Identification of patients with pancreatic adenocarcinoma due to inheritable mutation: Challenges of daily clinical practice

Table 1 European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer criteria[24]

EUROPAC criteria
Criterion 1	≥ 2 first-degree relatives with pancreatic cancer
Criterion 2	≥ 3 relatives with pancreatic cancer
Criterion 3	Possible associated cancer syndrome (defined as sub-criteria below) in addition to the case of pancreatic cancer being studied
Criterion 3.a: BRCA1/2	Personal/family history (≥ 1 first/second-degree relatives) of breast/ovarian cancer
Criterion 3.b: Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome	Personal/family history of melanoma in ≥ 1 first/second degree relative AND a high total body naevi count (often > 50)
Criterion 3.c: Lynch syndrome	Personal/family history (≥ 1 first/second-degree relatives) of a Lynch syndrome-associated cancer (such as colorectal, endometrial, small bowel, renal)
Criterion 3.d: Peutz-Jeghers syndrome	Oral/mucous membrane pigmentation +/- a personal/family history (≥ 1 first/second-degree relatives) of gastrointestinal cancers in first/second degree relatives

EUROPAC: European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer.

Table 2 Patient population baseline demographics

Parameter		Frequency	Relative percentage (%)
Patient demographic
Gender	Male	206	51.5
	Female	194	48.5
Age	Median	67.7 yr
	Range	29.9-94.2
Comorbidity grade (according to Adult Comorbidity Evaluation-27)[34]	None	149	37.32
	Mild	164	412
	Moderate	60	152
	Severe	27	6.82
Pathological confirmation of malignancy	Yes	355	88.82
	No1	45	11.32
Stage	Localised (I-II)	4	1.0
	Locally advanced (III)	202	50.5
	Metastatic (IV)	194	48.5
Eastern Cooperative Oncology Group Performance Status at time of PDAC diagnosis	0	43	10.82
	1	198	49.52
	2	98	24.52
	3	58	14.52
	4	3	0.82
Treatment characteristics
Treatment intent at time of referral3	Curative	62	15.5
	Palliative	338	84.5
Curative management
Patient received curative surgery?	Yes	65	16.3
Patient received adjuvant chemotherapy after curative surgery	Yes	42	65.6
	No	22	34.4
	Unknown	1	n/a
Type of adjuvant chemotherapy	5-fluorouracil	1	2.42
	Capecitabine	18	42.92
	Gemcitabine	23	54.82
Palliative management
Patient received palliative chemotherapy	Yes	230	57.5
	No	170	42.5
Type of palliative chemotherapy	FOLFIRINOX	37	16.1
	Gemcitabine/Capecitabine	60	26.1
	Gemcitabine/Cisplatin	5	2.2
	Gemcitabine NabPaclitaxel	27	11.7
	Gemcitabine monotherapy	94	40.9
	Other4	7	3.0

¹Refers to patients diagnosed based on clinical and radiological data only following agreement in multidisciplinary team discussion.

²Indicates rounding error.

³Curative treatment intent refers to patients treated with curative surgery (number of patients with curative surgery and number of patients treated with curative intent do not match due to some patients being referred to our centre for consideration of palliative treatment at time of tumour relapse following curative surgery) (3 patients).

⁴Other include: 5FU/oxaliplatin: 3 patients; Gemcitabine + TH-302/placebo: 2 patients; Gemcitabine plus vandetanib/placebo: 1 patient; Capecitabine single agent: 1 patient.

n/a: Not applicable; PDAC: Pancreatic ductal adenocarcinoma; FOLFIRINOX: Folinic acid, 5-fluorouracil (5FU), irinotecan, oxaliplatin; yr: Years.

Table 3 Non-inheritable risk factors for pancreas cancer in patients included in study

Non-heritable risk factors		Frequency	Relative percentage (%)
Smoking
Smoker (active or ex-smoker)	Yes	187	55.8
	No	148	44.2
	Unknown	65	n/a
Active smoker	Yes	71	21.2
	No	264	78.8
	Unknown	65	n/a
Alcohol
Alcohol consumption	Yes	233	74.9
	No	78	25.1
	Unknown	89	n/a
“Excess” consumption	Yes	33	14.2
	No	200	85.8
Pancreatitis
Previous pancreatitis	Yes	11	2.8
	No	386	97.2
	Unknown	3	n/a
Diagnosed > 2 yr before PDAC	Yes	6	54.6
	No	5	45.5
IPMN
Past medical history of IPMN	Yes	3	0.8
	No	394	99.2
	Unknown	3	n/a
Diabetes
Type 2 diabetes mellitus	Yes	103	25.9
	No	295	74.1
	Unknown	2	n/a
Diagnosed > 2 yr before PDAC	Yes	39	57.4
	No	29	42.7
	Unknown	35	n/a
Type 1 diabetes mellitus	Yes	5	1.3
	No	393	98.7
	Unknown	2	n/a

n/a: Not applicable; PDAC: Pancreatic Ductal Adenocarcinoma; IPMN: Intraductal Papillary Mucinous Neoplasm.

Table 4 Entire patient population family history of malignancy and whether European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer referral criteria were met

Risk Factor		Frequency	Relative percentage (%)
Any personal1/family history of cancer	Yes	202	50.5
	No	132	33.0
	Unknown	66	16.5
Any personal1 or family history of cancer meeting EUROPAC[24] criteria	Yes	113	28.3
	No	221	55.2
	Unknown	66	16.5
Criteria met	Criterion 1 (≥ 2 first-degree relatives with pancreatic cancer)	10	8.8
	Criterion 3.a (Personal/family history (≥ 1 first/second-degree relatives) of breast/ovarian cancer)	60	53.1
	Criterion 3.b [Personal/family history of melanoma in ≥ 1 first/second degree relative AND a high total body naevi count (often > 50)]	2	1.8
	Criterion 3.c [Personal/family history (≥ 1 first/second-degree relatives) of a Lynch syndrome-associated cancer (such as colorectal, endometrial, small bowel, renal)]	29	25.7
	Criterion 3.d (Oral/mucous membrane pigmentation +/- a personal/family history (≥ 1 first/second-degree relatives) of gastrointestinal cancers in first/second degree relatives)	12	10.6

¹In addition to the diagnosis of PDAC. EUROPAC: The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer.

Table 5 Univariate analysis exploring demographic characteristics as factors predictive of meeting European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer criteria

		Patients who did not meet criteria for referral (n = 221)		Patients who did meet criteria for referral (n = 113)		Univariate analysis
		Frequency	Relative percentage	Frequency	Relative percentage	P value
Demographic characteristics
Gender	Male	120	54.3	48	42.5	0.0041
	Female	101	45.7	65	57.5
Age (yr)	Mean (95%CI)	66.3 (64.9-67.7)		67.2 (65.4-68.9)		0.4726
Comorbidity grade (ACE-27)[34]	None	75	33.9	45	39.8	0.040
	Mild	97	43.9	39	34.5
	Moderate	28	12.7	24	21.2
	Severe	21	9.5	4	4.4
Pathological confirmation of malignancy	Yes	194	87.8	102	90.3	0.499
	No	27	12.2	11	9.7
Stage	Localised	4	1.8	0	0	0.015
	Locally advanced	120	54.3	46	40.7
	Metastatic	97	43.9	67	59.3
ECOG performance status	0	21	9.45	14	12.4	0.534
	1	107	48.4	58	51.3
	2	60	27.2	25	22.1
	3	32	14.5	14	12.4
	4	1	0.5	2	1.8
Treatment characteristics
Treatment intent	Curative	38	17.2	9	7.9	0.022
	Palliative	183	82.8	104	92.0
Curative surgery	Yes	38	17.2	13	11.5	0.171
	No	183	82.8	100	88.5
Adjuvant chemotherapy	Yes	23	10.4	9	7.9	0.465
	No	197	89.6	104	92.0
Palliative chemotherapy	Yes	125	56.6	65	57.5	0.867
	No	96	43.4	48	42.5

ACE-27: Adult Co-morbidity Evaluation- 27; ECOG: Eastern Cooperative Oncology Group; 95%CI: 95% confidence interval.

Table 6 Univariate analysis exploring risk-factors predictive of meeting European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer[24] criteria

		Patients who did not meet criteria for referral (n = 194)		Patients who did meet criteria for referral (n = 98)		Univariate analysis
		Frequency	Relative percentage	Frequency	Relative percentage	P value
Personal past medical history
Smoker (active or ex-smoker)	Yes	108	55.7	55	56.1	0.941
	No	86	44.3	43	43.9
Active smoker	Yes	45	23.2	16	16.3	0.173
	No	149	76.8	82	83.7
Alcohol consumption	Yes	131	70.8	75	83.3	0.025
	No	54	29.2	15	16.7
“Excess” alcohol consumption	Yes	24	12.9	5	5.6	0.060
	No	161	87.0	85	94.4
Previous pancreatitis	Yes	7	3.2	1	0.9	0.195
	No	213	96.8	112	99.1
Pancreatitis diagnosed > 2 yr before PDAC	Yes	5	2.3	0	0	0.3493
	No	2159	97.7	113	100
Past medical history of IPMN	Yes	0	0	0	0	n/a
	No	220	100	113	100
Type 2 diabetes mellitus	Yes	61	27.7	27	23.9	0.453
	No	156	72.3	86	76.1
Type 2 diabetes mellitus diagnosed > 2 yr before PDAC	Yes	22	11.0	11	10.6	0.910
	No	178	89.0	93	89.4
Type 1 diabetes mellitus	Yes	2	0.9	3	2.7	0.215
	No	218	99.1	110	97.4
Family past medical history
Any family history of cancer	Yes	93	42.1	109	96.5	< 0.0001
	No	128	57.9	4	3.5

Please note that patients for whom data regarding the variable analysed in this table was missing has been omitted for this analysis. IPMN: Intraductal Papillary Mucinous Neoplasm; PDAC: Pancreatic ductal adenocarcinoma.

Table 7 Multivariable logistic regression analysis exploring factors predictive of meeting European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer criteria

Characteristic	Multivariable analysis (logistic regression)
	OR(95%CI)	P value
Gender: Female (Ref) vs male	0.7 (0.4-1.2)	0.211
Comorbidity scale: None/mild (Ref) vs moderate/severe	1.1 (0.5-2.2)	0.787
Stage: Localised/locally advanced (Ref) vs metastatic	1.5 (0.8-2.9)	0.207
Treatment intent: Curative (Ref) vs metastatic	2.0 (0.8-5.4)	0.158
History alcohol consumption: No (Ref) vs yes	2.4 (1.1-5.1)	0.022
Family history of any malignancy: No (Ref) vs yes	25.3 (8.8-72.6)	< 0.001

Ref: Reference variable; OR: Odds Ratio; 95%CI: 95% confidence interval.