases are seen to affect conclusions of OMBC studies. The OLIGOCARE project, initiated by EORTC and ESTRO, will hopefully provide robust data on OMBC [13].

The weaknesses of the present study are quite common: as a retrospective study, data is inevitably incomplete, lacking harmonization or review of imaging or biological examinations. Nevertheless, it is a large and consecutive series. Restricting inclusion criteria to exclusively anatomical data improved the objectivity of data collection. Most importantly, however, we have developed and implemented a rigorous method for calculating metastases.

Our large cohort consists of consecutive patients, untreated at metastatic stage with either synchronous or metachronous OMBC.

OMBC incidence is 15.8% in our cohort and varies from 15.0–23.1% in the most recent cohorts where data are available. From a pathological and anatomical point of view, OMBC is a heterogeneous entity; depending on the subgroup, focal ablative treatment of all disease locations may thus not result in improved prognosis. A consequent proportion of OMBC are aggressive BC: the belief that the indolent nature of OMBC could explain observed prolonged survival must therefore be carefully weighed. No significant differences were found in either anatomical or biological characteristics between synchronous and metachronous OMBC. From a biological perspective, it may be relevant to restrict the definition of OMBC, to “up to three [metastases] and necessarily in the same organ” instead of “up to five and not necessarily in the same organ [11, 42]. Comparison with other cohorts of OMBC is difficult due to discrepancies in imaging techniques and variability in counting metastases; these points all need to be harmonized.

In conclusion, it must be noted that, since oligometastatic disease has been proposed as a new paradigm, no large and randomized trial has confirmed the benefits of intent-to-cure treatment for OMBC. Furthermore, if the latter is proven, what questions will remain? Do all metastases deserve to be treated and if so, according to what timeline? What is the optimal adjuvant treatment to implement? What is the impact on intent-to-cure strategy for OMBC in terms of quality of life and medico-economic results? The short-term question remains as to whether it is preferable to continue developing randomized studies to prove the benefits of intent-to-cure OMBC treatment or, on the contrary, to “bridge the gap” [45] henceforth, looking for answers to other questions.

Acknowledgements

We would like to thank Dr. Gail Taillefer, native speaker experienced in scientific publication and Emeritus professor of English, for her review of the manuscript.

Funding

The authors declare that no funds, grants, or other supports were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Dr Jean-Louis Lacaze, Dr Gauthier Glemarec, M. Bastien Cabarrou and M. Nils Monselet. The first draft of the manuscript was written by Dr Jean-Louis Lacaze, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available. They include personal data resulting from medical care but are available from the corresponding author on reasonable request.

Ethical approval

This retrospective and observational study was approved by our Multidisciplinary Breast Committee and our Institutional Board Committee (BEC-FO-0227).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Clinical and pathological characterization of 158 consecutive and unselected oligometastatic breast cancers in a single institution

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Journal Publication

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Abstract

Figures

1 Introduction

2 Materials And Methods

2.1 Patient selection

2.2 Synchronous and metachronous OMBC definition

2.3 Data collection

2.4 Review of the literature

2.5 Objectives

2.6 Statistical analysis

3 Results

3.1 Patient characteristics

3.2 OMBC subtypes

3.3 Comparison with the ESME cohort

3.4 Comparison with the NCR cohort

4 Discussion

5 Conclusion

Declarations

References

Status:

Journal Publication

Version 1