Abstract
OOTR_KBCCC 1
Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
OOTR_KBCCC 2
Tokyo Women's Medical University, Tokyo, Japan
The standard care for early-stage breast cancer is breast-conserving therapy consisting of conservative surgery and fractionated whole breast irradiation. However, five or more weeks of radiotherapy is a burden to the patient. Accelerated Partial Breast Irradiation (APBI) is an alternative to whole breast irradiation in patients with low-risk tumor, based on four randomized trials and more than 40 prospective trials. APBI focuses radiation on a 1 to 2 cm margin of tissue surrounding lumpectomy cavity. The rationale based on the majority of ipsilateral breast tumor recurrence (IBTR) occurred around lumpectomy cavity. In 2009, the American Society of Radiation Oncology presented a consensus statement for APBI. In this consensus statement, not only an APBI-suitable group but also an APBI-cautionary group and an APBI-unsuitable group are shown. According to this guideline, age 60 and over, negative BRCA1/2 variation, 2 cm or less tumor (T1), lymph vascular space invasion negative, estrogen receptor (ER) positive, unicentric tumor, invasive ductal or other favorable histology, without extensive intraductal component (EIC), pN0 are suitable for APBI. Patients aged 50–59 years were included in the ‘cautionary’ group in 2009 guideline, but patients in this age has come to be in a suitable group in recent years.
Multiple treatment modalities have been used to deliver APBI, including brachytherapy, intraoperative irradiation (x-ray or electron), and external beam radiotherapy with photon or particle radiotherapy. Multi-catheter interstitial brachytherapy technique has a longest follow-up in APBI technique and has most trustful data. But this technique needs procedures skilled. In RTOG 95–17 study, the 10-year rate of IBTR was 6.2%. Investigators at the National Institute of Oncology in Hungary have presented the rates of recurrence were not significantly different between APBI vs WBI (5.9% vs 5.1%).
Single-entry brachytherapy catheters are simpler for physicians and physicists and less invasive for patients. In United State, Ma mmoSite, Strut Assisted Volume Implant (SAVI™) and Contura™ MLB were approved. The American Society of Breast Surgeons has reported a 5-year actuarial IBTR rate of 3.8% with Ma mmoSite.
Intraoperative radiotherapy (IORT) has been investigated primarily in Europe. The Targeted Intra-Operative Radiotherapy (TARGIT-A) trial had compared IORT and external beam whole breast irradiation (WBI). The 4 years IBTR rate was equal in the two arms.
External beam irradiation using X-ray has been most widely used, which can be delivered noninvasively, using the standard linear accelerator. The RTOG 03-19 reported a 4-year IBTR rate of 6%. Proton beam radiotherapy has been used in limited number of institutes.
Adaptation of APBI will become more co mmon based on several studies.
OOTR_KBCCC 3
University of Texas Health Science Center, San Antonio, Texas, USA
In a patient with primary breast cancer and a clinically node-positive axilla, surgical clearance of the axilla is generally reco mmended. Two older trials, the NSABP-04 and Kings/Cambridge trials, demonstrated that axillary radiotherapy was as effective as axillary surgery in reducing the risk of recurrence in clinically node-negative patients. However, axillary surgery was considered at the time to be essential for staging and decision-making with regards to adjuvant systemic therapy. In more recent years, sentinel lymph node biopsy has been shown to be an effective option for staging clinically node-negative patients, and it significantly reduces the morbidity of axillary surgery. For patients with no evidence of metastasis in the sentinel lymph node, no further axillary clearance is warranted. However, the results of several recent randomized trials now suggest that even patients with metastasis to the sentinel lymph nodes may not necessarily require further axillary clearance. These trials, ACOSOG Z0011, IBCSG 23–01, and the AMAROS trials, have generated controversy, due to concerns about their design and interpretation of results. Yet, the results of these trials indicate that further axillary surgery can be omitted in some patients with metastasis to the sentinel node. In some instances, radiotherapy to the axilla might be preferable to further axillary surgery. In the years ahead, there will continue to be considerable interest in minimizing the morbidity of axillary therapy in patients with primary breast cancer.
OOTR_KBCCC 4
Department of Radiation Oncology and Image-applied Therapy, Kyoto University, Graduate School of Medicine, Kyoto, Japan
Axillary lymph node dissection (ALND) was the standard treatment for breast cancer for a long time till sentinel lymph node biopsy (SLNB) emerged in 1990's. Since then, SLNB has been the gold standard for the breast cancer patients with cN0, resulting lower axillary complication rates than ALND. Complete ALND was considered the standard treatment in breast cancer patients with a positive sentinel lymph node (SLN). But recently several studies showed that less extensive axillary surgery shows the comparable regional recurrence rate and it does not decrease overall survival (OS) in eligible patients. Currently new treatment option of avoidance of additional ALND in selected patients with positive SLN has been challenged.
In a few years three important papers, ACOSOG Z0011, IBCSG 23–01, and EORTC 10981-22023 AMAROS trials were published. The aim of Z0011 is to determine the effects of complete ALND on survival of patients with SLN involvement. Five-year OS and disease-free survival (DFS) in patients with ALND were comparable in patients with SLND alone. Z0011 showed that SLND alone did not result in inferior survival compared with ALND among early breast cancer patients with limited SLN metastases when treated with breast conservation therapy (BCT) and systemic therapy. IBCSG 23–01 is a randomised trial to determine whether no ALND was non-inferior to ALND in patients with micrometastatic SLN and tumour of maximum 5 cm. The majority of the patients were treated with BCT without regional node irradiation. No significant difference in five-year OS and DFS was observed between the two groups. Taken together, ALND could be spared in patients with early breast cancer and limited SLN metastases when treated with appropriate systemic therapy. AMAROS trial is a randomized non-inferiority trial to assess whether axillary radiotherapy (ART) provides comparable regional control with fewer side-effects. Five-year axillary recurrence in ALND group was comparable that in ART group, while lymphedema in the ipsilateral arm occurred significantly more often after ALND than after ART.
However, there remain some problems. For example, it was reported that the details of the Z0011 radiotherapy technique were not fully analysed and some patients did not receive radiotherapy at all, and 15% patients received irradiation to the supraclavicular region which should not be used by the Z0011 protocol, or the planned non-inferiority test of AMAROS trial was underpowered because of the low number of events.
Although in recent years there is a decline in complete ALND in patients with SLN involvement, further research is needed to determine the optimal radiotherapy approach in early stage breast cancer patients treated BCT without complete ALND.
OOTR_KBCCC 5
1Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau SAR, China; 2Organisation for Oncology and Translational Research, Hong Kong SAR, China; 3UNIMED Medical Institute, Hong Kong SAR, China; 4Jiujiang University, Jiujiang, China
In China, mortality rates for breast cancer are lower than in Western population. Nonetheless, in Caucasian women the mortality rates of breast cancer are in decline, whereas in Chinese women there is a vast increase in the mortality rates. As incidence rates in China are on the rise as well, breast cancer is becoming an increasing health burden to Chinese society.
Loco-regional management of breast cancer involves diagnostic imaging, neo-adjuvant therapy, surgery, radiotherapy and adjuvant therapy with subsequent monitoring for ipsilateral recurrences and/or second primaries. Disease aetiology, physical health, patient physical parameters, cultural preferences and availability of diagnostics and therapeutics all play a role in physician and patient choice for optimising treatment.
Compared to Western population, the onset and aetiology of breast cancer in Chinese women is quite different. Although the overall division of the different subtypes of breast cancer, namely luminal-type, HER2-type and triple negative breast cancer (TNBC) in Chinese women is comparable to their Western counterparts, the vast majority of luminal tumours is diagnosed at younger age before menopause with often a higher proliferative index and subsequent poorer prognosis. Over 50% breast cancers in Asia are diagnosed in premenopausal females.
Asian ethnicity and younger age are both associated with higher breast density, which in turn is associated with comparatively higher false-negatives and lower sensitivity for ma mmogram screening in Chinese than Caucasians females. Imaging modalities such as ultrasound, magnetic resonance imaging (MRI) and cone-bean computed tomography (CBCT) have shown promising results in reducing false-negative results in women with higher breast density.
Chinese women when compared to their Caucasian counterparts, more often undergo mastectomy instead of lumpectomy. Some studies suggest that larger surgical margins in lumpectomy are associated with lower ipsilateral tumour recurrence rates. Chinese women with often smaller breast volume are less likely to meet such ‘optimal’ margins and therefor would be considered candidate for mastectomy. It has to be noted that women in more recent studies may have better prognosis overall, likely not directly related to margin size but because of better, earlier, and more optimal diagnosis and treatment.
Current diagnostic and treatment guidelines are often derived from studies in mainly Western populations. It is i mminent that more studies in Asian and Chinese patients will help answer controversies that exist in current loco-regional management of breast cancer patients in China.
OOTR_KBCCC 6
1Department of Surgery, Kansai Medical University, Hirakata, Japan; 2Department of Breast Surgery, Graduated School of Medicine, Kyoto University, Kyoto, Japan
Sentinel lymph node (SLN) biopsy after neoadjuvant systemic therapy (NST) is an acceptable axillary management for node-negative breast cancer. Previous studies reported that conversion to node-negative disease was achieved in more than 30% of women with clinically node-positive disease after NST. Axillary lymph node dissection could be avoid in those patients with SLN negative biopsies. However, the false negative rate of SLN detection ranged from 8.4% to 14.2% and this false negative rate was also associated with the number of SLNs harvested. The accuracy of SLN biopsy was apparently improved when more than two SLNs were harvested using the dual mapping with blue dye and radioisotope (RI).
For SLN mapping, we demonstrated that the indocyanine green (ICG) fluorescence is superior to blue dye and an acceptable alternative to SLN detection using RI in breast cancer (Ann Surg Oncol 2013; 20:2213–8 and Ann Surg Oncol 2016; 23:44–50). The mean number of SLN removed for ICG fluorescence was 2.3, which was significantly greater than the figure of 1.7 for RI. In exploratory subgroup analysis in the patients undergoing NST (N = 70), the detection rate was significantly improved by using ICG fluorescence compared with RI (100% vs 91.4%, p = 0.04). This impairment of the SLN detection might be related with fibrosis and lymphatic obstruction by cytotoxic reagents. As the smaller size of ICG (<1 nm) can flow through narrowing lymphatic channels than the larger size of radio colloid (>50 nm). Fluorescence lymphatic imaging demonstrated the location of SLNB did not change after NST and ICG potentially enables to reach the first SLN or the further tier more smoothly than RI. Based on these results, we will discuss the clinical utility of the ICG fluorescence method for SLN biopsy after NST.
OOTR_KBCCC 7
Seoul National University College of Medicine, Seoul, South Korea
Ductal carcinoma in situ (DCIS) is a heterogeneous disease with varying potential for progression to invasive cancer. Appropriate treatment options for DCIS are primarily determined by the extent of disease in the breast relative to the size of the breast and location of the lesion in the breast. A detailed ma mmographic evaluation of the extent of DCIS is essential for treatment planning. MRI can be helpful but it is lacking evidence. Total mastectomy (with or without reconstruction) is theoretically 100% curative, but actual recurrence rate was 1–2% with breast cancer specific survival at 10 years are >98%. With skin sparing mastectomy, local recurrence rate was reported to be 0–4%. From the long-term follow-up of the four randomized DCIS radiation trials, the 15-year in-breast recurrence with local excision alone ranged from 20% to 30%. With adjuvant radiation therapy (RT), the event rate is reduced to 10% to 15%, and with hormone therapy, a relapse rate of well under 10% is achieved at 15 years. For surgery, positive resection margins for close margins are associated higher risk of local recurrence than negative margins. These numbers may be an overrepresentation of the breast events experienced by DCIS patients today, given the advances in screening and pathologic procedures. Actually, data showed that local recurrence rate of DCIS have decreased over time. Tamoxifen reduces the local recurrence rate after BCS in ER-positive DCIS. In a recent phase III study comparing tamoxifen and aromatase inhibitor for postmenopausal women with DCIS, 10 year breast cancer free interval rates were higher in the anastrozole group than tamoxifen (93.5% vs 89.2%). The benefit was primarily seen in women <60 years old.
Several studies tried to find subset of DCIS that can avoid RT after wide local excision alone (RTOG 98–04, WEA study, and ECOG 5194). Collectively, these data suggest that the longer a patient is followed, the higher the overall risk for in-breast recurrence. Current methods of stratify DCIS into a “low-risk” category, whether clinical-pathologic criteria or genomic testing, are not truly identifying indolent disease. A significant proportion of the potential low-risk DCIS patients develop in-breast (and invasive) recurrences without RT. Meanwhile, two prospective, randomized trials are currently examining no treatment for “low-risk” DCIS (asymptomatic, screen-detected, low- or intermediate-grade with calcifications) compared with the treatment arm of surgery with RT and/or hormonal therapy. These studies will also evaluate patient-reported outcomes such as anxiety and quality-of-life as important endpoints.
Sentinel lymph node biopsy is not routinely indicated in DCIS. In women undergoing mastectomy for extensive DCIS, sentinel biopsy in indicated. Nodal metastasis are present in 4–7% of patients with microinvasive disease, and sentinel lymph node biopsy is indicated when the results will influence subsequent treatment. Microinvasive breast carcinoma is defined as invasive carcinoma of the breast with no single invasive focus measuring >1 mm. The prognosis of microinvasive breast cancer is intermediate-better than that of small invasive breast cancer and approaching what is seen with DCIS.
OOTR_KBCCC 8
Peter MacCallum Cancer Centre, Melbourne, Australia
Ductal carcinoma in situ (DCIS) is a malignant proliferation of epithelial cells confined by myoepithelial cells and the basement membrane within the breast ducts and is considered a non-obligate precursor to invasive breast carcinoma. Once a rare diagnosis accounting for 2–5% of breast cancers, the reported incidence of DCIS has increased since the introduction of ma mmographic screening programs and has been reported to account for approximately 25% of new breast cancer diagnoses in some series. There is evidence to suggest that these former historical mass lesions differ in their nature from screen detected-lesions. In either case the aim of the treatment of DCIS is to prevent or abrogate progression to invasive carcinoma and subsequent potential for metastatic disease and death. DCIS is treated primarily by surgical excision, which can be in the form of breast-conserving surgery (lumpectomy) or mastectomy. While mastectomy is considered to be curative, the recurrence rate in DCIS patients treated with breast-conserving surgery alone has been reported to be greater than 25% over 10 years although this is dependent on the marginal status. As a result, patients treated with breast-conserving surgery may also receive radiotherapy and hormonal therapy lead to a significant reduction in recurrence rates (∼50%) with the addition of adjuvant treatments in patients treated with breast-conserving surgery for DCIS, such treatments are associated with not insignificant financial cost and side effects. Since nearly 75% of DCIS cases do not recur after surgical excision, there is a group of low risk DCIS patients who would not gain additional benefit from adjuvant treatment. Accurately identifying this group of patients is desirable, not only to avoid side effects of treatment, but also to allow better allocation of limited health resources. There is now a push for a reduction of so called over diagnosis of DCIS as many of these lesions behave in a benign fashion. The presentation will outline current concepts in the aetiology of DCIS including models of progression and tumour heterogeneity.
OOTR_KBCCC 9
Departments of Pathology and Surgery, Tohoku University School of Medicine, Sendai, Japan
The factors predicting the clinical course or outcome of the patients with DCIS or ductal carcinoma in situ has become pivotal in determining the choice of clinical algorithm or postoperative therapy. Among these factors, those established by the study of relatively large number of the cases include the size of the lesion, nuclear grade, the presence or absence of comedo necrosis and carcinoma cells in surgical margins, obviously in addition to an exclusion of invasive properties of the lesions using myoepithelial markers or others. Histopathlogical grading is still the gold standard of classification but the grading based upon the traditional architectures of the lesions such as cribriform or others has not been used. At present or in 2016, the grading of DCIS is based upon morphological nuclear features possibly in conjunction with the presence or absence of necrosis and/or cell polarization. Based upon the histological classification above, DCIS is currently classified into three different grades, low, intermediate and high. This grading system could be certainly subjective but the differentiation between low and high grade is fairly reproducible although that between low grade DCIS and ADH or atypical ductal hyperplasia could still pose diagnostic difficulties. It is also important to note that intratumoral heterogeneity of nuclear grades was certainly detected in the same lesion but carcinoma cells with low and high grades usually do not exist in the same glands. Recent moleculer and biological studies also indicated that low and high grade DCISs are two different lesions. Therefore, assigning the accurate grading to the lesions is the most important one as well as the status of resected margins and an exclusion of invasive properties in the management of DCIS patients among all the factors reported.
Among the biomarkers reported so far in DCIS, the only established one is still the status of ER or estrogen receptor. ER is expressed in around 80% of DCIS patients when the threshold is determined as more than 1% as in invasive ductal carcinoma cases. Adjuvant tamoxifen administration significantly reduced the risks of developing invasive carcinoma as well as the ipsilateral incidences of DCIS recurrence but this therapeutic benefit is only restricted to ER positive DCIS cases. Therefore, it is also important to obtain the accurate status of ER in DCIS using i mmunohistochemistry.
OOTR_KBCCC 10
University of Edinburgh, United Kingdom
The value of adjuvant WBI after BCS in DCIS is principally to reduce the risk of invasive recurrence. Whether there is a subset of patients with ductal carcinoma in situ (DCIS) from whom postoperative WBI can be omitted after BCS remains uncertain. This is mainly due to inconsistencies in prospective and observational studies in relation to the predictive value of clinico-pathological risk factors (1). There is concern that WBI may represent over treatment for low grade disease after BCS. Active monitoring is currently being compared to BCS in the LORIS trial (ISRCTN 27544579).
There is considerable heterogeneity in the use of adjuvant irradiation with increasing usage with for intermediate and high grade lesions.
In the Oxford overview of trials of adjuvant WBI in DCIS in 3729 women (2), the absolute 10 year risk of IBTR was reduced by 15.2% (SE 1.6%, 12.9% vs 28.1%, 2P<.00001). The rate of ipsilateral breast events roughly halved in all four trials. Radiotherapy reduced local IBTR irrespective of age, type of surgery (local or sector excision) and whether tamoxifen was given or not. The proportional impact of radiotherapy was higher in older women. There was no difference in the risk of death between irradiated and non irradiated patients. The benefit of radiotherapy was seen in all subgroups. It was not possible to identify a subgroup of women who do not gain from radiotherapy.
In the ECOG-ACRIN W5194 study (3) women with grade 1 or 2 DCIS <2.5 cm treated by breast BCS with margins = />1 mm (or no residual disease on reexcision) [cohort 1] or high grade DCIS = /<1 cm [cohort 2] without tamoxifen. At a median follow of 3.3 years, the number of IBTRs reached the threshold defined by the study stopping rules (3). The 5 year IBTR rate was 12%. In a recent update (4) at a median follow up of 12.3 years, there had been 99 ipsilateral breast events of which 51 (52%) were invasive. The ipsilateral breast rates were 14.4% for cohort 1 and 24.6% for cohort 2. The 12 year rates for an invasive recurrence for the two cohorts were 7.5% and 13.4% respectively. Over the 12 year period the risks of invasive recurrence increased without any plateau. The ipsilateral breast event rate was 1.2% for cohort 1 and 0.6% for invasive recurrence. The Oxford overview (2) identified 291 women with small (1–20 mm), clear margins and low nuclear grade. Their risk of local recurrence at 5 and 10 years after BCS alone was 20.6% and 30.1% respectively. Unfortunately to date there are no biomarkers to predict either recurrence with DCIS or invasive disease after BCS. At present there is no subset of patients with DCIS following BCS from whom WBI can be systematically omitted.
OOTR_KBCCC 11
Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
Before the advent of breast cancer screening programs, ductal carcinoma in situ (DCIS) comprised only 2–5% of symptomatic cancers with presentation as a palpable mass unco mmon. Following widespread introduction of regular screening for women aged 40–70 years almost 20% of newly diagnosed breast cancer is DCIS which represents up to half of all screen-detected cases. Screening programs are tapping into a reservoir of indolent non-progressive DCIS within a target population. Once detected, DCIS must be treated with the main goals of preventing recurrence of invasive disease whilst minimizing treatment-related morbidity. It estimated that between 25% and 50% of DCIS will progress to invasion over 10–15 years [Rosen PP et al. Cancer 1980; 46: 919–925] but some cases of DCIS would never become invasive during a woman's lifetime and are clinically non-consequential. A principal determinant of recurrence is lesion grade with some low grade DCIS lesions more appropriately termed pseudo-disease and linked to a degree of overdiagnosis (estimated at 19% in the UK National Health Service Breast Screening Program). This can potentially undermine the value of screening when 3 cancers are over-diagnosed for each life saved [Independent UK Panel Lancet 2012; 380: 1778–1786]. Adjuvant treatments for DCIS such as radiotherapy and tamoxifen reduce the chance of ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) for DCIS but no improvement in breast cancer-specific survival has been demonstrated-although number of breast cancer deaths is small and overall survival 97–99% for DCIS patients. Determinants of IBTR after BCS are multifactorial and involve factors related to the patient, tumor and treatment with specific indices such as Van Nuys incorporating independent predictors of IBTR into clinically useful tools. The issue of margin width for DCIS may differ from invasive disease due to the discontinuous growth pattern of DCIS which occurs in up to 40% of cases and may render ‘no tumor at ink’ inadequate. A large meta-analysis of more than 4000 patients found that a margin threshold of ≥2 mm was associated with a lower risk of IBTR than a margin of <2 mm and margins of >5 mm did not further lower rates of IBTR. Several authorities have endorsed a margin of 2 mm for patients with pure DCIS receiving whole breast radiotherapy. The Van Nuys Prognostic Index incorporates tumor size along with pathological classification, surgical margins and grade. There is a positive correlation between DCIS size/higher grade/presence of comedo necrosis and recurrence risk despite problems with accurate measurement of maximum tumor size. Differences in rates of IBTR between low and high grade lesions disappear with longer term follow up and molecular predictors of recurrence appear promising. A molecular phenotype can be defined based on expression of oestrogen, progesterone and HER2 receptor expression and possibly Ki-67 which provides a pragmatic risk stratification [Benson JR, Wishart GC. Lancet 2013;14(9):e348–57]. A 12-gene continuous recurrence score can likewise divide patients into low, intermediate and high risk for 10 year local recurrence (p≤0.006) [Solin L et al. J Natl Cancer Inst 2013;105:701–10]. It seems likely that standardized pathological reporting with consistency in labelling of various proliferative lesions in conjunction with molecular profiling may increase predictive accuracy. A comprehensive management strategy for DCIS should incorporate patient-related factors (pathology, molecular profile, age, comorbidities), breast size and patient preference. Patients should be encouraged to accept treatments which reduce risk of invasive recurrence whilst being reassured that in selected cases no treatment may be appropriate with radiological surveillance only.
OOTR_KBCCC 12
Department of Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan
OOTR_KBCCC 13
Molecular Imaging Program, NCI/NIH, Bethesda, MD, USA
Three modes of cancer therapy, surgery, radiation and chemotherapy, have been central to modern oncologic therapy. Molecular targeted cancer therapies have been introduced to target specific pathways, while minimizing side effects but have had limited success except in several notable cases. Here, we employ an activatable hydrophilic photosensitizer based on a near infrared (NIR) phthalocyanine dye, IRdye700DX (IR700), which is covalently conjugated to one of several humanized monoclonal antibodies (MAb) targeting cancer-specific cell-surface molecules. When exposed NIR light, the conjugates visualize cancer cells with low dose of NIR light and induce highly selective cell death in vivo with therapeutic dose of NIR light, a process termed “near infrared photo-i mmunotherapy” (NIR-PIT). Antibody-photosensitizer conjugates (APC: MAb conjugated with IR700) bound target-specific cell death could be induced within 1 minute of exposure to NIR light and resulted in cellular swelling, bleb formation, and rupture of vesicles indicating necrotic cell death. No phototoxicity was observed in co-cultured receptor-negative cells after incubation with APC, even when APC was not removed from the medium during light exposure. Greater than 95% of cancer cell death in vivo was demonstrated with bioluminescence imaging and 18F-FDG PET. Thereafter, greater than 90% tumor shrinkage was observed in vivo within 3 days of the NIR irradiation, with no apparent side effects, only in target tumors with NIR light exposure, and more than 80% of mice showed tumor-free survival for more than a year with an optimized regimen. IR700 fluorescence produced by the APC permitted guidance of light delivery and allowed for monitoring after therapy. Disappearance of IR700 fluorescence indicates sufficient exposure of NIR light for inducing maximum therapeutic NIR-PIT effects. Furthermore, i mmediately after NIR-PIT, as much as 24-fold superior delivery and retention of nano-sized particles (SUPR effect) was induced in NIR-PIT treated tumors compared with non-treated tumors with conventional enhanced permeability and retention (EPR) effects. Therefore, NIR-PIT combined with nano-sized cancer agents showed synergic therapeutic effects. The MAb-IR700 NIR-PIT was most effective, when conjugates were bound to the cell membrane, but showed no phototoxicity, when unbound, suggesting a novel mechanism for NIR-PIT compared with conventional photodynamic therapies. Successful pre-clinical NIR-PIT studies have been performed or are on-going against more than 20 different molecular targets expressing on different cancers including EGFR, HER2, PSMA, CD25, GPC3, mesothelin, CD20, CD133, CD44, CEA, Iaminin322, and more. Now the first-in-human clinical trial of NIR-PIT against head and neck cancer patients targeting EGFR has started by employing the cetximab-IR700 photo-i mmunoconjugate (RM-1929) in May 2015. In conclusion, theranostic NIR-PIT based on MAb-IR700 cell membrane binding enables selective treatment of cancer with no apparent side effects to normal cells or surrounding tissue.
OOTR_KBCCC 14
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
OOTR_KBCCC 15
Department of I mmunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Since the first hypothetical description on cancer i mmune surveillance by Burnet and Smith more than half a century ago, i mmunological control of human cancer continued to be one of the major issues, with the fluctuation of hope and frustration. Numerous attempts of cancer i mmunotherapy have been made, including active i mmunization such as vaccine therapy and various adoptive cell therapies. Although some of them provided significant benefits for cancer patients, few have been established as standard therapies so far due to various reasons, such as low response rates, technical laboriousness, and severe adverse effects. Most recently, a new concept of cancer i mmunotherapy targeting checkpoint i mmunoreceptors, CTLA-4 and PD-1, has been proposed, which intends to release the potential anti-tumor i mmune responses from negative regulation intrinsic to the i mmune system. PD-1, originally discovered by Dr. Honjo's group at Kyoto University in 1992, functions as a TCR-coinhibitory receptor by the engagement with the specific ligands (PD-Ls) and plays an important role in the checkpoint of T-cell autoi mmunity. In 2002, we first reported that the PD-1 checkpoint profoundly restricts endogenous anti-tumor i mmunity, and the blockade of this checkpoint causes significant therapeutic effects on cancers in animal models. This finding was followed by large-scale clinical studies in 2012, revealing that checkpoint blockade with the use of humanized anti-PD-1 or anti-PD-L1 antibody provided remarkable beneficial effects on the patients bearing various types of cancers with tolerable adverse effects. FDA approved humanized anti-PD-1 antibody for melanoma in 2014 and for non-small cell lung cancer in 2015, and anti-PD-L1 antibody has been designated as a breakthrough therapy. Currently, numerous clinical studies on the checkpoint blockade including various combination therapies are underway worldwide in almost all types of cancers, and the rationales and biomarkers for the therapy are being disclosed. History of PD-1 research and recent advances are reviewed, and future perspectives of checkpoint blockade cancer i mmunotherapy will be discussed.
OOTR_KBCCC 16
Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
Fewer than 5% of women present with an intact primary tumor and evidence of distant metastases. Historically, these patients were offered surgery in the form of toilet mastectomy if the primary tumor was symptomatic to prevent uncontrolled chest wall disease leading to problems of skin ulceration, secondary infection, bleeding and ultimately cancer en cuirasse. Over the past 2 decades, advances in treatment with newer systemic agents (taxanes, aromatase inhibitors, anti-HER2 therapy and tyrosine kinase inhibitors) have increased 3 year survival rates for metastatic breast cancer (MBC). Surgery is increasingly being undertaken in the setting of MBC for local control rather than palliation with many patients surviving up to 5 years with bone metastases. Breast surgical procedures have relatively low morbidity and both patients and physicians may fear subsequent development of complications locally. There is evidence that local control with removal of all gross disease and clear surgical margins is associated with a survival benefit when adjustments are made for chest wall status and confounding factors. A seminal observational study examined the influence of aggressive local therapy on overall survival in more than 16,000 patients with distant metastases at presentation [Khan S. et al Surgery 2002;132:620–627]. Surgical resection of the primary tumor with negative margins was associated with a 39% reduction in mortality [HR 0.61; 95%CI 0.58–0.65]. A subsequent pooled analysis of 10 non-randomized retrospective studies incorporated data from the entire Kaplan-Meier curves with censoring of data and extraction of hazard ratios directly from papers. Seven studies showed a statistically significant increase in overall survival with the remaining 3 revealing a trend for increased overall survival with surgery for MBC. The pooled hazard for overall mortality was 0.65 [95% CI 0.59–0.72] and those patients with tumor-free resection margins demonstrated the greatest gains in overall survival amongst all studies [Ruiterkamp J et al. Breast Cancer Res Treat 2010;120:9–16]. Patients with MBC undergoing surgery are more likely to be younger with smaller tumors, distant disease at a single site and to have fewer co-morbidities. There is however conflicting data from pre-clinical and retrospective studies and ideally prospective randomized data is required. Two randomized controlled trials from India and Turkey have addressed the potential value of early surgical intervention for MBC. These were presented back to back at the 2013 San Antonio Breast Cancer Symposium and reached similar conclusions with median follow up 24 and 54 months respectively - that local therapy has no benefit on mortality in the metastatic setting. There is continued controversy over the harms and value of loco-regional therapies for advanced breast cancer patients with most clinicians opting for systemic therapy alone. MBC patients now have a smaller tumor burden at both primary and distant sites and essentially the primary tumor should be treated like the metastatic site and removed. This will prevent the primary tumor acting as a source of distant metastases and reduce re-seeding with ‘escapee’ cell seeding to distant sites and returning to the primary. This will increase the efficacy of systemic therapies. Conversely, there is no evidence that manipulation of the primary tumor will disinhibit angiogenesis and kick start dormant micrometatases.
OOTR_KBCCC 17
Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
These trials were initiated in a time where treatment techniques just started to improve, enabling to limit the dose to the organs at risk. With modern RT techniques, the benefits of optimising locoregional control will likely not be counterbalanced by side effects including late cardiovascular mortality. Moreover, the new ESTRO guidelines for target volume delineation clearly reduce the size of the target volumes while simultaneously considering the regional lymph nodes even more than before as a whole. We also calculated that the real benefit of loco-regional RT used to be diluted in the past (including the recently presented trials) by suboptimal dose coverage of the target volumes. Therefore, we expect that with contemporary RT techniques and appropriate target volume delineation, not only a significant reduction of the dose to the organs at risk but also a much better coverage of especially the internal ma mmary lymph nodes is achievable, which is likely to result in a further improvement of the benefit of locoregional RT for patients with early stage breast cancer that have a risk for bearing microscopical tumor deposits in the regional lymph nodes.
OOTR_KBCCC 18
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
Insensitivity to antigrowth signals is a hallmark of cancer.
Cyclin-dependent kinases (Cdks) are serine/threonine kinases and their catalytic activities are modulated by interactions with cyclins and Cdk inhibitors (CKIs). Close cooperation between this trio is necessary for ensuring orderly progression through the cell cycle. In addition to their well-established function in cell cycle control, it is becoming increasingly apparent that ma mmalian Cdks, cyclins and CKIs play indispensable roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions.
Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy.
Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer. The role of CDK4/6 in tumorigenesis and the clinical trial experience with inhibitors of these CDK inhibitors in breast cancer will be discussed.
OOTR_KBCCC 19
Department of Breast Surgical Oncology, St. Luke's International Hospital, Tokyo, Japan
President Obama in the United States announced the “Precision Medicine Initiative” in January 2015. Due to advancements in medical technology, we could offer a genetic test to estimate one's cancer risk, plan precision screening to one's risk and consider preventive measures including pre-emptive surgery. While pre-emptive surgery is one of the established options for high-risk women in western countries, it is not accepted well in the Asian community, including Japan.
Hereditary Breast and Ovarian Cancer Syndrome (HBOC) is know as a syndrome that causes breast and ovarian cancer at an exceptionally high rate in patients who have genetic mutations in BRCA 1 and 2. Penetration rate of BRCA 1 and 2 in the Japanese population with a strong family history showed 26.7% as high as in the Western population. To protect the population from developing the disease, it is critical to distinguish this population and encourage them to have genetic counseling and precision screening. While other protective strategies for women with HBOC are chemoprevention with tamoxifen and oral contraceptives, pre-emptive mastectomy or bilateral salphingo oophrectomy are strong strategies for women with mutated BRCA since the data confirmed the benefits. It is urgently required to establish consensus and support a system for pre-emptive surgery in the Asian co mmunity.
Our hospital ethics committee discussed pre-emptive surgery to apply to women with BRCA mutation and who wish to have this surgery for decreasing their risk after understanding the risks and benefits enough regarding this procedure in 2011. Since 2011, we performed prophylactic surgery for about 50 women who have BRCA mutation.
In this new era, it is necessary to consider precision screening and pre-emptive surgery to fit one's genetic risk. We should discuss how we can work together to develop precision medicine.
OOTR_KBCCC 20
Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan
OOTR_KBCCC 21
Peter MacCallum Cancer Centre, Melbourne, Australia
Clinical cancer molecular diagnostics is undergoing a transformation, the result of a shift towards using targeted therapies that are matched to mutations, coupled with the widespread availability of affordable high throughput sequencing (HTS) which is becoming standard of care in the management of cancer patients. It holds the promise of a step change in our understanding of fundamental biology with an impact on disease and patient care reminiscent of the introduction of the microscope in the 1840s. However, this realisation is currently limited by the use of diagnostic formalin-fixed paraffin embedded tissues, the inherent biology of cancer, our understanding of gene variants and the absence of decision support tools to analyse HTS data. To implement HTS in clinical diagnostics we used the Cancer 2015 cohort study. Cancer 2015 is a large-scale, prospective, multi-site cohort of newly diagnosed cancer patients from Victoria, Australia. This is a whole of system Framingham type cohort, which follows patients and collects epidemiological, quality of life, treatment, follow up, conventional pathology, molecular cancer profiling and health economic data on participants. Tumour profiling has been performed for 48 cancer genes on tumours and clinically relevant mutations have been identified in two thirds of patients, with approximately one quarter of patients displaying a mutation with therapeutic implications. While the prevalence of mutations was consistent with other institutionally based series for some tumour types, others were different which has significant implications for health economic modelling of particular targeted agents. Further, in some tumour types new areas of research were identified through recognition of novel genotypes. Reliable delivery of a diagnostic assay to screen for a range of actionable mutations was achieved, providing evidence for a reclassification of some cancers and opening unexpected avenues for investigation and treatment of cancer patients.
OOTR_KBCCC 22
Netherlands Cancer Institute, Amsterdam, The Netherlands
Neoadjuvant or primary systemic treatment is increasingly applied in the treatment of operable breast cancer. Down staging of the primary tumor is one of the important goals of neoadjuvant systemic treatment (NST), thereby permitting breast-conserving treatment without affecting the risk for a local relapse. Complete pathological response rates after NST vary across histological subtypes and can be more than 50% in HER2-positive disease. Down staging of the axilla is also observed in patients initially presenting with metastatic lymph nodes. Complete pathological response rates in the axilla vary between 22% and 42% in reported series, again depending on tumor subtype. The therapeutic effect of a complete axillary lymph node dissection (ALND) is limited in case of a complete pathologic response in the axilla. If reliably identified, such patients can be offered a more conservative therapy of the axilla, sparing them the substantial short- and long-term morbidity of an ALND. Postchemotherapy sentinel node (SN) biopsy (SNB) in patients with proven metastatic lymph nodes before NST is under debate, because different rates of identification rates (between 68% and 100%) and false-negative rates (between 5% and 30%) are reported. We aimed to develop a new technique to assess the response to NST in patients presenting with nodal metastasis. For this purpose, radioactive iodine (125I) seeds were used. The use of 125I seeds is increasingly applied in breast-conserving surgery. Recent studies have described the use of 125I seed localization to facilitate breast-conserving surgery also after NST. Before the start of systemic treatment, a 125I seed is placed in the center of the tumor. In case of a good clinical response after systemic treatment, a local excision can be performed around the 125I seed to remove residual disease or confirm the complete response by histological examination.
This MARI procedure [marking the axillary lymph node with radioactive iodine (125I) seeds] is a new minimal invasive method to assess the pathological response of nodal metastases after neoadjuvant systemic treatment (NST) in patients with breast cancer. Before the NST, a I125 seed was placed in the FNAC proven positive axillary lymph node under ultrasound guidance, and local anaesthics. After NST, the MARI node was selectively removed using a [ga mma]-detection probe. A complementary axillary lymph node dissection was performed in all patients to assess whether pathological response in the MARI node was indicative for the pathological response in the additional lymph nodes. A tumor-positive axillary lymph node was marked with a 125I seed in 100 patients. The MARI node was successfully identified in 97 of these 100 patients (identification rate 97%). Two patients did not undergo subsequent axillary lymph node dissection, leaving 95 patients for further analysis. The MARI node contained residual tumor cells in 65 of these 95 patients. In the other 30 patients, the MARI node was free of tumor, but additional positive lymph nodes were found in 5 patients. Thus, the MARI procedure correctly identified 65 of 70 patients with residual axillary tumor activity (false negative rate 5/70 = 7%). Our experience shows that marking and selectively removing metastatic lymph nodes after neoadjuvant systemic treatment has a high identification rate and a low false negative rate. The tumor response in the marked lymph node may be used to tailor further axillary treatment after NST.
We have adapted this procedure now in routine clinical practice: patients with a complete pathological response after NST in the Mari node will not have any treatment of the axillary nodes. Patients with extensive pre-NST nodal involvement (>3 avide nodes on pre-NST PET/CT scan) and a positive post-NST Mari node will undergo complete axillary clearance. Patients with limited nodal involvement on PET/CT scan (<4 nodes) and histological proven post-NST Mari node will receive RT to the axilla (together with the breast or thoracic wall).
OOTR_KBCCC 23
Graduate Institute of Oncology, National Taiwan University Hospital, College of Medicine, Taiwan
Mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase domain is the most co mmon genomic alterations in East Asian lung adenocarcinoma patients. EGFR TKIs such as gefitinib, erlotinib and afatinib are the standard front-line treatment for patients with co mmon EGFR mutations. Most if not all patients eventually develop resistance to EGFR TKIs. In about 50-60% of those patients, a new mutation T790M can be found in the re-biopsy specimen along with the previous activating EGFR mutation. Other frequent genetic alterations including cmET amplification, loss of P53 and RB1 function and small cell transformation, Other mutation are also frequently found if the sequencing is deep. For patients who become resistant to EGFR TKIs, the stand of care is to start platinum-based chemotherapy. Recently, a novel mutant specific EGFR TKI, osimertinib is currently approve in US for the treatment of these patients who has T790M detected in re-biopsy tumor tissue. T790M can be detected in the cell free plasma DNA with good sensitivity and specificity, therefore, potentially can replace some of the rebiospy procedures and testing. Combination of EGFR TKI with pathway inhibitors that control resistant mechanisms such a cmET inhibitor is also being examined in patients whose rebiopsy tumor overexpress cmET or has cmET gene amplification. In addition to traditional chemotherapy, another alternative other than combination of targeted therapies is to use PD1/PDL1 monoclonal antibody as i mmunotherapy. However, the role of this treatment in EGFR mutant tumor is yet to be determined.
OOTR_KBCCC 24
Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
With the accumulations of whole genome/exome analysis data in various types of cancers, target sequencing with the NGS panel is now rapidly being developed in association with new agent trials (so called “basket type trial”). In 2013, we have started an investigator-initiated IND registration trial of vandetanib for RET fusion gene positive NSCLC following the nation-wide screening organization (LC-SCRUM). Similar nation-wide screening system was also established in CRC using originally developed panel for all RAS/BRAF mutations (GI-SCREEN) for new agent trials targeting these mutations. With a rapid progress in NGS pan-cancer panel, we integrated these two organizations and restarted as the “SCRUM- Japan” in collaboration with 14 pharmaceutical companies from Feb 2015. A cutting-edge pan-cancer panel detecting more than 140 mutations, amplifications, and fusion genes, which is the same panel as used in NCI-MATCH trial, is used for the genome screening. Approximately 200 hospitals in Japan are participating to SCRUM-Japan with a shared information of more than 30 various types of new agent IND registration trials. Expert panel consisted of genome/TR researchers and medical oncologists work for annotation of the genome analysis data, which is available for adequate agent selections (mostly in IND registration trial). Target sample size is 4,500 genome screening for lung and gastrointestinal tract cancer within 2 years. To date, more than 1,500 samples have already been accrued for genome analysis. The genome screenings will soon expand for hepato-biliary-pancreatic cancer and GIST. The on line genome database is planning to be shared with all participating industries and investigators from the end of January 2016.
The SCRUM-Japan will make a large genome database of Japanese patients with precise clinical outcomes, activate new agent clinical trials and be followed by possible establishment of precision medicine in Japan.
OOTR_KBCCC 25
University of Edinburgh, United Kingdom
Precision Medicine in oncology may be defined as ‘discovering unique therapies that treat an individual's based on the specific abnormalities of their tumor’. It is well recognized that breast cancer is not a single disease but composed of several heterogeneous molecular subtypes each with its own natural history and risk of recurrence. Current multigene assays for prognosis rely heavily on measuring the transcriptional output of ER signaling and proliferation related genes. While much of focus of gene profiling has been on predicting benefit from systemic therapy, there is increasing interest in predicting benefit from radiotherapy in patients where the benefit of adjuvant radiotherapy is uncertain. For example frozen tissue from 191 patient in the Danish Cooperative Group 82bc trial of postmastectomy radiotherapy in high risk women receiving systemic therapy identified the ‘DBCG-RT’ gene profile based on 7 genes. Those identified by the gene signature as at low risk of loco-regional recurrence (LRR) experienced no additional benefit in reduction of LRR from PMRT. More recently researchers at the University of Michigan have utilised clonogenic survival from breast cancer cell lines to stratify breast cancers into radiosensitive and radioresistant subsets. They correlated the response to radiotherapy with gene expression by statistical modeling. They identified 147 genes associated with radiosensitivity.
Controversy persists over whether there is a subset of older women from whom postoperative whole breast irradiation (WBI) can be safely omitted after breast conserving surgery (BCS). The level 1 evidence base in this subgroup of patients is relatively limited. Benefits in local control have to be balanced against risks of radiation toxicity. However improvements in radiation planning and delivery are reducing these risks.
The Oxford meta-analysis of trials of BCS+/- postoperative WBI after BCS for early breast cancer shows a halving of the risk of first recurrence (mainly local) and reduces mortality by 18% across all risk groups. The CALGB 9343 trial in women = />70 years with receptor positive T1 tumours receiving tamoxifen +/- WBI demonstrated a 3% reduction in local recurrence at 5 years from RT (1% vs 4%.0, p = <0.001). At a median follow up of 10.5 years the difference in IBTR had widened (2% RT+, 9% RT-). Omission of WBI did not compromise overall survival (OS). More recently the PRIME II trial of 1326 T1–T2 (up to 3 cm), pNO, hormone receptor positive tumours = />65 years treated with BCS, endocrine therapy +/- WBI. It showed a 2.8% reduction in IBTR from WBI (4.1% vs 1.3%, p = 0.02) at a median follow up of 5 years. Omission of WBI did not compromise OS. They concluded that in T1–T2 (pt to 3 cm), grade 1 or 2, HR+, pN0 patients =/>65 years omission of WBI should be an option. Some argue that clinico-pathological factors alone are inadequate to define a genuinely ‘low risk’ group for the omission of WBI. This area of clinical uncertainty lends itself to a precision medicine approach. Molecular markers are under investigation to refine this selection in the Canadian LUMINA and UK PRIME TIME studies based on i mmunohistochemical markers.
OOTR_KBCCC 26
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical & Dental University, Tokyo, Japan
Hereditary breast cancer is estimated to be 5% to 10% of all breast cancers in Japan. We identified the BRCA1 gene in 1994, and Wooster and colleagues identified the BRCA2 gene in 1995 as the responsible genes. Hereditary breast cancers caused due to a mutation either in BRCA1 or BRCA2 are called Hereditary Breast and Ovarian Cancer (HBOC). Currently, in the medical care of breast cancer patients exceeding 80,000 people per year in Japan, each patient is always required to determine whether or not her breast cancer is hereditary. If it is hereditary, it is necessary to present an appropriate clinical strategy for an individual patient, such as sophisticated medical examination, risk-reducing mastectomy (RRM), risk-reducing salpingo-oophorectomy (RRSO), and application of molecular target drug (PARP inhibitor). Therefore, construction of an HBOC comprehensive medical care system based on the collaboration of medical institutions is progressing for the best practices of HBOC management. In addition, the nationwide registration of HBOC and construction of HBOC database are also progressing. On the other hand, we have been promoting research activities of HBOC. The analysis of BRCA1 and 2 functions has revealed that both genes have a DNA damage repair function and its dysfunction leads to breast carcinogenesis. In recent years, a new breast and ovarian cancer therapy based on synthetic lethality such as PARP inhibitors has been also developing. In this presentation, I will describe the research and clinical activities for HBOC.
OOTR_KBCCC 27
Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
The apparent discrepancy between the results of the surgical and radiation trials can be easily explained by a number of factors: 1) the prognostic risk groups of the participating patients; 2) the duration of follow-up where 5 years is too short for a disease where an indolent course is seen in the majority of the patients; 3) the initial “blurring” of the results for patients who receive adjuvant endocrine therapy for 5 years and 4) the complex interaction between the long-term effects of locoregional and systemic treatments on survival for breast cancer patients.
With modern RT techniques, based on individualised target volume delineation using the recently published ESTRO guidelines, the total target volume will be greatly reduced by removing excessive margins around the lymph nodes which where common when working with standard open RT fields. It also enables to reduce the dose to the non-target part of the body, which will results in lowering the side effects at short- as well as at long-term. We for example expect that this will result in a clear reduction of the incidence of impaired shoulder functioning after axillary irradiation compared to the results of AMAROS, where excessive parts of the lateral side of the axilla and the upper arm where included in the conventional RT field.
OOTR_KBCCC 28
1Tokyo Women's Medical University, Tokyo, Japan; 2National Institute of Radiological Sciences, Chiba, Japan; 3Chiba Cancer Center, Chiba, Japan; 4Tokyo Medical University, Tokyo, Japan; 5Juntendo University, Tokyo, Japan
At the time of analysis, all phase I CTr patients underwent surgery and 2 of them reached pathological CR. The AMC patients had 5 CR, 5 PR, 3 SD and 1 PD on MRI. Most of the patients were required 6 months to have CR. One patient with basal subtype tumor had recurred local and axillary lymph node was successfully salvaged by surgery.
OOTR_KBCCC 29
1Department of Surgery, Kansai Medical University, Hirakata, Japan; 2Department of Breast Surgery, Graduated School of Medicine, Kyoto University, Kyoto, Japan
Sentinel lymph node (SLN) biopsy after neoadjuvant systemic therapy (NST) is an acceptable axillary management for node-negative breast cancer. Previous studies reported that conversion to node-negative disease was achieved in more than 30% of women with clinically node-positive disease after NST. Axillary lymph node dissection could be avoid in those patients with SLN negative biopsies. However, the false negative rate of SLN detection ranged from 8.4% to 14.2% and this false negative rate was also associated with the number of SLNs harvested. The accuracy of SLN biopsy was apparently improved when more than two SLNs were harvested using the dual mapping with blue dye and radioisotope (RI).
For SLN mapping, we demonstrated that the indocyanine green (ICG) fluorescence is superior to blue dye and an acceptable alternative to SLN detection using RI in breast cancer (Ann Surg Oncol 2013;20:2213–8 and Ann Surg Oncol 2016;23:44–50). The mean number of SLN removed for ICG fluorescence was 2.3, which was significantly greater than the figure of 1.7 for RI. In exploratory subgroup analysis in the patients undergoing NST (N = 70), the detection rate was significantly improved by using ICG fluorescence compared with RI (100% vs 91.4%, p = 0.04). This impairment of the SLN detection might be related with fibrosis and lymphatic obstruction by cytotoxic reagents. As the smaller size of ICG (<1 nm) can flow through narrowing lymphatic channels than the larger size of radio colloid (>50 nm). Fluorescence lymphatic imaging demonstrated the location of SLNB did not change after NST and ICG potentially enables to reach the first SLN or the further tier more smoothly than RI. Based on these results, we will discuss the clinical utility of the ICG fluorescence method for SLN biopsy after NST.
OOTR_KBCCC 30
Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, South Korea
High-resolution volumetric optical imaging modalities, such as confocal microscopy, two-photon microscopy, and optical coherence tomography, have become increasing important in biomedical imaging fields. However, due to strong light scattering, the penetration depths of these imaging modalities are limited to the optical transport mean free path (∼1 mm) in biological tissues. Photoacoustic imaging, an emerging hybrid modality that can provide strong endogenous and exogenous optical absorption contrasts with high ultrasonic spatial resolution, has overcome the fundamental depth limitation while keeping the spatial resolution. The image resolution, as well as the maximum imaging depth, is scalable with ultrasonic frequency within the reach of diffuse photons. In biological tissues the imaging depth can be up to a few centimeters deep.
In this presentation, the following topics of photoacoustic imaging will be discussed; (1) multi-scale photoacoustic imaging systems (i.e., Photoacoustic Nanoscopy, Optical-Resolution Photoacoustic Microscopy, Fast 2-Axis MEMS based Optical-Resolution Photoacoustic Microscopy and Endoscopic Probe, Intravascular Photoacoustic/Ultrasound Catheter, Virtual Intraoperative Surgical Photoacoustic Microscopy, Acoustic-Resolution Photoacoustic Microscopy, Clinical Photoacoustic/Ultrasound Scanner), (2) morphological, functional, and molecular photoacoustic imaging, (3) potential clinical applications, and (4) contrast agents for photoacoustic imaging.
OOTR_KBCCC 31
Department of Breast Surgery, Kyorin University Hospital, Tokyo, Japan
Therapeutic monitoring is an important aspect for clinical management of cancer patients. In the neoadjuvant settings, the treatment strategy is based on the prediction of therapeutic response to a certain treatment, which does not necessarily work as expected. Thus, it is inevitable to monitor therapeutic efficacy in order to optimize the therapeutic outcomes. Currently, monitoring is essentially performed by images such as ultrasound and MRI but tumor burden is not the only marker to indicate therapeutic response and sometimes does not reflect the response accurately. Biological monitoring using cancer tissues and blood samples would be the key in order to maximize the treatment efficacy. Changes in biological properties of cancer would tell us not only how cancers react to the certain treatment but also what to do in the following settings. In this session, developing bio-markers for therapeutic monitoring, especially for non-cytotoxic therapy including metronomic therapy and endocrine therapy, and future perspectives will be discussed.
OOTR_KBCCC 32
Departments of Pathology and Surgery, Tohoku University School of Medicine, Sendai, Japan
The status of tumor-infiltrating lymphocytes has been considered to play pivotal roles in biological and/or clinical behavior of the patients with various malignancies including breast cancer as tumor-stromal interactions. Therefore, it has become important to obtain the accurate status of those lymphocytes in clinical specimens not only as a predictive marker of clinical outcome but also a potential surrogate marker of i mmune therapy including those newly developed i mmune checkpoints modulators. Flow cytometry is usually considered the gold standard methodology of evaluating the subpopulation of lymphocytes but requires fresh frozen tissues and the correlation between carcinoma and lymphocytes could not be obtained because the tissue is treated as a mass. Immunohistochemistry of lymphocytes specific antigens could provide inert information as to the localization of specific types of infiltrating lymphocytes and also the correlation with changes of carcinoma cells. However, i mmunohistochemical demonstration of the lymphocytes surface antigens required fresh frozen tissue sections. Recent advent of development of specific antibodies has made it possible to demonstrate various lymphocytes subtypes in archival or 10% formalin fixed and paraffin embedded tissue materials and to evaluate the correlation between the infiltrating lymphocytes and the status of carcinoma cells such as degeneration or apoptosis or the expression levels of PDL-1 or programmed death-ligand 1using double or triple i mmunostaining. In particular, i mmunohistochemical demonstration of the equilibrium of cytotoxic T cells (CD8+ T cells) and the regulatory T cells defined as forkhead box protein 3 (FOXP3)+, each facilitating and suppressing anti-tumor immunity, respectively, could provide pivotal information as to carcinoma-stromal interaction in breast cancer patients. However, as in other i mmunohistochemical analysis, analytical factors including those in pre/post analytical ones should be standardized to prove its clinical efficacy as both prognostic and surrogate biomarkers of the patients with breast cancer.
OOTR_KBCCC 33
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
Preoperative systemic therapy (PST) was initially developed as a method to downstage the tumor to enable local treatment in locally advanced breast cancer. Now with wider range of drug options, PST has broader clinical indication for women with operable breast cancer and it has widely been used as a platform of drug development and exploration of predictive markers. So far, however, the clinical impact of the findings from PST researches, seems to be limited, contradictory to the previous assumption that PST would raise the efficiently of drug and biomarker development.
There are controversies over PST studies. Overall outcome of patients with primary breast cancer has improved with the contemporary systemic treatments: The better the baseline risk is, the harder it gets to prove that an additional moderate improvement of response to PST would translate into meaningful absolute clinical benefit, particularly in patient groups with relatively good prognoses. From the viewpoint from more efficient drug development, it is necessary to enrich study participants to those who have resistant tumor or worse prognosis. Secondly, achievement of pathological complete response (pCR) is an indicator of good prognosis in individual patient, but the impact of pCR on long-term outcome is different among tumor groups with different biology. Improvement in pCR ratio does not necessarily correlate with greater risk reduction of recurrence in patient cohorts.
The objective of PST studies are to develop effective drugs for patients with worse prognoses and to identify predictive biomarkers to select right target population for a certain drug. So far, few drugs have obtained approval for PST indication from regulatory agencies and there are hardly any biomarker confirmed for clinical utility. To make a clinical breakthrough by making the most of the advantage of PST study, response-guided study design, i.e. utilization of PST as in vivo enrichment system, and adaptive design trials seems to be promising.
OOTR_KBCCC 34
Pathology and Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, Japan
It comes to a new era of anti-cancer therapy since a subset of cancer patient showed dramatically responded to the i mmune checkpoint inhibitor targeted to a PD1/PD-L1 system and CTLA-4. PD1/ PD-L1 system is one of the principal gate (“checkpoint”) molecules on certain immune cells to recognize cells as self (non-targets) or as non-self (targets). Cancer cells that express PD-L1 can survive by inactivation of anti-cancer i mmune response through binding to PD1-expressed T lymphocyte. Anti-PD1/PD-L1 target therapy can boost the i mmune response against cancer cells, such as melanoma or lung cancer.
Several clinical trials revealed that i mmunohistochemical PD-L1 expression associated with response to anti-PD1/PD-L1 target therapy. High PD-L1 expressed patient likely resulted in a good response. PD-L1 IHC can be a useful biomarker although there are several critical issues to set the optimal patients' screening. Concerning to lung cancer, four different clinical trials (CHECKMATE/Nivolumab, KEYNOTE/Pembrolizumab, POPLAR/ Atezolizumab, MEDI/Durvalumab) resulted in good response to “PD-L1-positive” lung cancer patients, but each clinical trials have used four different clones of anti-PD-L1 monoclonal antibodies and different criteria of “PD-L1 positivity”. Intra- and intertumoral heterogeneity can affect IHC results in these setting, especially in small samples. For personalized therapy, it is required to establish a suitable companion diagnostic strategy for an adequate molecular target.
In this presentation, a new clinical trial, namely LC-SCRUM-IBIS, which has just launched in Japan, will be introduced. LC-SCRUM-IBIS will be able to resolve the clinical questions about biomarker related to the i mmune checkpoint therapy.
OOTR_KBCCC 35
Department of Molecular Biology Graduate School of Medicine, Hokkaido University, Sapporo, Japan
A series of our studies established that a small GTPase Arf6 and its signaling pathway employing AMAP1 drive invasion and metastasis under receptor tyrosine kinases in breast cancers, to be statistically correlated with poor overall survival of patients.