Endocrine therapy as first line and maintenance therapy to ...1301733/FULLTEXT01.pdf · Endocrine therapy as first line and maintenance therapy to patients with metastatic oestrogen

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Endocrine therapy as first line and maintenance therapy to patients with

metastatic oestrogen receptor-positive, HER2-negative breast cancer

By: David Söderberg, Medical student

Supervisor: Antonis Valachis, MD, PhD

Assistance: Henrik Lindman, MD, PhD

Date: 2018-08-29

Source: https://pixabay.com/sv/band-symbol-

cancer-mama-br%C3%B6st-rosa-2818640/

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Title: Endocrine therapy as first line and maintenance therapy to patients with metastatic oestrogen receptor-

positive, HER2-negative breast cancer

Innehållsförteckning ....................................................................................................................................................................... 1

Endocrine therapy as first line and maintenance therapy to patients with metastatic oestrogen receptor-

positive, HER2-negative breast cancer .......................................................................................................... 1

Abstract ......................................................................................................................................................... 3

Populärvetenskaplig sammanfattning ............................................................................................................ 4

Bakgrund: ............................................................................................. Fel! Bokmärket är inte definierat.

Metod:................................................................................................... Fel! Bokmärket är inte definierat.

Resultat/diskussion: .............................................................................. Fel! Bokmärket är inte definierat.

Konklusion: .......................................................................................... Fel! Bokmärket är inte definierat.

1. Background: .......................................................................................................................................... 5

2. Methods: ................................................................................................................................................ 6

2.1 Study population: ................................................................................................................................ 6

2.2 Data collection: .................................................................................................................................... 6

2.3 Statistical analyses: .............................................................................................................................. 6

3. Results: .................................................................................................................................................. 7

3.1 Patient, tumour and treatment characteristics ...................................................................................... 7

3.2 Association between CT vs ET in terms of OS, PFS and TTP .......................................................... 10

4. Discussion ............................................................................................................................................ 12

Conclusion ................................................................................................................................................... 13

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Abstract Background: For hormone receptor-positive (HR+), human epidermal growth factor receptor 2

negative (HER2-) metastatic breast cancer the international guidelines suggest endocrine therapy

(ET) as first line treatment, except in case of ‘visceral crisis’. For the latter case, chemotherapy

(CT) is recommended. After CT, maintenance ET or a wait-and-see approach is possible. There are,

however, a lack of robust evidence supporting either. This study is trying to address these two

questions.

Methods: Patients undergoing either endocrine therapy or chemotherapy at Uppsala Academic

Hospital and Mälarsjukhuset during 2008-2015 were selected. Patients had to be oestrogen receptor

positive, HER2-negative and survived at least 3 months from diagnosis. Objective of the study were

to evaluate the time to progression (TTP), progression-free survival (PFS) and overall survival (OS)

according to the type of first line treatment and maintenance endocrine therapy using a propensity

score analysis and inverse propensity score weighting.

Results: Two hundred eighty-five patients were eligible: 234 (82.1%) received ET as first line

therapy, while 51 (17.9%) received CT as first line therapy. Among the latter 36 (70.5%) got a

response on chemotherapy and all received maintenance endocrine therapy. Mean follow up were 37 months

(range 3-118 months). There was no statistical difference between first line treatment; TTP hazard ratio 0.96

(P=0.811, 95% confidence interval [CI] 0.66-1.39), PFS hazard ratio 0.99 (P=0.940, CI 0.69-1.42) and OS

1.19 (P=0.409, CI 0.78-1.78). When using Propensity score and inverse propensity score there were still no

statistical difference.

Conclusion: In this retrospective cohort there were no statistical difference between ET or CT as first line

treatment in terms of TTP, PFS and OS. Maintenance ET was generally used in all patients that responded on

first line CT. In agreement with the international guidelines, endocrine therapy should be the first choice for

first line systemic treatment for luminal A/B metastatic breast cancer in the absence of visceral crisis.

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Populärvetenskaplig sammanfattning

Bakgrund: För hormonreceptorpositiv (HR+), humant epidermal tillväxtfactor receptor 2 negativ

(HER2-) metastaserad bröstcancer föreslår de internationella riktlinjerna att man börjar med

endokrin terapi (ET) som första linjens behandling, förutom i fall det finns tecken till ’visceral kris’.

För det senare är kemoterapi (CT) rekommenderat. Efter CT kan man välja underhållsbehandling

med ET eller en vänta och se strategi. Det finns dock inte tillräckligt med studier som stödjer varken

valet för första linjens behandling som valet av strategi efter CT. Denna studie gjordes för att

undersöka dessa två frågeställningar.

Metod: Patienter som undergick antingen ET eller CT på Uppsala Akademiska Sjukhus och

Mälarsjukhuset i Eskilstuna mellan 2008 till och med 2015 ingick i studien. Inklusionskriterierna

var östrogenreceptorpositiv, HER2-negativ metastaserad bröstcancer, som överlevde minst 3

månader efter metastasdiagnos. Målet med studien var att undersöka skillnaden mellan ET och CT

som förstalinjens behandling i form av Tid till progression (TTP), Progressionsfri överlevnad (PFS)

och Total överlevnad (OS). Vi använde oss av en propensity score analysis och en inverse

propensity score weighting.

Resultat: 285 patienter passade in i inklusionskriterierna: 234 (82.1%) fick ET som första linjes

behandling medan 51 (17.9%) fick CT som första linje. Av den senare gruppen fick 36 (70.5%)

patienter en respons på CT och alla dessa fick senare underhållsbehandling med ET. Den

genomsnittliga tiden som patienten följdes var 27 månader (spann 3-118 månader). Det återfanns

ingen statistisk signifikant skillnad mellan förstalinjens behandlingsalternativ; TTP hazard ratio

(HR) 0.96 (P=0.811, 95% konfidens intervall [CI] 0.66-1.39), PFS HR 0.99 (P=0.940, CI 0.69-1.42)

och OS HR 1.19 (P=0.409, CI 0.78-1.78). Vid sensitivitets analyserna sågs fortfarande inga

skillnader.

Konklusion: Denna retrospektiva kohortstudie hittade inga statistiska signifikanta skillnader mellan

ET och CT som första linjens behandling i form av TTP, PFS och OS. Underhållsbehandling med

ET användes hos alla patienter som fick respons på första linjens CT. I linje med internationella

rekommendationer är det rimligt att endokrin terapi bör vara första valet som första linjes

behandling för HR-positiv, HER2- negativ metastaserad bröstcancer vid avsaknad av ’visceral kris’.

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1. Background:

In Sweden, breast cancer (BC) is the most common cancer in women, measuring up to 14,6 % of

all cancers in both men and women.1 With over 7 500 new diagnosed patients and almost 1 400

women deaths, it is the third cause of cancer-related deaths in Sweden 2016.2,3

The main cause of breast cancer-related deaths is the act that metastatic breast cancer (MBC) is

“incurable” with the treatment options that exists today. It is estimated that around 6% of patients

have metastatic disease at the time of diagnosis and 20% to 50% with primary breast cancer will

develop a metastatic disease later in life.4

There are four main molecular subtypes of breast cancer, and up to 21 distinct histological

subtypes, that has their own prognosis and available treatments. Hormonal receptor (HR) status and

human epidermal growth factor receptor 2 (HER2) status are the two predictive factors that

influence the treatment strategy in patients with breast cancer.

Luminal A (71%) subtype has oestrogen receptor (ER) and/or progesterone receptor (PR)

positivity (+) and HER2 negativity (-) as well as a low Ki67 (a proliferation indicator) and is the

most common and less aggressive than other subtypes.

Luminal B (12%) subtype is ER+ and/or PR+ as well as either HER2+ or a high Ki67 and are

associated with a poorer survival than luminal A.

Triple negative (12%) subtype is ER-, PR- and HER2- and has a poorer prognosis than the other

subtypes.

HER2-enriched (5%) subtype is ER-, PR- and HER2+ and tends to grow and spread more

aggressively than other subtypes.5

In patients with Luminal A or B MBC, there are two treatment options as first line: chemotherapy

(CT) or Endocrine Therapy (ET). The choice of which line to start with is influenced by but not

limited to tumour burden, biological age, comorbidities, menopausal status and patients’

preferences. The European Society for Medical Oncology recommends starting with ET in most

cases whereas CT is recommended in case of visceral crisis where rapid response to oncological

treatment is necessary.6 When choosing CT as the first line treatment, it is recommended to use ET

as maintenance therapy until disease progression. However, the expert panel recognised the lack of

robust evidence behind this recommendation because the meta-analysis that lies behind the currents

recommendations included studies that used outdated systemic oncological therapies and did not

exclude patients with unknown/negative ER-status. 7

The aim of this retrospective study was to investigate whether there is a difference to time to

progression (TTP), progression-free survival (PFS), or overall survival (OS) between the two

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treatment options, namely ET or CT as first line treatment in patients with MBC of Luminal

subtype and whether maintenance ET could offer a benefit in prognosis compared to treatment

pause after first line CT.

2. Methods:

2.1 Study population:

The cohort included patients who had undergone treatment for MBC diagnosed between 2008 to

2015 at Uppsala Academic Hospital and Mälarsjukhuset in Eskilstuna, Sweden. The patients in

Uppsala where extracted from the database Real-Q whereas the patients in Eskilstuna where

extracted from the database MOSAIQ oncology information system. After identifying the patients,

data were gathered from the databases and patient records.

The inclusion criteria included ER+ and/or PR+, HER2- metastatic breast cancer in a palliative

setting, with a cut-off in survival for at least three months after diagnosis to exclude patients with

rapid disease progression and aggressive tumour biology in whom the oncological treatment would

be meaningless irrespectively the type of treatment given.

2.2 Data collection:

Data were collected about the following parameters: age at diagnosis, comorbidities (Charlson

comorbidity index), date for diagnosis, ER-status, PR-status, Ki67, histological grade, HER2-status,

type of primary surgery, adjuvant treatment, date for relapse, location of metastasis, bone-only

metastasis, number of metastatic sites, performance status at the start of oncological treatment, type

of 1st to 4th line of treatment; Response to the treatment (complete remission, partial remission,

stable disease, progressive disease), date for the start and the end of each treatment line, reason for

the switching treatment, date of death and cause of death.

Outcomes and definitions:

TTP was defined as the time from treatment initiation until disease progression, PFS was defined

as the time from treatment initiation until either disease progression or death due to any cause. OS

was defined as the time from treatment initiation until death for any reason. The cut-off date for the

whole cohort was 1st of May 2018. Luminal B was defined as either a Ki67 >20% or Ki67 >14%

and PR <20%. All tumours that did not meet the criteria for Luminal B disease were classified as

Luminal A.8

2.3 Statistical analyses:

Categorical variables were summarized by the number and percentage of patients in each

category. Continuous variables were summarized by mean, median, minimum and maximum

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values.

For the bivariate analyses between variables, chi-square test for categorical variables and t-test or

Mann-Whitney U-test (depending on the distribution of the variable) for continuous variables were

used.

For the time-to-event outcomes (TTP, PFS, OS) the potential association between groups in

comparison first line CT vs. first line ET was assessed by the Kaplan-Meier method (log rank test

for statistical significance). In addition, multivariable Cox proportional hazards model was created

after adjustment for the following variables: age, breast cancer intrinsic subtype (Luminal A-like vs.

luminal B-like), de novo metastasis (yes vs. no), performance status (0-1 vs. 2-3), presence of

visceral metastases (yes vs. no), liver metastases (yes vs. no), bone-only metastases (yes vs. no).

Two propensity score methods, namely the inverse propensity score weighting and the propensity

score adjustment regression was used as sensitivity analyses for the comparison CT vs. ET.

Specifically, a logistic regression propensity score model of the type of first line treatment was

created using the same variables used in the cox proportional hazard model.

All reported P values of statistical tests are two-tailed and P<0.05 was taken to be statistically

significant. All analyses will be performed using the SPSS.

3. Results:

3.1 Patient, tumour and treatment characteristics

In total, 612 patients were identified, 144 in Mälarsjukhuset and 468 in Uppsala Academic

Hospital, which resulted in 285 eligible patients (Figure 1). The most common reason for exclusion

was either a diagnosis outside the enrolment dates or HER2+. The mean follow up was 37 months

(range 3-118 months).

The median age at first diagnosis and at recurrence was 61 (range 31-88) and 68 (range 35-94),

respectively. There was a difference between patients receiving ET and CT as first line therapy

when looking at age at recurrence, 69 (range 35-94) and 62.5 (range 37-81) respectively, with a P-

value <0.001. Charlson comorbidity index had a median of 2 (range 0-7), with a difference between

ET (3, range 0-7) and CT (2, range 0-6) with a P-value

<0.001. Primary tumour characteristics are summarized

in Table 1A and the treatment for the primary tumour is

summarized in table 1B. The differences in initial

tumour characteristics between ET vs CT as first line

treatment are shown in the tables.

Ki67 had a median of 23% (range 1-90) for the

primary tumour pathological anatomical diagnosis Figure 1: cohort identification

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Overall ET as 1st CT as 1st p-value

N (%) N (%) N (%)

Primary tumour characteristics N=285 N=234 N=51

Histology

Ductal

181 (63.5)

147 (68.1)

34 (69.4)

0.439 Lobular 77 (27) 62 (28.7) 15 (30.6)

Other 7 (2.5) 7 (3.2) 0 (0)

Missing 20 (7)

Tumour stage

I 47 (16.5) 42 (22.5) 5 (11.4)

0.287

II 27 (9.5) 23 (12.3) 4 (9.1)

III 86 (30.2) 68 (36.4) 18 (40.9)

IV 71 (24.9) 54 (28.9) 17 (38.6)

Missing 54 (18.9)

Elston-ellis grade

I 22 (7.7) 18 (11.0) 4 (9.1)

0.398 II

123 (43.2)

100 (61.0)

23 (52.3)

III 63 (22.1) 46 (28.0) 17 (38.6)

Missing 77 (27)

Progesterone receptor positivity

Yes

190 (66.7)

149 (63.4)

41 (82.0) 0.011

No 95 (33.3) 86 (36.6) 9 (18.0)

Histological subtype

Luminal A

124 (43.5)

100 (56.5)

24 (52.2)

0.599 Luminal B 99 (34.7) 77 (43.5) 22 (47.8)

Missing 62 (21.8)

Metastasis at diagnosis

Yes 71 (24.9) 54 (23) 17 (34)

0.102

No

214 (75.1)

181 (77) 33 (66)

Tabell 1A: Primary tumour characteristics


N (%) N (%) N (%)

Metastatic site N=285 N=234 N=51

Bone-only 101 (35.4) 90 (38.3) 11 (22.0) 0.029

Visceral 72 (25.3) 51 (21.7) 21 (42.0) 0.003

Pulmonary 85 (29.8) 72 (30.6) 13 (26.0) 0.515

Liver 63 (22.1) 46 (19.6) 17 (34.0) 0.026

Central nervous system 4 (1.4) 3 (1.3) 1 (2.0) 0.540

No of metastatic sites, median (range) 1 (1-4) 1 (1-4) 2 (1-4) 0.122

Biopsy at recurrence 141 (49.5) 114 (48.5) 27 (54.0) 0.481 Tabell 2: Metastatic site at metastasis diagnosis

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N (%) N (%) N (%)

Treatment of primary tumour N=285 N=234 N=51

Type of surgery

No surgery 36 (12.6) 33 (14.2) 3 (6.0) 0.338

Breast conserving 112

(39.3) 93 (39.9) 19 (38.0)

Mastectomy 134 (47) 106

(45.5) 28 (56)

Missing value 3 (1.1)

Lymph node surgery

Sentinel node biopsy 26 (9.1) 23 (9.9) 3 (6.0) 0.430

Axillary node dissection 212

(74.4)

170

(73.0) 42 (84.0)

No surgery 44 (15.4) 39 (16.7) 5 (10.0)


Adjuvant radiotheraphy

No radiotherapy 119

(41.8) 98 (41.9) 21 (42.0) 0.945

Breast only 75 (26.3) 61 (26.1) 14 (28.0)

Breast and lymph nodes 90 (31.6)

75 (32.1) 15 (30.0)


Adjuvant chemotherapy

No chemotherapy 182

(63.9) 152

(64.7) 30 (60.0) 0.805

Anthracyclines and Taxanes 57 (20)

46 (19.6) 11 (22.0)

Anthracyclines only 35 (12.3) 29 (12.3) 6 (12.0)

Other 11 (3.9) 8 (3.4) 3 (6.0)

Adjuvant Endocrine therapy

No therapy 111

(38.9) 86 (36.8) 25 (50.0) 0.176

Aromatase inhibitors (AI) 45 (15.8)

37 (15.8) 8 (16.0)

Tamoxifen 73 (25.3) 65 (27.8) 7 (14.0)

Tamoxifen and AI sequentially 56 (19.6)

46 (19.7) 10 (20.0)

Missing value 1 (0.4) Tabell 1B: Primary tumour treatment

that most patients received adjuvant ET and/or radiotherapy after radical surgery, not including

primary metastasized patients. Overall 20 patients were pre/perimenopausal at recurrence, standing

for 7.0% of all patients.

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The metastatic sites are summarized in

table 2, including biopsy frequency at

recurrence. The treatment received, PS,

best response during a treatment line and

reason for discontinuation is summarized

in table 3. It was shown that most patients

(n=234, 82.1%) received ET as first line

treatment, and of which Aromatase

inhibitors was most commonly used

(n=181, 77.4%).

In all treatment-lines except the fourth there was more patients who received ET than CT. All

patients that responded on CT received maintenance ET (n=36, 70.6%). Figure 2D shows best

treatment results in a graph.

3.2 Association between CT vs ET in terms of OS, PFS and TTP

The Kaplan Meier curve for TTP (figure 2A), PFS (figure 2B) and OS (figure 2C) show that there

was no statistically significant difference between getting ET or CT as first line treatment (p=0.557,

p=0.653 and p=0.850 respectively). When using the cox regression analysis, it was shown that there

is no statistically significant difference between ET and CT in terms of TTP, PFS and OS. The same

Figure 2A-D: Kaplan Meier curve and treatment response

Table 3: Treatment after metastasis and treatment results

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result was shown when using propensity score adjustment regression and inverse propensity score

weighting.

In the Cox regression analysis (Table 4A-C), having a metastasis at first diagnosis (de novo) was

shown to have hazard ratio (HR) of 2.10 for time to progression (p=<0.001, confidence interval

95% (CI), 1.39-3.23). In addition, a luminal A primary tumour was shown to be associated with a

longer TTP compared to luminal B subtype with a hazard ratio of 0.64 (P=0.003, CI 0.48-0.86)

compared to luminal B.

Similar result traits were shown for PFS with de novo metastasis HR 2.25 (p=<0.001, CI 1.48-3-

41) and luminal A primary tumour HR 0.66 (P=0.004, CI 0.50-0.88).

For OS it was shown that visceral metastasis had a HR 3.40 (P=0.005, CI 1.45-8.00). De novo

metastasis HR 2.41 (P=0.001, CI 1.47-3.95) and Luminal A primary tumour HR 0.58 (P=0.001, CI

0.42-0.81) results traits that were similar to both TTP and PFS.

P-value

Hazard ratio

Lower 95,0 % CI

Upper 95,0 % CI

De novo vs. Recurrence <0.001 2.10 1.39 3.23

Luminal A vs B 0.003 0.64 0.48 0.86

Bone-only metastasis 0.052 0.72 0.51 1.02

Precence of viceral metastasis 0.138 1.82 0.82 4.02

Age at recurrence 0.003 0.98 0.97 0.99

Presence of liver metastasis 0.636 1.21 0.55 2.69

Performance status (0-1 vs 2-4) 0.364 0.78 0.46 1.33

Type of 1st line Theraphy (CT vs ET) 0.811 0.96 0.66 1.39

CT vs. ET (propensity score adjustment regression) 1.08 0.74 1.57

CT vs. ET (inverse propensity score weighting) 1.19 0.80 1.77

P-value

Hazard ratio

Lower 95,0 % CI

Upper 95,0 % CI

De novo vs. Recurrence <0.001 2.25 1.48 3.41

Luminal A vs B 0.004 0.66 0.50 0.88









Table 4A: Cox regression analysis for time to progression

Table 4B: Cox regression analysis for progression-free survival

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P-value

Hazard ratio

Lower 95,0 % CI

Upper 95,0 % CI

De novo vs. Recurrence 0.001 2.41 1.47 3.95

Luminal A vs B 0.001 0.58 0.42 0.81









4. Discussion

Our results show that there is no statistically significant impact on TTP, PFS or OS between

receiving CT versus ET as first line treatment in a cohort of luminal breast cancer patients. An

aggressive primary tumour (luminal B) had a negative impact on TTP, PFS and OS as well as the

presence of de novo metastatic disease.

What we could see concerning maintenance ET was that all patients who responded on first line

CT received ET afterwards. This observation shows that the clinical practice is to give maintenance

ET instead of a treatment break in these two institutes and might reflect the treatment tradition for

patients with luminal metastatic breast cancer in Sweden in general.

Our results are in accordance with prior studies on this topic. Bonotto et al.9 showed similar

results, with no impact on OS between CT vs. ET after matching for covariates. Song et al10 also

showed no significant impact on OS between CT vs. ET when adjusting for baseline covariates. In

the largest study investigating this research question so far by Jacquet et al.11 the authors concluded

that there was no significant difference on OS and PFS between CT vs. ET. Considering the lack of

difference in survival between ET and CT in these patients and the fact that ET has better

tolerability than CT, it is reasonable to offer ET as first line treatment.

Maintenance ET is a reasonable option in responding patients,12,13,14 and with our result, it could

be hard to find enough patients who have a treatment break after first line CT to perform a study

with adequate power. This observation could be useful for research funders when studies on this

breast cancer population are planned because the tradition of using ET maintenance in all patients

can influence the potential eligible population as well as the expected survival.

The retrospective and observational study format is two of the limitations of this study, although

our results is in line with newly published data which is in favour to its validity. A small study

cohort is also a limitation that we had to regard, as well as the limitation that all data were collected

Table 4C: cox regression analysis for overall survival

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using electronic medical records where not all data could be found sometimes leaving missing

values. Another limitation was the fact that we were unable to investigate the role of maintenance

ET after first line CT because all patients that responded to CT received maintenance ET as well.

Further studies should be concentrated in investigating the potential role of new treatment options

such as CDK 4/6 inhibitors in the clinical question of CT vs. ET in patients with MBC. Considering

the fact that all the studies of ET vs. CT included patients before the CDK 4/6 inhibitor era and the

positive effect of the combination of CDK 4/6 inhibitor with ET compared to ET alone15, one could

argue that this combination therapy could offer a survival advantage compared to chemotherapy.

Conclusion

Our results suggest a similar prognosis between CT and ET as first line therapy in patients with

MBC of Luminal subtype, supporting the use of ET as a first line treatment considering the better

tolerability profile than CT. Although, no conclusion about the efficacy of maintenance ET can be

drawn from this study, our study found that the clinical practice in Sweden seems to be to use

maintenance ET instead of a watch-and-wait approach after first line CT, an observation that could

have an impact in the design of future MBC studies in Sweden.

__________________________________________________________________________________

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