Grazi breast cancer final

Gian Luca Grazi
Hepato-Biliary-Pancreatic Surgery
National Cancer Institute Regina Elena
Rome
Breast Cancer Liver Metastases:
Indications and Timing for Resection
20 minute presentation followed by 10 minutes for questions and answers
1

Breast Cancer Liver Mets: Indications & Timing for Resection
Introduction
Literature reviews
Comparative studies
Cost utility analysis
AGENDA
2

• In 2012, the estimated age-adjusted annual incidence of breast
cancer in 40 European countries was 94.2/100,000 and the
mortality 23.1/100,000.
• The incidence increased after the introduction of mammography
screening, and continues to grow with the ageing of the
population.
INTRODUCTION (1)
Primary breast cancer: ESMO Clinical Practice, Ann Oncol 2015; 26 (Supp 5): v8–v303

• The estimated 5-year prevalence of breast cancer in Europe in
2012 was 1,814,572 cases.
• Prevalence is increasing, as a consequence of increased
incidence and due to improvements in treatment outcomes.
• In most Western countries, the mortality rate has decreased in
recent years, especially in younger age groups, because of
improved treatment and earlier detection.
• However, breast cancer is still the leading cause of cancer-
related deaths in European women.
INTRODUCTION (2)
Primary breast cancer: ESMO Clinical Practice, Ann Oncol 2015; 26 (Supp 5): v8–v304

• The leading cause of these deaths was metastatic spread.
• The timing and distribution of breast-cancer metastases
vary considerably.
• In approximately 5% of women with breast cancer,
metastases are clinically evident at the time of diagnosis.
• In other women, metastases become apparent years or
even decades after the initial diagnosis.
• Moreover, the number of metastases varies considerably.
INTRODUCTION (3)
Schwartz RS, New Engl J Med 2017, 376(25): 2486-24885

• Regular history, physical examination, and mammography are
recommended
• Examinations should be performed every 3 to 6 months for the first
3 years, every 6 to 12 months for years 4 and 5, and annually
thereafter
• Use of CBCs, chemistry panels, bone scans, chest radiography, liver
ultrasounds, CT scans, [18F] fluorodeoxyglucose-PET scanning, MRI,
or tumor markers (CEA, CA 15-3, and CA 27.29) is not
recommended for routine breast cancer follow-up in an otherwise
asymptomatic patient with no specific findings on clinical
examination
Khatcheressian JL, J Clin Oncol 2012, 31: 961-9656

Skeletal system Other sites
Median survival 48 months 17 months p<0.01
First hormonal therapy effective 87% (56/64)
(median 10 months)
Initial CHT effective 93% (43/46)
(median 11 months)
Metastatic breast cancer confined to the skeletal system.
An indolent disease.
Sherry MM, Am J Med 1986, 81(3): 381-3867

• Approximately 30% of patients with breast cancer will develop
distant metastases at some point during their disease course.
• While liver is the third most frequent site of metastatic spread
(after lymph nodes and lung), only 5–25% of patients will have
isolated breast cancer liver metastases (BCLM) and will, in turn,
be eligible for liver directed surgery.
INTRODUCTION (4)
Margonis GA, HPB 2016, 18: 700–7058

Mariani P, EJSO 2013, 39: 1377–1383
LIVER METS FROM
BREAST CANCER
LIVER METS FROM
COLON CANCER
Effective chemotherapy Established long Established recently
Role of liver surgery Even if disease readily
resectable, always
treated by first-line CHT
Only effective first-line
treatment
Surgical treatment Excessively invasive
9

Margonis G et al
(HPB 2016, 18: 700-705)
8 International Centers
5 United States
2 Italy
1 Portugal
over 24 years
In the same period in the United
States:
approximately 5.5 million new cases
(230,000 x 24 years)
Approximately 10% of the
patients with metastatic
disease limited to the liver
96,000 cases of BCLM
119 cases of liver
resections for BCLM
D’Angelica M, HPB 2016, 18: 631–63210

Annual number of hepatic resections for patients
with noncolorectal nonendocrine liver metastases
at 41 centers from 1983 to 2004.
11

Groeschl RT, J Am Coll Surg 2012, 214: 769–77712

Variable Points
Extrahepatic metastases present prior
to or at the time of hepatectomy
Yes 1
No 0
Major Hepatectomy
(>2 segments)
Yes 1
No 0
R2 resection
Yes 1
No 0
Patient age Less than 30 years 0
30–60 years 1
Greater than 60 years 2
Patient with a disease-free interval Greater than 24 months 0
12–24 months 1
Less than 12 months 2
Primary cancer Breast primary tumor 0
Squamous primary tumor histology 2
Choroids melanoma primary tumor 3
All other primary tumor sites and histologies 1
Adam R, Ann Surg 2006, 244: 524–53513

Analysis of survivals based on a risk model for patients
with noncolorectal nonendocrine liver metastases.
Adam R, Ann Surg 2006, 244: 524–53514

The principal question relative to liver resections
for LMBC remains proof of their usefulness
Elias D, Lasser P, Spielmann M, May-Levin F, el Malt O, Thomas H, Mouriesse H.
Surgical and chemotherapeutic treatment of hepatic metastases from carcinoma
of the breast.
Surg Gynecol Obstet. 1991 Jun;172(6):461-4.
Institut Gustave-Roussy, Villejuif, France.
15

Introduction
Literature reviews
Comparative studies
16

Author Year Journal # of studies Therapy Minimun # pts
Elias 2006 HPB 9 Resection > 10
Howlader 2011 Int J Surg 11 Resection ≥ 9
Chua 2011 Eur J Cancer 19 Resection > 10
Vogl 2013 Eur Radiol 8 Thermal ablation
Vertriest 2015 Dig Surg 17 Resection
Fairhurst 2016 The Breast 33 Resection > 5
Golse 2017 Clin Breast Cancer 18 Resection Principal series
published
since 2000
Yoo 2017 The Breast 43 Resection
Ercolani 2017 Dig Surg 10 Resection > 40
Tasleem 2018 Irish J Med Sci 25 Resection
Recent reviews appeared in the literature
17

Golse N, Clin Breast Cancer 2017, 17(4): 256–26518

21

Yoo TG, The Breast 2017, 32: 162–17222

Yoo TG, The Breast 2017, 32: 162–172
Some patients characteristics
Median time between breast surgery and diagnosis BCLM 35 months 11-71 months
Synchronous 13% 123/412 pts
Solitary 55% 503/913 pts
Unilobar 64% 263/412 pts
CHT prior to LR 74% 523/705 pts
CHT after LR 66% 486/733 pts
30 day mortality 0.7% 6/918
Median 3- and 5-year survival 56% - 37%
Recurrence 62% 325/523 pts
Liver 61% 197/325 pts
Skeletal 11% 36/325 pts
Lungs 7% 24/325 pts
Brain 5% 17/325 pts
Pleura 2% 6/325 pts
23

Yoo TG, The Breast 2017, 32: 162–172
Quality of the reported and included 43 studies 1686 pts
Systematic criteria to select patients 21 studies
More than 50 patients 6 studies
Extrahepatic as an exclusion criteria 7 studies 150 pts
Potentially curative 8 studies 207 pts
Extent of BCLM 7 studies
Response to pre-hepatectomy CHT 2 studies 154 pts
In combining the articles with small sample sizes, there is a
significant heterogeneity between the
• selection criteria,
• disease stage and
• treatment characteristics.
24

Yoo TG, The Breast 2017, 32: 162–172
Reported analysis included 43 studies 1686 pts
Analysis done 22 studies 826 pts
Age irrelevant 12/15 123/412 pts
Better for pts aged ↑ 50 years 2/15 503/913 pts
Better for pts aged ↓ 50 years 1/15 263/412 pts
Primary tumor histology grade irrelevant 3
Grade irrelevant 12
Lymph node status irrelevant 7
Type of breast surgery irrelevant 2
Positive hormone receptor status at primary BC 6 341 pts
Absent hormone receptor status at primary BC 1 486/733 pts
Hormone receptor status at primary BC irrelevant 8 325/523 pts
Extrahepatic metastases worse 5 205 pts
Extrahepatic metastases irrelevant 5 154 pts
25

Yoo TG, The Breast 2017, 32: 162–172
Positive factors Irrelevant
Prolonged interval between breast
cancer treatment and diagnosis of BCLM
Timing
(synchronous/methachronous)
Solitary
Unilobar
Small tumor size
Extent of resection
Hormonal status
Grade of the tumor
26

Period: 1/1985 – 12/2012
139 consecutive female
162 hepatectomies
27

Ruiz A, Ann Surg Oncol 2017, 24: 535–545
Negative predictors of survival Positive predictors of survival
> 1 liver metastasis Negative resection margin
Max tumor size ≥ 20 mm at diagnosis Administration of hormonal therapy
before and after hepatectomy
Negative receptor status for estrogen,
progesterone, and HER2/Neu receptor
(triple negative)
Targeted therapy after hepatectomy
Microscopic vascular invasion Performance of repeated hepatectomy
28

Calibration plot for the probability of survival at 3 and 5
years, demonstrating good calibration between the
prediction by the normogram and the actual observation.
30

Hepatectomy should be considered for all patients with
BCLM responding to systemic treatment when
technically feasible.
Liver resection provides a chance of long-term survival
for selected patients with an acceptable risk of
morbidity and mortality.
Accurate selection of patients for hepatectomy remains
crucial.
A nomogram can help to identify patients who may
benefit most from hepatic resection and can help
clinicians and patients to make a more informed decision
when advocating for resection.
31

Introduction
Literature reviews
Comparative studies
32

33

Mariani P, EJSO 2013, 39: 1377–138334

Mariani P, EJSO 2013, 39: 1377–138335

Mariani P, EJSO 2013, 39: 1377–1383
Patients were candidates for surgical resection if they had
• resectable liver metastases (≤4 metastases),
• had stable disease or disease responding to
chemotherapy and/or hormone therapy, and
• achieved a performance status of 0-1.
The only extra-hepatic site metastases allowed were bone
metastases if they were not growing during treatment.
36

Mariani P, EJSO 2013, 39: 1377–138337

Mariani P, EJSO 2013, 39: 1377–138338

Mariani P, EJSO 2013, 39: 1377–1383
• In select patients, the resection of liver metastases from
primary breast cancer is associated with a genuine survival
benefit.
• An aggressive and multidisciplinary approach, including
surgery of metastases, should be considered even if
patients had bone metastases controlled by medical
treatment.
39

Period May 2004 – May 2011
26 patients with BCLM
Cancer confined to one
lobe regardless of the
number of lesion
12
Liver resections
Bilobar distribution and
no lesions greater than 6
cm in maximum diameter
14
RFA
38 patients with BCLM
treated with CHT during the
same time period
(no brain metastases or visceral
metastatic spread)
40

Treated Liver
resections
RFA Control group
Overall survival from
the BC diagnosis
47.69 ± 22.25
(median 45.5)
52.25 ± 14.57
(median 48.5)
43.79 ± 27.14
(median 39)
Overall survival from
BCLM treatment
21.12 ± 12.78
(median 15.5)
29.42 ± 14.53
(median 29.5)
14 ± 4.45
(median 13.5)
(median 9.7)
Overall disease-free
survival from BCLM
15.96 ± 13.15
(median 12)
23.22 ± 16.2
(median 18.5)
9.64 ± 4.22
(median 9)
Overall 1-, 2- and 5-
year actuarial survival
80.7, 57, 31% 100, 66.6, 34% 64.2, 21.4,
11.5%
5.2, 0, 0
Polistina F, World J Surg 2013; 37: 1322–1332
Overall survivals and median survivals are expressed in months
41

• A retrospective review of consecutive patients with isolated BCLM (167/2150 patients,
7,7%) from January 1991 to January 2014 treated at Memorial Sloan Kettering Cancer
Center (MSKCC)
• Surgical cases were discussed on a case-by-case basis at a multidisciplinary meeting
where consensus concerning resectability and appropriateness of liver resection were
determined.
• Patients with isolated BCLM treated with liver resection and/or ablation (surgical cohort:
69 patients, 41%) and those receiving medical therapy alone (medical cohort: 98
patients, 59%) were analyzed and compared.
• A propensity score analysis was used to control for selection bias, which resulted in
uneven distribution of covariates among the surgical and medical cohorts.
42

Sadot E, Ann Surg 2016, 264: 147–15443

Sadot E, Ann Surg 2016, 264: 147–154
Overall survival of the low
propensity score subgroup
stratified by surgical intervention
Overall survival of the intermediate
propensity score subgroup stratified
by surgical intervention
Overall survival of the high
propensity score subgroup
stratified by surgical intervention
44

Sadot E, Ann Surg 2016, 264: 147–154
Surgical therapy for BCLM is safe and, in a subset of carefully
selected cases, may provide a substantial period of time free of
recurrent disease during which systemic chemotherapy might
be avoided.
This does not appear to compromise OS.
At the same time, there are no associated OS benefits in these
selected patients when compared to patients receiving standard
medical care.
Surgical intervention should only be considered in highly
selected patients with the goal of providing time off systemic
therapy, and this may be most appropriate for patients requiring
cytotoxic chemotherapy.
45

Abbas H, Int J Surg 2017, 44: 152–15946

Abbas H, Int J Surg 2017, 44: 152–15947

Abbas H, Int J Surg 2017, 44: 152–15948

Abbas H, Int J Surg 2017, 44: 152–15949

Mariani Polistina Sadot Abbas
Year 2013 2013 2016 2017
Nature of the
study
Retrospective Retrospective Retrospective Retrospective
(report of UK tertiary center
tumor board meeting)
Medical cohort Medical therapy
alone
Medical therapy
alone
Medical therapy
alone
Medical therapy
alone
Inclusion
criteria for
medical cohort
≤ 4 liver mets
With/without bone
mets
No other mets
Not reported Not reported Not reported
Surgical cohort Resection only Resection or
ablation
Resection and/or
ablation
Resection and/or
ablation
Inclusion
criteria for
surgical cohort
≤ 4 liver mets
Stable disease at CT
With/without
stable bone mets
PS 0-1
Stable liver disease
Karnofsky > 80
No general
contraindication
No underlying CLD
Non reported Resectable
Statistics Case control study Analysis of survival Propensity score
analysis
Analysis of survival
(Mariani and Polistina’s
studies not cited)
(Mariani and Polistina’s
studies not cited)
50

Introduction
Literature reviews
Comparative studies
51

52

Spolverato G, Ann Surg 2017, 265: 792–799
Scenario 1 Strategy A Liver Resection Postoperative
conventional systemic
therapy
Letrozole for hormone estrogen
receptor-positive [ER+] patients;
Docetaxel + trastuzumab for human
epidermal growth factor receptor 2
[HER2+] positive patients
Strategy B Conventional systemic
therapy
Scenario 2 Strategy A Liver Resection Postoperative
conventional systemic
therapy
Strategy C Newer systemic
therapy alone
Letrozole + palbociclib for ER+
patients;
Docetaxel + trastuzumab +
pertuzumab for HER2+ patients
53

Patients with ER+: unadjusted
survival curves of strategy A vs.
strategy B or C in patients with
BCLM.
Patients with HER2+: unadjusted
survival curves of strategy A vs.
strategy B or C in patients with
BCLM.
54

Strategy A: LR + letrozole
Strategy A:
LR + docetaxel + trastuzumab
Strategy A:
LR + letrozole
Strategy B: letrozole alone Strategy B:
Docetaxel + trastuzumab alone
Strategy B:
Letrozole + palbociclib
Strategy A:
LR + docetaxel + trastuzumab
Strategy B:
Docetaxel + trastuzumab + pertuzumab
ER+
ER+
HER2+
HER2+
57

Liver resection plus conventional systemic therapy was more
cost-effective for patients with ER+ tumors than systemic
therapy alone.
For patients with HER2+ tumors, LR plus systemic therapy that
included trastuzumab had a cost-effectiveness that was
comparable to conventional systemic therapy alone.
The use of newer systemic chemotherapeutic agents such as
palbociclib and pertuzumab for patients with resectable BCLM
was not cost-effective.
Although certain therapies may have a clinical effect, the cost-
effectiveness of these agents may not justify their use
compared with other therapies such as surgical resection and
standard systemic chemotherapy.
58

 Up to now, metastatic disease from
breast cancer should be controlled by
systemic therapy.
TAKE HOME MESSAGE (1)
59

Liver resection is an effective treatment for some
liver metastases from breast cancer
We have not been able to define solid prognostic
factors
• Systemic reviews on BCLM suffer of the significant
heterogeneity between the selection criteria, disease stage
and treatment characteristics
• Papers included in systemic reviews usually describe liver
resection performed over very long periods and report
limited number of cases
It is unlike that a prospective single center trial is
feasible
60

Evaluation for surgery should include:
 the presence of isolated liver metastases (their
survival is improved compared to CHT alone) which
respond or are stable with chemotherapy
(≤ 4 ??)
 the interval between breast cancer treatment and
diagnosis of BCLM
(the longest, the better ?)
 The feasibility of an oncologically correct liver
resection
(free margins, adequate remnant liver)
Skeletal metastases are not an absolute contraindication
61

No teams has reported unresectable LMBC that
became secondarily resectable.
Resection could also:
• decrease the need for repetitive cycles of cytotoxic
chemotherapy;
• reduce the tumor burden potentially providing an
immunologic benefit;
• at least allow time off cytotoxic chemotherapy during
the disease-free period («treatment-free holiday»).
62

The selection of patients with LMBC for
surgery should be performed only in
tertiary centers that can offer the best
short-term (low morbidity, nil postoperative
mortality) and long-term outcomes.
63

64

Gian Luca Grazi
Hepato Biliary Pancreatic Surgery
National Cancer Institute “Regina Elena”, Rome, Italy
gianluca.grazi@ifo.gov.it
www.chirurgiadelfegato.it
65

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