Endometrial cancer: Disease & Treatment Overview & Journal club

Presented By: Farah Al Souheil
Supervised by: Dr. Lama Faddoul

Lebanese International University
School of Pharmacy
Advanced Pharmacy Practice Experience
Hematology Oncology Rotation
Effect of Metformin For Decreasing Proliferative
Marker in Women with Endometrial Cancer: A
Randomized Double-blind Placebo-Controlled Trial
May 6, 2020
Effect of Metformin For Decreasing Proliferative Marker in
Women with Endometrial Cancer: A Randomized Double-
blind Placebo-Controlled Trial

OUTLINE
• General Overview
• Journal Club
• Journal
• Title
• Authors
• Abstract
• Introduction
• Methods
• Results
• Discussion
• Conclusion
• Reference Evaluation
• Overall Evaluation
• Related Study
3

Uterine serosa, adnexa,
peritoneal cavity (ascites)
STAGING
Limited to the uterus
Myometrial invasion< 50%
Myometrial invasion≥ 50%
Uterus & Cervix
Extension to uterine
serosa, peritoneal
cavity &/ LN
Vagina/ parametrium
Pelvic LN
Para-aortic LN
Extension to adjacent
organs/ beyond true
pelvis
Adjacent organs(bladder/
bowel): T4
Distant metastasis/ +ve
inguinal LN
85
%
75
%
45
%
25
%
Most patients are
diagnosed when disease is
still confined to the uterus
4
Lee-may Chen, MDJonathan S Berek, MD, MMS. (2020, April). UpToDate. Retrieved from https://www.uptodate.com/contents/endometrial-carcinoma-clinical-features-
diagnosis-prognosis-and-screening?search=endometrial%20cancer&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

QUICK FACTS
5
Most common cancer in female
reproductive organs
second rank of female genital tract
cancer after breast cancer
4th most common cancer in
women
Uterine cancer is the most
common gynecologic malignancy
Most cases occur in women ≥55
years of age
(U.S.:
annually) ≈
42000
women new
EC cases
(Worldwide:
2019) 61,880 new
EC cases
worldwide
(Worldwide:
2019) 12,160
deaths
related to EC
Endometrial thickness
<4 mm: low risk of
EC
When endometrial
thickness≈ 20 mm on
transvaginal
ultrasound
In postmenopausal
women, the risk of
cancer is increased
versus benign disease
Lee-may Chen, MDJonathan S Berek, MD, MMS. (2020, April). UpToDate. Retrieved from https://www.uptodate.com/contents/endometrial-carcinoma-clinical-features-
diagnosis-prognosis-and-screening?search=endometrial%20cancer&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

SIGNS AND SYMPTOMS
6
Irregular vaginal bleeding
after menopause (75-90%
of cases)
Heavy periods
DysuriaDyspareunia
Pain in the pelvis
Brownish/ bloody
vaginal spotting/
discharge
Change in bowel/ bladder habbits
Pelvic lumps

DIAGNOSIS
7
Transvaginal Ultrasound
Endometrial thickness, D&C
Endometrial Biopsy
Confirm histology & Grade
Test for MSI/ dMMR
Manual P/V Examination
Normal in early-stage
(no enlargement or tenderness)
Myometrial Invasion/ LN/ cervix/
Hysteroscopy
Site & volume of tumor
Ki67 is a predictive &
prognostic factor of EC
Lee-may Chen, MDJonathan S Berek, MD, MMS. (2020, April). UpToDate. Retrieved from https://www.uptodate.com/contents/endometrial-carcinoma-clinical-features-diagnosis-prognosis-and-
screening?search=endometrial%20cancer&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

RISK FACTORS
8
Age (50-70 years)
Early menarche
Late menopause
(After 55 years)
HRT
Tamoxifen therapy
PCOS (chronic
anovulation)
Obesity
DM
Family history of
endometrial, ovarian
breast or colon cancer
Lynch syndrome
(22-50% risk)
Cowden syndrome
(13-19% risk)
Lee-may Chen, MDJonathan S Berek, MD, MMS. (2020, April). UpToDate. Retrieved from https://www.uptodate.com/contents/endometrial-carcinoma-clinical-features-diagnosis-prognosis-and-
screening?search=endometrial%20cancer&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

TH: total hysterectomy
BSO: bilateral salpingo-oophorectomy
EBRT: External beam radiation therapy
TREATMENT
9
Ovarian preservation (not standard) is safe if:
• Premenopausal woman
• Early stage endometroid cancer
• Normal appearing ovaries
• No family history of breast, ovarian cancer or lynch
syndrome
• Salpingectomy is recommended
NCCN guidelines. (March). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf

TREATMENT
10
TH: total hysterectomy
BSO: bilateral salpingo-oophorectomy
EBRT: External beam radiation therapy
Cont’d

TREATMENT
11
 Consider ablative therapy for 1-5 metastatic lesions if hysterectomy is
performed
 Stereotactic radiotherapy (SBRT) vs palliative treatment in oligo metastatic
cancer
Cont’d

TREATMENT
12
Endometroid
histology
IA
G1,G2
Observation* or
vaginal
brachytherapy^
G3
Vaginal
brachytherapy*
or observation^
IB
GI
Vaginal
brachytherapy*
or observation ^
G2
Vaginal
brachytherapy*
G3
EBRT or
vaginal
brachytherapy
II G1-3 EBRT*
III-IV
Systemic
therapy
+/- EBRT+/- vaginal
brachytherapy
^ If lymphovascular space
invasion or age>60
^ If no myoinvasion or
EBRT if HIR
^ if no other risk factors
Or EBRT if HIR or
observation if no other RF
+/- systemic therapy if RF
present
+/- vaginal brachytherapy
+/- systemic therapy
G
1
G
2
G
3
Cont’d

FERTILITY SPARING TREATMENT
13
Cont’d

SURVEILLANCE
14
Cont’d

PHARMACOLOGIC TREATMENT
15
Cont’d

METFORMIN
16
Lactic acidosis, B12 deficiency,
GI side effects
Avoid use in unstable or
hospitalized patients with heart
failure, hepatic impairment,
renal impairement (eGFR <30
ml/min)
Off-label: Antipsychotic-
induced weight gain; DMII
prevention, GDM; PCOS:
Oligomenorrhea; prevention of
ovarian hyperstimulation
syndrome (OHSS) in PCOS
women undergoing IVF/ ICSI
Decreases hepatic glucose
production, decreases intestinal
absorption of glucose and
improves insulin sensitivity
(increases peripheral glucose
uptake and utilization)
Risk of birth defects or adverse
fetal/neonatal outcomes
Maximum effects in 2 weeks
UpToDate. (2020). Retrieved from https://www.uptodate.com/contents/metformin-drug-
information?sectionName=Adult&topicId=9621&search=metformin&usage_type=panel&anchor=F193863&source=panel_search_result&selectedTitle=1~148&

EVALUATION OF THE JOURNAL
Publishes papers in a wide spectrum of cancer sciences
Official publication of the Asia Pacific Organization for Cancer Prevention (APOCP)
High-quality, peer-reviewed articles
Public Access Journal
Language: English
Frequency: Monthly
Impact Factor for 2014 was reported at 2.52
Cont’d
19

EVALUATION OF THE TITLE
21
Cont’d
Study design
& type of
blinding
Metformin
vs Placebo
Outcome
of interest
Non conclusive
and unbiased
Brief and clear
Effect of Metformin For Decreasing Proliferative
Marker in Women with Endometrial Cancer: A
Randomized Double-blind Placebo-Controlled Trial
Mentions
Population of interest
Women with endometrial
cancer

EVALUATION OF THE AUTHORS
23
Cont’d
Department of
Obstetrics and
Gynecology, Rajavithi
Hospital, Bangkok,
Thailand
Primary Author
Kittisak Petchsila
Department of
Pathology and
Laboratory Medicine,
Rajavithi Hospital,
Bangkok, Thailand
Last Author
Nutpacha Chotikawichean
Department of
Obstetrics and
Gynecology, Rajavithi
Hospital, Bangkok,
Thailand
Email: nisa3054@gmail.com
Nisa Prueksaritanond
Corresponding Author

EVALUATION OF THE AUTHORS
24
• 5 reputable authors & experienced in the field of medicine
(gynecology and oncology)
• However
• No biostatistician was included
• No PhD holder was included
• A clinical pharmacist & a dietitian were not included
• The corresponding author can be contacted
Cont’d

EVALUATION OF THE FUNDING
26
Cont’d
This research investigation was made in part by grants from the
Research Fund of Rajavithi Hospital
No Conflict of Interest
DISCLOSURE

EVALUATION OF THE ABSTRACT
28
Cont’d
Objective:
• Mentions :
• Objective
• Intervention
• Comparison group
• Population of interest
To compare the Ki-67 index of endometrial cancer cells before and after
treatment between the metformin and placebo group in women with
endometrial cancer (EC)

Metformin 850 mg 1
tab once daily for at
least 7 days ( from
recruitment till surgery)
Placebo 1 tab once
daily for at least 7 days
( from recruitment till
surgery)
Ki-67 index after hysterectomy by immunochemistry
Metabolic effect of metformin: FBG, HbA1C
Adverse events: N&V, dizziness, and
hypoglycemic symptoms
Inclusion/exclusion criteria
Total number of patients
enrolled
29
Cont’d
Post treatment assesment
Randomized
double blind
Trial
Non-diabetic women
diagnosed with EC
Methods:
Assessment of Ki67 (endometrial curettage)
Baseline demographic (age, BMI, co-morbidities),
surgical & pathological characteristics
25 24

30
Results:
Cont’d
Metformin significantly changed the Ki-67 index relative to placebo, with a
mean decrease of 23.3% (p=0.001) and a mean proportional decrease of 39.1%
(p=0.006)
No significant differences in metabolic effects and adverse events between the
metformin and the placebo groups
 Total number of participants
 Baseline characteristics
 Interventions
 Confidence intervals & p values
 Adverse effects
 Results consistent with the
study’s outcome

31
Conclusion:
 Clear and concise
 Doesn’t offer a base for future clinical trials
Cont’d
Short-term treatment with an oral metformin significantly reduced a proliferative marker
Ki-67 index in women with endometrioid EC awaiting surgical staging. This study supports
the biological effect of metformin in EC and potential applications in the adjuvant treatment
in EC patients

Evaluation of the Introduction
32

EVALUATION OF THE INTRODUCTION
33
Literature Review & GAP:
Cont’d
(Zhan et al., 2014; Hanprasertpong et al., 2017; Xu et al., 2015)
Metformin use significantly
• Decreased the incidence and improved survival outcomes of a wide
range of cancers
• ( Breast, lung, liver, pancreatic, colorectal, prostate, cervical, and
ovarian cancer & EC)
(Viollet et al., 2012; Pollak et al., 2012) Metformin’s anti-cancer effects
Quality of evidence of previous studies , suggesting a potential benefit from
metformin treatment in reducing tumor growth and increase apoptosis, was
low because of an inadequate methodology
GAP
MOA
Summary
of
Evidence

34
Rationale:
Cont’d
The association between obesity, diabetes, and EC
Impaired glucose tolerance and insulin resistance may facilitate the
initiation and progression of EC
Effective diabetes control has been suggested to prevent EC
Novel therapeutic targets which target glucose metabolism and insulin
resistance have a role in combatting EC burden

35
Hypothesis:
Cont’d
Metformin may be effective in preventing and treating EC by the main effect in
lowering blood glucose concentrations, increasing insulin sensitization, reducing
plasma fasting insulin levels & sustained weight loss

36
Objective:
Cont’d
• Compare the proliferative marker (Ki-67) index of EC cells before and after
treatment between the pre-operative oral metformin versus placebo in women
with newly diagnosed EC waiting for primary surgery
• Compare the metabolic effects before and after metformin treatment

37
Suggested Mecahnism of Action:
Cont’d
Alteration in the mTOR pathway as well as inactivating PTEN mutations and PIK3CA
amplification are common in EC, thus metformin use is believed to have a great benefit in this
cancer
Inhibition of liver
gluconeogenesis
Decrease in both
insulin and glucose in
the circulating system
Activation of critical
signaling pathways:
Adenosine
monophosphate-activated
protein kinase (AMPK)
Inactivation of mammalian
target of rapamycin
(mTOR) pathway
Indirect Effects
Direct Effects

38
Overall Evaluation:
 Disease and treatment overview
 Mentions the results of previous studies
 Mentions the rationale, hypothesis and
objective respectively
 Based on facts
Cont’d

40
EVALUATION OF THE METHODS
Flow diagram
Cont’d

41
• Double-blind
• Placebo controlled
• Randomized clinical trial
• Single center: Department of Obstetrics and Gynecology,
Rajavithi Hospital, Bangkok, Thailand
Study design
Pretreatment assessment
Metformin or placebo for a
minimum of 7 days
Hysterectomy
Post-treatment assessment
Cont’d

42
Ethical considerations:
Approved by the
Institutional Research
Committee (IRB)
of Rajavithi Hospital
All women were treated
with the same standard
guidelines
An informed consent
was signed by the
patient before
enrollment in the study
Cont’d

43
Patients:
Eligibility criteria followed
Randomization numbers were stored in
sequentially numbered sealed opaque
envelopes
1:1 using a computer-generated central
randomization schedule with a block size of
4
When a study subject met the inclusion
criteria, the nurses selected a sequentially
numbered sealed-opaque envelop
Cont’d

44
Inclusion Criteria:
Inclusion Criteria
Histologically
confirmed
endometrioid EC
≥18 years
women
Scheduled for elective
comprehensive surgical staging
in the next 30 days
Cont’d

45
Concomitant or prior cancer within 5 years
Non-endometrioid histologic subtype
Taking HRT (Estrogen/
progesterone)
Taking chemotherapy within 3 months
(ECOG) PS >2
Medically inoperable
Pregnancy
Inability to give informed consent
History of diabetes
Currently taking metformin or other
hypoglycemic drugs
Severe renal impairment (SCr >1.5 mg/dL)
hepatic impairment
Contraindication to biguanides
Exclusion Criteria:
Cont’d

46
Intervention
Intervention Dose Duration Route
Metformin
850 mg
after
breakfast
7 days minimum
(12-30 days)
Oral
Placebo
After
breakfast
7 days minimum
(12-30 days)
Oral
Placebo and active drug were
identical in appearance,
packaging, labeling, and
instruction for use
Cont’d

Medical history
Serum renal and liver
function, FBS & HbA1C
Pregnancy test
Height, weight, BMI
Endometrial tissue from the
curettage procedure was
requested and sent to the
Department of Pathology and
Laboratory Medicine, Rajavithi
Hospital for assessment
Baseline Characteristics Record:
47
Cont’d

1ry outcome: Compare the % of Ki-67 expression measured at baseline and after
treatment
• Ki-67 is associated with the proliferative activity of malignant tumors: marker of tumor aggressiveness
• Positive prognosis: negative or low Ki-67% expression
FFPE was obtained from the hysterectomy specimen for immunochemistry (Ki-
67) staining
The histological subtype, grade, stage, depth of myometrial invasion, the presence
of lympho-vascular invasion, LN status, and peritoneal fluid/cytology were
assessed by using the (FIGO) 2009 for EC staging
Assessment of end points
48
Biweekly telephone contact
with the research team

49
Slides were estimated by using a scoring system (Jonat et al., 2011)
Low: ≤15% Ki-67 positive cells
Intermediated : 16-30% Ki-67 positive cells
Highly proliferative: >30% Ki-67 positive cells
Performed by two independent blinded pathologists
46.9% agreement on the pretreatment Ki-67 index with a kappa of 0.15 vs 53.1% agreement on post-treatment ki67
index with a kappa of 0.28
Slides Analysis :
Cont’d

Secondary outcome: Tumor grading of post-treatment endometrial cancer
cell and the change in serum markers of insulin resistance (FBS) from
baseline to the end of treatment between metformin and placebo group
Drug adverse events (N&V, diarrhea, dizziness, hypoglycemic symptom,
and anaphylaxis)
Secondary End Points:
50
Cont’d

51
Initially planned for intention-to treat analysis but per protocol analysis was followed
when only one patient denied for surgery
Categorical variables were expressed as frequency and percentage & comparison of
proportions between groups was performed using a Chi-square or Fisher’s exact test
Continuous variables were expressed as the mean and SD for normally distributed data
and were compared between groups using an independent t-test
The nonparametric continuous variables were reported as the median with their
interquartile range (IQR) and compared between groups using a Mann-Whiney U test
Changes in the Ki-67 index was compared between the treatment groups using a repeated
measure analysis of variance (ANOVA) with treatment group as a fixed effect
Statistical Analysis :
Cont’d

52
Statistical Analysis :
All statistical analyses were performed using
IBM SPSS Statistics version 23.0 (IBM
Cooperation, New York, USA)
Level of p-value less than 0.05 was accepted
as being statistically significant
Cont’d

Calculated sample size is based on the rate of mean Ki-
67 expression using the formula for two independent
means
The rate of mean Ki-67 expression and SD in the
metformin and control group from Sivalingam’s study
were 37.4±20.9% and 58.1±26.2%, respectively
The sample size of each group was 21 women
The adjusted sample size of each group (by 10%) is a
minimum of 24 women to detect a statistical difference
with 80% power at the 0.05 α 53
Power Analysis:
Cont’d

55
EVALUATION OF THE RESULTS
Baseline Characteristics:
Metformin Placebo P value
Cont’d

56
Baseline Characteristics:
• The demographics and baseline characteristics were well balanced
between treatment groups
• Broadly representative of the patients with EC
• Percentages according to the per-protocol analysis
Cont’d

57
Primary Outcome:
[Pre-treatment Ki-67 – Post-treatment Ki-67]
/ Pre-treatment Ki-67
Cont’d

58
Primary Outcome:
-17.57% (95%CI; -
27.95%, -7.20%), p=
0.001)
Cont’d

59
Adverse Effects:
Cont’d

60
Adverse Effects:
 No patients experienced serious adverse events (e.g.,
hypoglycemia, lactic acidosis, and anaphylaxis) or
withdrawal from the study due to the unacceptable
adverse event
 Only 1 patient dropped out due to surgery refusal
Cont’d

Evaluation of the Discussion
61

62
EVALUATION OF THE DISCUSSION
Summary of Important Results
Effects of metformin on EC cell proliferation (Ki-67) were significantly decreased among women who
received a daily metformin
Metformin modulates insulin sensitivity and inhibits tumor cell growth
Metformin in EC also plays a role in disease prevention and treatment by improving insulin resistance and
reducing the incidence of type 2 diabetes which are major risk factors for EC
Low toxicity and short half-life make it interesting as a potential adjunctive therapy or even as monotherapy
for some EC patients with contraindication to chemotherapy or radiation therapy, including consideration to
preserve fertility
Cont’d

63
Suggested Mechanism:
• More than half of the patients were overweight or obese that predisposing to undiagnosed
type 2 diabetes and insulin resistance
• An alternative explanation is that the restriction only women with endometrioid EC in this
study that diabetes and insulin resistance are major risk factors and could be a great benefit
from metformin treatment
Cont’d

64
Evidence from Other Studies:
Schuler et al., 2015
Mitsuhashi et al., 2014
Laskov et al., 2014
Cantrell et al., 2010)
Tseng et al., 2015
Ko et al., 2015
Luo et al., 2014
Have shown promising
results in metformin’s
ability to reduce
proliferation index,
such as Ki-67, and
increase apoptosis
Increasing doses of
metformin decreases
cell proliferation in EC
Effect of metformin on
the incidence and risk
of EC in women
Cont’d

65
Clinical Implications:
Ki-67 proliferation index
• Increasingly being used as a surrogate marker
of anti-tumor efficacy in various cancers
• Affected after a short course of oral
metformin therapy
• strongly correlated with patient survival
Cont’d

66
Optimal Dosing and Duration
The benefit of a short schedule was the usual time frame for diagnosis to surgical management was not
affected and did not interrupt the standard treatment for women who newly diagnosed with EC
At least 7 days in order to make sure that the change of Ki-67 index was from the effect of metformin use
850 mg per day as the dose of metformin generally in treatment of diabetes and has been shown effective in
preoperative settings & prevents the common side effects such as gastrointestinal symptoms
Cont’d

67
Future Thoughts:
Do higher doses have a greater impact including
proliferative marker, grading, and also clinical endpoints?
Cont’d

68
Study Strengths:
Well-designed placebo controlled
double blinded RCT
Standard protocol in the specimen
preparation process,
immunochemistry staining, and
slide review by two independent
pathologists in order to eliminate
the difference in observation and
discrepancies
Intensive protocol for monitoring
toxicity from metformin treatment
in EC patients to ensure that no
serious adverse events occur
Cont’d

69
Study Limitations:
Small sample size, larger randomized trial may be needed before
applying in clinical practice guidelines for EC management
Reliance on surrogate biomarkers of response (Ki-67 expression) rather
than clinical endpoints (Tumor size or cancer-specific survival)
Pre-operative window study to screen for potential therapeutic efficacy
Long-term clinical outcomes, such as cancer-specific and recurrence-
free survival, in EC patients are lacking
Cont’d

71
STUDY WEAKNESS
Single
centered
Dose &
duration?
Small
sample
size
No long-
term
follow-
up
OS &
PFS?
Cont’d

72
STUDY STRENGTHS
Mention
limitations
Double
blinded
P values &
CI stated
Unbiased
conclusion
Power
analysis
done
No
conflict of
interest
Base for
future
clinical
trials
Cont’d

Evaluation of the Conclusion
73

74
EVALUATION OF THE CONCLUSION
• Brief and clear
• Summarize the main points
• Includes future recommendations
In conclusion, the present study confirmed that short-term pre-operative treatment with an
oral metformin dose of 850 mg/day significantly reduced a proliferative marker Ki-67
index in women with endometrioid EC. This evidence supported the biological effect of
metformin in EC and it should be implemented in the primary, adjuvant, neoadjuvant, and
advanced disease settings in EC management strategy
Cont’d

76
RELATED CLINICAL TRIAL
Measuring the Biological Effect of Presurgical Metformin Treatment in Endometrial Cancer
Assessment of the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points for
inhibiition of cellular proliferation
Metformin 850 mg bid or no drug in the presurgical window between diagnosis and hysterectomy
Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry
Metformin treatment (median 20 days, range 7–34) was associated with a 17.2% reduction in tumour Ki-
67 (95% CI −27.4, −7.0, P=0.002), in a dose-dependent manner
Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after
adjusting for changes in controls
Cont’d

77
RELATED CLINICAL TRIAL
Hypoxia and Hyperglycemia Determine Why Some Endometrial Tumors Fail to Respond to Metformin
Evaluate the role of tumor hypoxia and glucose in endometrial cancer response to metformin
EC cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell
viability, mitochondrial biogenesis, function and energy metabolism were assessed
In women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours
Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium
(25 mM glucose)
In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in
hypoxia
Tumors treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells
metformin decreased mitochondrial function
Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a
switch to glycolytic metabolism and decreased metformin response
Dec 10, 2019
Cont’d

Evaluation of the References
78

79
EVALUATION OF THE REFERENCES
The article included 28 references
• Correctly cited
• Up-to-date (majority in 2019) oldest in 2002
• Related to the topic
All the articles mentioned in the study were:
The authors didn’t cite themselves
• Primary : original articles
• tertiary : Books
They included the following literature :
Cont’d

80
REFERENCES
• Lee-may Chen, MDJonathan S Berek, MD, MMS. (2020, April). UpToDate. Retrieved
from https://www.uptodate.com/contents/endometrial-carcinoma-clinical-features-
diagnosis-prognosis-and-
screening?search=endometrial%20cancer&source=search_result&selectedTitle=1~150&
usage_type=default&display_rank=1
• NCCN guidelines. (March). Retrieved from
https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
• UpToDate. (2020). Retrieved from https://www.uptodate.com/contents/metformin-drug-
information?sectionName=Adult&topicId=9621&search=metformin&usage_type=panel
&anchor=F193863&source=panel_search_result&selectedTitle=1~148&k
• Sivalingam VN et al. Hypoxia and hyperglycaemia determine why some endometrial
tumours fail to respond to metformin. Br J Cancer. 2020 Jan;122(1):62-71. doi:
10.1038/s41416-019-0627-y. Epub 2019 Dec 10
• V N Sivalingam et al. Measuring the biological effect of presurgical metformin treatment
in endometrial cancer. Br J Cancer. 2016 Feb 2; 114(3): 281–289.
Published online 2016 Jan 21. doi: 10.1038/bjc.2015.453

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