Hindawi International Journal of Breast Cancer Volume 2018, Article ID 4879406, 11 pages https://doi.org/10.1155/2018/4879406
Clinical Study Rate of Clinical Complete Response for 1 Year or More in Bone-Metastatic Breast Cancer after Comprehensive Treatments including Autologous Formalin-Fixed Tumor Vaccine Fumito Kuranishi ,1 Yuki Imaoka,1 Yuusuke Sumi,1 Yoji Uemae,2 Hiroko YasudaKurihara,2 Takeshi Ishihara,2 Tsubasa Miyazaki,2 and Tadao Ohno2 1
Department of Surgery, Innoshima-Ishikai Hospital, Innoshima, Onomichi, Hiroshima 722-2211, Japan Cell-Medicine, Inc., 2-1-6 Sengen, Tsukuba, Ibaraki 305-0074, Japan
2
Correspondence should be addressed to Fumito Kuranishi;
[email protected] Received 28 September 2017; Revised 12 December 2017; Accepted 20 December 2017; Published 22 January 2018 Academic Editor: Mattia Capulli Copyright © 2018 Fumito Kuranishi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. No effective treatment has been developed for bone-metastatic breast cancer. We found 3 cases with clinical complete response (cCR) of the bone metastasis and longer overall survival of the retrospectively examined cohort treated comprehensively including autologous formalin-fixed tumor vaccine (AFTV). Patients and Methods. AFTV was prepared individually for each patient from their own formalin-fixed and paraffin-embedded breast cancer tissues. Results. Three patients maintained cCR status of the bone metastasis for 17 months or more. Rate of cCR for 1 year or more appeared to be 15% (3/20) after comprehensive treatments including AFTV. The median overall survival time (60.0 months) and the 3- to 8-year survival rates after diagnosis of bone metastasis were greater than those of historical control cohorts in Japan (1988–2002) and in the nationwide population-based cohort study of Denmark (1999–2007). Conclusion. Bone-metastatic breast cancer may be curable after comprehensive treatments including AFTV, although larger scale clinical trial is required.
1. Introduction Bone metastases of breast cancer are frequently found in the rib, sternum, vertebrae, or pelvis and are refractory to radiation therapy combined with standardized HER2binding monoclonal antibody and/or endocrine treatments and, if necessary, cytotoxic chemotherapy comprising a widespread regimen such as cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) [1]. Severe pain from bone metastasis limits the mobility of breast cancer patients and compromises their quality of life. A nationwide population-based cohort study in Denmark (1999–2007) revealed that the 5year survival rate was only 8.3% for patients with bone metastasis, 2.5% for those with bone metastasis and skeletalrelated events (SREs), and 23% for those with bone metastasis but no SREs, whereas the survival was 75.8% for breast cancer patients without bone metastasis [2]. Therefore, bone metastasis strongly influences survival of the breast cancer patients.
However, no effective method has been developed for treatment of bone metastasis. For example, agents such as zoledronate and aromatase inhibitors are effective in limiting further progression of the cancer and can significantly improve overall survival [3] and disease-free survival [4], yet they are not expected to completely cure breast cancer with bone metastasis. To date it is widely believed that bonemetastatic breast cancer is incurable, as Mundy has described: “once tumor cells become housed in the skeleton, cure is no longer possible and only palliative therapy is available” [5]. Autologous formalin-fixed tumor vaccine (AFTV) is the ultimately personalized drug, custom-made after resection of the tumor against the patient’s own residual tumor. It has been used to treat patients with chemorefractory tumors since 2002 [6]. The efficacy of AFTV has been reported in a randomized clinical study on hepatocellular carcinoma (HCC) [7], a pilot study and two subsequent phase I/IIa studies on glioblastoma multiforme [8–10], and case reports
2 on advanced glioblastoma [11], malignant fibrous histiocytoma [12], recurrent HCC [13], recurrent peritoneal serous carcinoma [14], uterine cervical small cell carcinoma [15], upper tract urothelial carcinoma [16], and gall bladder cancer and colon cancer [17]. AFTV has been shown to induce cytotoxic T lymphocytes specific to glypican-3, the protein frequently expressed in HCC [18]. In parallel with these small-scale clinical settings, we searched retrospectively patients treated with AFTV in the course of comprehensive treatments for bone-metastatic breast cancer since 2004 in two nearby regional hospitals in Onomichi city, Hiroshima, Japan, in both of which one of the authors (FK) has been working. We encountered an advanced case of breast cancer with bone metastasis in a patient who had shown strong uptake of 99m Tc at the location of vertebra Th7 in August 2006. After combined treatments with AFTV, palliative radiation therapy, and adjuvant chemotherapy, the patient’s vertebra revealed no uptake of 99m Tc in December 2010 [20]; therefore we diagnosed eradication of the bonemetastatic breast cancer. However, our case report attracted the criticism that bone scintigraphy sometimes leads to a false conclusion. Here we report 20 cases of bone-metastatic breast cancer patients followed in August 2017, including their survival indices which were apparently greater than those of the Denmark study [2] and follow-up confirmation by singlephoton emission computed tomography combined with Xray computed tomography (SPECT-CT) or by positronemission tomography combined with CT (PET-CT) of the clinical complete response (cCR) of three breast cancer cases showing long-term cCR of metastatic bone cancer after comprehensive treatments including AFTV. To our knowledge, the rate of cCR maintained for 1 year or more has not been documented in breast cancer patients with bone metastasis.
2. Patients and Methods Breast cancers are normally treated according to established guidelines [1]. After resection of the primary cancerous tissue and according to the expression level of HER2, estrogen receptor (ER), and progesterone receptor (PgR) in the carcinoma cells, we treated patients with anti-HER2 antibody, endocrine treatments or aromatase inhibitors, combined with cytotoxic agents, and if applicable X-ray irradiation. The dose of radiation was selected case-by-case, with 50–60 Gy administered to the main target lesion and/or 30–36 Gy to any bone-metastatic lesions to suppress bone-derived pain and to avoid induction of further skeletal-related adverse events. Regular screening of bone metastasis of breast cancer depends on 99m Tc bone scintigraphy. The precise locations of advanced bone metastases were determined by singlephoton emission computed tomography combined with Xray computed tomography (SPECT-CT) or by positronemission tomography combined with CT (PET-CT). If patients required any extra-standard treatments, frequently required in bone-metastatic breast cancer cases or in the cases with high probability of bone metastasis that was estimated
International Journal of Breast Cancer by the skilled medical doctor (FK), we introduced AFTV treatment. The AFTV was prepared individually for each patient from their own formalin-fixed and paraffin-embedded breast cancer tissues as has been described for cases of glioblastoma multiforme [8]. The prepared AFTV was injected intradermally during the course of comprehensive treatment, whenever possible before the start of fractionated boneirradiation. Each course of AFTV treatment consists of three intradermal injections every 2 weeks. To prepare AFTV for one course, we need 2.0 g of paraffin-removed breast cancer tissue specimen. If the amount of resected primary tumor was sufficient to prepare AFTV for multiple courses, two or more courses of treatment with AFTV were administered. Adverse effects of treatment with AFTV were graded according to the National Cancer Institute Common Toxicity Criteria version 2 [21] or, later, according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. The present treatment with AFTV has been approved by the ethics authorities of JA Onomichi General Hospital and Innoshima-Ishikai Hospital, both of which are located in Onomichi city, Hiroshima, Japan. Informed consent was provided by all of the patients for the treatment with AFTV and publication of the clinical data. The present retrospective study was registered to the UMIN clinical trials registry, Japan, as UMIN000029726.
3. Results Among 119 breast cancer patients so far given comprehensive treatment including AFTV between 2004 and 2013, 20 bonemetastatic cases were screened, 16 of which bore bone metastasis before AFTV treatment and four revealed bone metastasis after AFTV treatment (Cases #10, #15, #17, and #18) (Table 1). The eradication of a 3 cm diameter bone metastasis in vertebra Th7 of Case #6 was previously reported based on the simple observation of whole body 99m Tc bone scintigraphy [20]. We confirmed maintenance of her cCR status by SPECT-CT after more than 6 years as described in the Case Presentations. Two new cases (Cases #17 and #20) are shown in Table 1 who maintained long cCR status. They remain well with no evidence of recurrence or new metastasis, the former for 18 months and the latter for 17 months. These 3 cases, all showing solitary bone metastasis, are described more fully in the following section. In Case #18, complete local control of the metastatic vertebra L5 was successful for 22 months. However we observed parallel multiple metastases in lymph nodes. Case #19 achieved cCR after AFTV therapy and radiation therapy (36 Gy) and maintained their cCR status for 11 months (bone metastases in both of the vertebrae L3 and L5 disappeared on PET-CT), but then new lymph node metastasis was found, though after irradiation to the new lesion the patient remains well in February 2017 without any signs of lumbago and recurrence. We also found six cases with long-term stable disease (SD) in the metastatic bone(s) but without any new lesions. Local SD status was maintained for variable times, from the shortest one at 5 months (Case #1) to the longest one
Primary resection
2004/4/21
2001/2/2
1999/5/10
1999/6/18
2003/7/8
2006/8/7
2004/3/5
2001/3/9
2004/3/23
Age, at diagnosis
59
74
50
56
52
52
42
45
71
1
2
3
4
5
6
7
8
9
Case #
2006/12/15
2007/3/1
2006/6/24
2006/7/31
2004/11/10
2003/3/6
2005/7/11
2003/1/15
2004/2/9
First diagnosis of bone metastasis
Lymph node, bone (multiple), lung
Vertebra Th7
Liver, lung, chest wall, lymph nodes, pelvis
HER2(−), ER(−), PgR(−) HER2(−), ER(−), PgR(−) HER2(−), ER(+), PgR(+)
PD
PD
PD
CR for 50 months or more
PD
SD for 13 months
SD for 12 months
PD
Rib resec, RT (30 Gy), chemo, AFTV 2 cr Brain operation, RT to brain (35 Gy), AFTV 1 cr, aromatase inhib, RT to sacrum (30 Gy) RT (50 Gy), resec, aromatase inhib, chemo, resect, RT (35 Gy to pelvis, 35 Gy to brain), AFTV 1 cr + chemo RT (30 + 30 Gy), chemo, AFTV 4 cr + RT (Th6 30 Gy, Th11 30 Gy) AFTV 1 cr, RT (36 Gy), chemo, aromatase inhib (misprescription), zoledronate RT (30 Gy), chemo, resec, chemo + aromatase inhib, RT (35 Gy), zoledronate, AFTV 3 cr, chemo Resec, aromatase inhib, zoledronate, AFTV 3 cr, RT (30 Gy)
SD for 5 months
Chemo, AFTV 4 cr, chemo, RT (30 Gy), aromatase inhib
Bone (multiple), skin, Chemo, aromatase inhib, lymph node, chest wall AFTV 1 cr, chemo
Bone (multiple)
Lymph node (19/20), sternum, lung (multiple), liver, brain (multiple), pelvis
HER2(+), ER(+), PgR(−)
HER2(−), ER(−), PgR(++) HER2(−), ER(+), PgR(−)
Brain, pelvis, sacrum
Rib, neck, sacrum
Multiple bones (more than 30), liver
Any metastasis before AFTV treatment
Not tested
HER2(−), ER(++), PgR(++) HER2(−), ER(−), PgR(−)
Receptor status
Best response of bone metastasis after AFTV treatment
Treatments after primary resection and before diagnosis of PD
Table 1: Characteristics of the present cohort (cut-off, August 31, 2017).
Dead 2008/7/28
Dead 2012/11/16
Dead 2007/11/18
Ongoing
Dead 2009/8/30
Dead 2007/07/28
Dead 2008/05/07
Dead 2009/01/15
Dead 2008/02/21
Outcome by Feb & Aug 2017
20
70
17
128+
58
54
34
73
49
OS after the first diagnosis of bone metastasis (months)
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Primary resection
2007/6/16
2004/3/10
1992/10/7
1998/5/12
1999/6/28
2007/11/9
2000/6/30
2009/3/18
Age, at diagnosis
62
46
75
64
61
39
52
50
10
11
12
13
14
15
16
17
Case #
2015/6/18
2007/9/27
2008/12/9
2004/12/16
2006/6/14
2007/5/25
2007/5/14
2010/1/28
First diagnosis of bone metastasis
HER2(−), ER(+), PgR(−)
Sternum
PD
SD for 25 months
PD
PD SD for more than 80 months CR for 18 months or more
Resec, chemo, aromatase inhib, RT (28 Gy, 30 Gy, 30 Gy), zoledronate Resec, AFTV 1 cr, TAE, chemo, zoledronate Chemo, AFTV 1 cr, zoledronate, RT (30 Gy) RT (60 Gy), AFTV 1 cr, zoledronate AFTV 2 cr, aromatase inhib, RT (36 Gy), zoledronate, anti-PD-1 Ab
SD for 55 months
PD
Best response of bone metastasis after AFTV treatment
Chemo, resec, AFTV 1 cr
Chemo, AFTV 1 cr, Lymph node (2/7) [bone chemo, aromatase inhib (misprescription), (multiple) after AFTV] zoledronate Lymph node, lung, rib (2 AFTV 4 cr, zoledronate, sites), pedicle of thoracic aromatase inhib, chemo vertebra
Any metastasis before AFTV treatment
HER2(−), ER(++), PgR(++) HER2(−), ER(−), Rib PgR(−) HER2(+++), Chest wall, bone ER(+++), (multiple) PgR(+++) HER2(+++), Lung, vertebra Th10 ER(+), PgR(−) HER2(−), Lymph node (23/24), ER(−), pelvis PgR(+++) HER2(+), Lymph node (1/26), bone ER(−), (multiple) PgR(++)
HER2(−), ER(−), PgR(−)
Receptor status
Treatments after primary resection and before diagnosis of PD
Table 1: Continued.
Ongoing
Ongoing
Dead 2013/11/12
Dead 2015/4/4
26+
114+
60
125
130+
12
Dead 2008/5/23 Ongoing
118+
8
Ongoing, bearing bone-meta
Dead 2010/9/20
Outcome by Feb & Aug 2017
OS after the first diagnosis of bone metastasis (months)
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Primary resection
2011/3/11
2004/12/2
2000/7/14
Age, at diagnosis
56
64
46
18
19
20
2013/10/20
2013/9/4
2013/8/9
Any metastasis before AFTV treatment
Best response of bone metastasis after AFTV treatment
AFTV 2 cr, RT (30 Gy to vertebra + 50 Gy to axilla), chemo, Bone local control for 22 HER2(++), zoledronate, Vertebra L5, lymph node months, but clinically ER(+++), tumorectomy of chest (1/5) PD PgR(+++) wall meta, aromatase inhib, RT (40 Gy) to lymph node Chemo, G-CSF, RT (60 Gy to neck lymph node), trastuzumab, AFTV 1 cr, RT (36 Gy) to HER2(+++), CR for 11 months, then Lymph node (4/5), vertebra L3, vertebra L5, ER(−), PD vertebrae L3, L5 zoledronate, resect PgR(−) (chest wall), RT (60 Gy) to chest wall, RT (60 Gy) to lymph node HER2(−), Toremifene, RT (60 Gy), CR for 17 months, then ER(+), Sternum, lymph node AFTV 2 cr, zoledronate, PD PgR(++) anti-PD-1 Ab
Receptor status
Treatments after primary resection and before diagnosis of PD
40+
42+
Ongoing
Ongoing
39
Dead 2016/10/17
Outcome by Feb & Aug 2017
OS after the first diagnosis of bone metastasis (months)
AFTV, autologous formalin-fixed tumor vaccine; chemo, chemotherapy; CR, complete response; cr, course; inhib, inhibitor; meta, metastasis; OS, overall survival; PD, progressive disease; resec, resection; RT, radiation therapy; SD, stable disease.
Case #
First diagnosis of bone metastasis
Table 1: Continued.
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6
International Journal of Breast Cancer Table 2: Comparison between the present cohort and the historical control, Koizumi et al.’s combined cohort, in Japan.
Survival (years) 0 1 2 3 4 5 6 7 8 9 10 Present cohort Number at risk 20 18 16 14 11 8 6 5 5 5 3 Koizumi et al.’s combined cohort Number at risk (solitary, sternum + other, from Table 5 of [19]) 289 222 157 106 75 53 38 19 8 4 2 Difference of population ratio at each year Chi square test, 𝑝 = 0.003 0.005 0.019 0.037 0.003