Rethinking the role of hyponatremia in metastatic cancer...

Giovanni Fucà, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy

Rethinking the role of hyponatremia in

metastatic cancer patients:

the HYPNOSIS and the i-HYPNOSIS studies

TERAPIE DI SUPPORTO IN ONCOLOGIA:

STRATEGIA “SISTEMICA” AL SERVIZIO DEL PAZIENTE

2a EDIZIONE

Milano, 5 ottobre 2018 - Fondazione IRCCS Istituto Nazionale dei Tumori

Fucà G et al. submitted – Please, do not post

The HYPNOSIS STUDY

BACKGROUND

• Regardless of the etiology, hyponatremia has been associated with high mortality risk

in cancer pts1

• The association between hyponatremia and poor prognosis in the metastatic setting

has been extrapolated from studies intrinsically biased by small sample size, inclusion

of mixed stages or restriction to terminally-ill pts2-4

• We aimed at weighing the prognostic impact of hyponatremia in hospitalized pts with metastatic solid tumors

1. Mohan et al. Am J Med (2013)2. Castillo et al. BMC Cancer (2016)3. Berardi et al. Support Care Cancer (2015)4. Yoon et al. Support Care Cancer (2015)

The HYPNOSIS STUDY

METHODS• Retrospective, cohort analysis

• Pts with metastatic solid tumors admitted to our Medical Oncology Department from

January 2014 to December 2015

• Hyponatremia cohort: at least one finding of baseline hyponatremia at any admission

during the study period

• Control cohort: no evidence of hyponatremia at any admission during the study

period

• Hyponatremia: serum sodium concentration < 135 mEq/l


The HYPNOSIS STUDY

RESULTS

Admissions identified through

registries searching(n = 2166)

- Admissions with evidence of hyponatremia at hospitalization

(n = 402)

- Admissions with no evidence of hyponatremia at hospitalization

(n = 1764)

Patients screened for

the hyponatremia cohort(n = 319)

Patients screened

for the control cohort(n = 1054)

Patients included in

the control cohort (n = 746)

Patients excluded:

- Hematologic malignancies (n = 2)- Early stage/locally advanced (n = 38)

Patients excluded: -No oncologic disease (n = 12)

- Hematologic malignancies (n = 12)- Early stage/locally advanced (n = 270)

- No data available (n = 14)


The HYPNOSIS STUDY

RESULTS

Characteristic

Association with

hyponatremia

(P)

Gender <0.001

Age (years) 0.30

ECOG PS <0.001

Histology <0 .001

Metastatic sites (N) <0.001

Liver metastases 0.001

Lung metastases 0.50

Bone metastases 0.01

Brain metastases 0.02

Adrenal metastases 0.03

Pleural metastases 0.10

Lymphnodal metastases <0.001

Completed lines of treatment (N) <0.001

Other electrolyte imbalances <0.001


The HYPNOSIS STUDY

RESULTS

Biliary tract 51%

Prostate cancer 45%

SCLC 38,9%

GE cancer 34,5%

Pancreatic cancer 34%

Melanoma 32,2%

RCC 28,2%

NSCLC 25,3%

NET 25%

CRC 22,2%

Breast cancer 20,7%

Other 20,7%

Pre

vale

nce

of

hyp

on

atre

mia

39/176 pts

44/174 pts

35/169 pts

30/87 pts

19/59 pts

18/53 pts

25/49 pts

11/39 pts

14/36 pts

7/28 pts

9/20 pts

28/135 pts


The HYPNOSIS STUDY

RESULTS

Control cohort 13.2 months (4.1-35.4)Hyponatremia cohort 2.0 months (0.7-8.2)

Unadjusted HR 2.65 (95% CI 2.26-3.11)P < 0.001

Adjusted HR 1.66 (95%CI 1.38-2.01)P <0.001

Median OS (IQR)


The HYPNOSIS STUDY

RESULTS

Log-rank test P < 0.001


Control cohortMild hyponatremia (Na 134-130 mEq/L)Moderate hyponatremia (Na 129-125 mEq/L)Profound hyponatremia (Na <125 mEq/L)

The HYPNOSIS STUDY

RESULTS

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Su

rviv

al P

rob

ab

ility

Ctrl

ipoNA

137 114 95 79 70 61 52 42 32 22 14 14 8

39 19 11 11 9 6 4 3 3 3 3 2 2

No. pts at risk

Histology Colorectal: raw and adjusted OS, according to cohort

Ctrl, raw OS

ipoNA, raw OS

Ctrl, adjusted OS

ipoNA, adjusted OS

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Su

rviv

al P

rob

ab

ility

Ctrl

ipoNA

130 85 70 54 43 37 33 25 19 16 9 8 4

44 16 9 7 5 5 4 4 4 2 2 1 1

No. pts at risk

Histology NSCLC: raw and adjusted OS, according to cohort

Ctrl, raw OS

ipoNA, raw OS

Ctrl, adjusted OS

ipoNA, adjusted OS

Unadjusted HR 2.94 (95%CI 1.96-4.41)P < 0.001

Adjusted HR 1.52 (95% CI1.00-2.32)P = 0.05


Adjusted HR 1.97 (95%CI 1.31-2.95)P = 0.001

CRC NSCLC


Control cohortHyponatremia cohort


The HYPNOSIS STUDY

RESULTS

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Su

rviv

al P

rob

ab

ility

Ctrl

ipoNA

134 104 92 84 78 73 63 55 44 32 25 21 15

35 17 13 11 9 8 7 7 5 5 3 1 1

No. pts at risk

Histology Breast: raw and adjusted OS, according to cohort

Ctrl, raw OS

ipoNA, raw OS

Ctrl, adjusted OS

ipoNA, adjusted OS

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Su

rviv

al P

rob

ab

ility

Ctrl

ipoNA

57 43 29 20 15 12 7 6 5 3 2 2 1

30 11 10 8 5 4 4 4 4 3 2 1 1

No. pts at risk

Histology Gastroesophageal: raw and adjusted OS, according to cohort

Ctrl, raw OS

ipoNA, raw OS

Ctrl, adjusted OS

ipoNA, adjusted OS


Adjusted HR 1.70 (95%CI 1.10-2.61)P = 0.02

Unadjusted HR 1.72 (95%CI 1.06-2.80)P = 0.03

Adjusted HR 0.88 (95%CI 0.53-1.47)P = 0.63

Breastcancer

GEcancer




The HYPNOSIS STUDY

RESULTS


The HYPNOSIS STUDY

RESULTS

T1T2T3

Validation set (N = 87)


The HYPNOSIS STUDY

TAKE HOME MESSAGE

• In this large cohort study including 1025 hospitalized pts with metastatic solidtumors, hyponatremia was independently associated with poor OS (adjusted HR 1.66; 95% CI 1.38-2.01; P < 0.001)

• Serum sodium assessment can be exploited to design integrated prognostic tools

• A strong clinical and translational effort is needed to characterize the biological role of extracellular sodium levels and the interplay with ion channels located on tumor cell membranes in promoting cancer initiation, progression and resistance to treatment


Cancer immunotherapy comes of age…

Giovanni Fucà, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy

Fucà G et al. Target Oncol. 2018

The i-HYPNOSIS STUDY

BACKGROUND

• A complex interaction between genetic and acquired factors contribute to the inter-patient

heterogeneity of IO efficacy in metastatic NSCLC

• Sodium pumps and ion channels participate in the modulation of immune cells activity1

• Hyponatremia has been associated with poor prognosis in pts with NSCLC2

• We aimed at assessing the association between pre-treatment serum sodium

concentration and clinical outcomes in metastatic NSCLC pts treated with IO

1. Ramirez et al. Cells (2018)2. Castillo et al. BMC Cancer (2016)


METHODS

• Retrospective, cohort analysis

• Pts treated from April 2013 to April 2018 (APOLLO institutional

prospective registry)

• Low-sodium cohort: pre-treatment serum sodium concentration

≤ 135 mEq/l (institutional lab lower limit of normal)



RESULTS

Characteristic

Total

(N = 197)

N (%)

Control

(N = 171)

N (%)

Low-sodium

(N = 26)

N (%)

p

Age (years)

< 65

≥ 65

84 (43)

113 (57)

71 (42)100 (58)

13 (50)13 (50)

0.42

ECOG PS

0-1

≥ 2

175 (89)

22 (11)

154 (90)17 (10)

21 (81)5 (19)

0.18

M+ sites (N)1-2≥ 3

84 (43)

113 (57)

73 (43)98 (57)

11 (42) 15 (58)

0.97

IO regimen

Mono

Combo

191 (97)

6 (3)

166 (97)

5 (3)

25 (96)

1 (4)

0.58

0%

20%

40%

60%

80%

100%

Controlcohort

Low-sodiumcohort

CR+PR+SD

PD

31%56%

44% 69%

P = 0.02



RESULTS

171

26

68

4

37

1

17

0

8

0

171

26

28

1

14

0

8

0

3

0

mos mos

OS

(pts

pro

po

rtio

n)

PF

S (

pts

pro

po

rtio

n)


Control cohort 11.6 months (9.3-15.2)Low-sodium cohort 2.8 months (1.8-6.2)


Adjusted HR 3.11 (95%CI 1.91-5.05)P < 0.001

Median OS (95% CI)

Control cohort 3.3 months (2.6-4.3)Low-sodium cohort 1.8 months (1.1-2.5)


Adjusted HR 1.69 (95%CI 0.85-3.38)P = 0.14

Median PFS (95%CI)


TAKE HOME MESSAGE

• Low pre-treatment sodium concentration was independently associated with

worse OS and disease control in metastatic NSCLC pts treated with IO

• Low pre-treatment sodium concentration was also associated with worse PFS,

but failed to confirm an independent association in the multivariable model

• The role of serum sodium concentration as prognostic and predictive factor in

this setting warrants further investigation

• Pharmacological modulation of sodium pumps/ion channels could be exploit to

improve IO efficacy in metastatic NSCLC pts


ACKNOWLEDGEMENT

Giovanni Fucà, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy. Email: [email protected]

The authors would like to thank all the patients, their families, and the staff who contributed to these projects.

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