Treatment of disorder
It is reported that the numbers of female cancer patients in 2012 (excluding skin cancer other than malignant melanoma) are 6,658,000 cases and fatalities number is 3,548,000 cases. Numbers of breast cancer patients among them is 1,671,000 cases (approximately 25%), fatalities number is 522,000 cases (approximately 15%), according to WHO.
In Japan, 2015 prognostics for breast cancer by National Cancer Research Center reports that the numbers of breast cancer patients are 89,400 cases increased by 2,700 cases from previous year, and this takes 21% of total female cancer patients of 421,800 cases which is number 1 in female cancer rate. Fatality number is 13,800 increased by 400 persons in previous year. This takes 9% of total female cancer fatality number of 151,700 cases. Breast cancer is 5th rank following to large bowel, lung, stomach, and pancreas. As it is known by now, breast cancer becomes relatively common disease. Social interest for breast cancer is increasing as topics so that opportunity is increasing also in TV or magazine.
There are many people exist who do not know about the fact that breast cancer takes 7 to 8 years from occurrence to clinically identifiable size, and in onset it is a systemic illness which may possibly develop microscopic metastasis to entire body. It therefore becomes necessary to use several drugs as well because the treatment will not complete only with surgery. Because of this special characteristic, it is necessary to have deep understandings for breast cancer, so from the diagnosis procedure to latest treatment method are explained here.
Breast cancer, like other cancer, is developed by abnormality of the genes in the cell stuck. Human beings have roughly about 6 trillion cells and each cell contain about 30 thousand genes. Among them, there are genes which control the differentiation of cell or cell growth. In case if a change occurs in the form of abnormality of gene and if they are stuck, it will lose control on differentiation of cell or cell growth, so that abnormal cell starts growing disorderly. This is the cancer. Especially, the most of breast cancer is heavily related with female hormone on its development and the process of growth, latter explained hormone treatment becomes important. Also, as the risk factor of breast cancer, they can list up like, early menstrual period, late menopause, no birth experience or aged primiparity, no breast-feeding experience, fullness after menopause, anamnestic history for breast cancer or family history, too much alcoholic drinking. In these factors, many are included in these factors which female hormone is related.
Cancer, in its proliferative process, needs new blood vessel hyperplasia to supply nutrients or oxygen. For example, in case of breast cancer, to grow over 2mm lump, it becomes necessary to secrete growth factor so that new blood vessel creation is facilitated. Systemic illness is the characteristic of breast cancer which may possibly develop microscopic metastasis from its’ early stage through newly created blood vessel. The reason for the insufficiency of only local treatment like surgery or exposure to radiation arises from this. And for entire body treatment, drugs are used, but its selection is conducted in accordance with biological background based on gene abnormality pattern. Previously, hormone therapy or chemotherapy with cytotoxic anti-cancer agent are considered as basics, but by the latest advancement in molecular biology, cancer growth mechanism has been clarified so that new drug therapy corresponded with this has been conducted.
Clarifying the Genome information is remarkably advanced by the success of Human Genome Project which has mapped entire base sequence of human genome in 2003, and by tapping of the next generation sequencer. In fact, gene mutant pattern of each cancer case becomes apparent by means of analyzing enormous amount of data gained from large-scale genome decoding project, The Cancer Genome Atlas: TCGA, so that the primary method in drug therapy is changing from chemotherapy using conservative cytotoxic anti-cancer agent, to molecular target therapy which specifically inhibit the molecular which is necessary for growth or displacement based on the cancer gene abnormality. Especially, molecular target therapy become taking the primary part in cancer therapy, which is to differentiate driver gene abnormality which takes critical role of cancer development or growth and passenger gene which is irrelevant to driver gene, and to inhibit the activation with targeting the products produced from driver gene. The detail of these therapy is explained in entire body section.
Breast Cancer is the cancer developed in mammary gland inside of chest. In addition, mammary gland is divided into lobular producing breast milk and breast duct bringing breast milk to nipple papilla. And most of the case it is called as breast cancer because the cell forming breast duct turns to cancerized. In any case, it is developed from body surface organs so that lump can be commonly touched by oneself. It is important to make scheduled daily self-check like, for female before menopause one week to 10 days after menses finished at the time of mammary gland is softer, once a month for female after menopause. But depend on the position or size of lump there are many cases which is difficult to palpate for findings so that periodical breast cancer diagnosis is important. In addition to visual palpation, X-ray equipment exclusive for breast examination, mammography, is used, and this mammography can identify lump which is unable to find by palpation, and fine calcification.
However, there are locations that is hard to detect even with mammography due to the background breast aspect. Breast is made by fat and mammary gland, but in case there are many mammary gland anatomies exist and under the condition of high mammary gland concentration, background mammary gland is taken as white so that it becomes difficult to differentiate with also white pictured lump. Breast having high concentration of mammary gland is called as “dense breast”. Female who has dense breast is not only it is difficult to find lumps, but also has higher risk for breast cancer development. Therefore, it is necessary to consider combination usage of other image examination like echography and breast MRI. In the U.S.A, Dense Breast Notification Laws is mandatory required to notify to the patients in many states. This dense breast is common among younger generation, and although other factors like BMI or size of breast is related with this disease, it is going to be a large issue in Japan where many breast cancer patients exists.
Like Mammography, there is an important image diagnose method, known as breast echography examination. Since it uses ultrasonic, there is no radiation exposure so that female having possibility of pregnancy can take this examination.In fact, in case if lump exist, echography examination commonly finds this lump, and with looking into this image, cytological diagnosis which picks up cells using thin needle and needle biopsy which picks up a part of anatomy with using thicker needle is conducted. In case when diagnosis is made as breast cancer and when treatment begins, as it is necessary to have confirmed diagnosis by tissue diagnosis, finally this needle biopsy or isolated biopsy which removes the lump is conducted. As an indicator showing the advance stage of breast cancer, staging classification is used. This classification becomes the important factor at the time of treatment start. It is decided by the size of lump, status of surrounding lymphatic node (axillary fossa and supraclavicular / infraclavicular region), existence or non-existence of displacement of other organs (bone, lung, kidney), and divided into 0 through IV stage. This stage is used for presuming recurrent risk with combining the latter explained characteristic of cancer cell and decide drug therapy method.
In time when drug therapy for entire body therapy was difficult, primary treatment was the local treatment mainly mammary amputation. Later days, it becomes epidemic that the local recurrence in randomized controlled trial with breast conservation therapy does not affect too much on the survival, so that breast cancer is to be recognized as “systemic disease” corresponding to blood cancer. In other words, in case when breast cancer treatment starts, even though displacement to other organs has not been identified, with assuming micro metastatic lesion may possibly exist in body, treatment is selected.
Existence /Non-existence of this micro metastatic lesion is assumed by pathological characteristic, like tumor diameter based on morphological studies, metastatic status of lymph node, histological type, nuclear atypicality level, but recently it is assumed by gene abnormality of cancer cell. Further, effect assumption for used drug is made simultaneously and local and entire body treatment method is to be reviewed. As you may understand by now, recent breast cancer treatment is changing from “One Size Fits All” therapy which is considered most effective treatment for the greatest numbers gained from large scale clinical examination, to Individual therapy based on individual characteristics.
As aforementioned, since the local treatment limitation becomes epidemic for breast cancer from the systemic disease characteristics, surgery or radiation therapy is requested to take less invasive method. Advancement on systemic treatment has contributed greatly for the improvement of local control, thus it influences a lot to less invasive treatment.
In the contrary, Oxford Overview has reported that the recurrence by incomplete local therapy may become one of reason for decline of survival rate. So that, instead of pursuing for cosmetics or low invasiveness easily, it is important to carefully review its adaptability. Also, the risk for local recurrence may vary with gene abnormality pattern or systemic treatment contents. Hereafter, it is necessary to review adaptation in considering above mentioned factors. Hereafter, regarding the breast cancer local treatment which is changing towards low invasive, it is explained with broadly divided group, breast conservation therapy, sentinel lymph node biopsy, and Partial Breast Irradiation.
Pectoral breast resection (Stereotypes of the mastectomy) established by Halstead in late 19th century lowered the postsurgical local recurrence rate with removing not only breast itself but also greater pectoral muscle underneath, so that it has been conducted as standard surgical treatment. In later days, Pectoral muscle preserving breast resection (Modified radical mastectomy) was introduced, but breast resection was the standard surgical method.
In 1980, randomized controlled trial was conducted at same time in Italy and USA, it reported that breast conservation therapy (full breast irradiation after breast conserving operation) showed the same level of survival rate and local recurrence rate with traditional breast resection operation. Supported by this report, breast conservation therapy is introduced as the alternate method to breast resection. Currently in Japan, 58.6% of breast cancer surgery is made by breast conservation therapy. (2011 Patient Registration Survey by Japanese Breast Cancer Society)
Lately, to improve postoperative cosmetics further, “Oncoplastic Surgery” concept aiming for both cure and cosmetics becomes popular. This means that in addition to positively conduct breast reconstruction surgery after breast resection, reduction mammaplasty on opposite side breast is added to make right/left breast in balanced.
Because breast cancer is often displaced to lymph node on under arm (axillary fossa), these lymph nodes has been all extracted (remove all) at the time of surgery. However, this axillary lymph node dissection becomes concerned about postsurgical complication disease, like a sense of discomfort on axillary. Also, it has a problem that the hospitalized period is getting longer because drain is left inside of the body. Especially at early stage where no axillary lymph node displacement occurs, omission of extraction is requested further. But lymph node displacement assumption is difficult by traditional image examination so that off-the-shelf axillary resection has been made then.
Therefore, sentinel lymph node where lymph in entire breast flow in at first has been focused. This sentinel lymph node is defined as lymph node where lymph fluid around the cancer flow in at first so that it is considered that lymph node displacement occurs at first. Sentinel Lymph Node Biopsy, where lymph node displacement status is presumed based on the existence or non-existence of lymph node displacement to decide the necessity of breast resection, has tried out to skin cancer in early period. Later days, clinical application has tried out for breast cancer with the method of using pigment or radioactive isotopes. At breast cancer surgical operation, examination is conducted with extracting sentinel lymph node, and in case displacement is negative, axillary resection is omitted as no other lymph displacement has occurred
Authors has been reported firstly in Japan the method of using radioactive isotope, but currently its safeness and effectiveness has been reassured by large scale clinical trial so that it is set as standard treatment for axillary lymph node. According to the research report conducted by Japan Breast Cancer Society, case where only sentinel lymph node biopsy is made, reaches to 58.9%. Recently at USA conducted clinical trial, it is reported that even omitting axillary resection to sentinel lymph node displacement positive case, with adding axillary exposure instead of axillary resection, same result has been achieved. From these facts, therefore, facility where omitting axillary resection to sentinel lymph node displacement positive case, are increasing.
In Breast conservation therapy, radiation therapy (full breast exposure) is made for five consecutive days in a week after conservation surgery and continued for 5 to 6 weeks, but this method requires not only enormous amount burden to patient but also concerned with complicate disease like interstitial lung disease, heart muscle inflammation or cardiac infarct since a part of lung or heart is included in radiation area. 3 weeks short period of radiation exposure is focused nowadays, but still burden to patients is large enough. And, as local recurrence after breast conservation therapy is developed mostly around the primary lesion, meanings of exposure to entire breast is questioned. Furthermore, as full breast exposure do not have preventive benefit for new breast cancer, breast partial exposure, which expose only at incision surroundings to which breast conservation surgery is conducted, is focused as an alternative method of full breast exposure.
Several methods are used for partial breast exposure, and clinical examination is made for each method and the effectiveness of them are to be reported. In each method, treatment is completed within 1 to 5 days hospitalization so that burden to patient gets minimized, but even though large scale clinical trial is taking place in USA mainly regarding the most appropriate hand skill, applicable case. American Society of Therapeutic Radiology and Oncology (ASTRO) has introduced a guideline for clinical application of breast partial radiation in 2009, and revised in 2016 showing the applied case increase, evidenced by report showing accumulated of its effectiveness.
Breast partial radiation therapy has been conducted in our facility by Intraoperative Open Cavity Implant (IOCI) method which uses brachy therapy immediate after surgery. This method is reported from European research group, Group European de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-RSTRO) regarding the non-inferiority against the full breast exposure, in 2015. Radiation exposure will complete within the first surgical hospitalization period, and health insurance program has been authorized in Japan. The burden to the patients are extremely less.
Entire body therapy for breast cancer is mainly by drug treatment, but its function is greatly different in supplemental treatment before/after surgery and recurred breast cancer. Before or after the surgery for primary lesion, treatment is called as preoperative/ postoperative supplemental therapy where micro metastasis resided in entire body are stamped out using drugs and aim for complete cure of cancer. On the other hand, for breast cancer, which has a displacement to other organs already, is difficult to completely cure so that treatment is aimed for maintaining the good quality of life (QOL) and aiming for life extension. It is therefore that the drugs used and its combination (therapy regimen) and dosage amount are all different.
In the supplemental therapy, it aims to exterminate the underlying micro metastasis, but it is impossible to identify existence/non-existence of micro metastasis thus it is assumed from the detail evaluation of primary lesion. Drug therapy can be grouped into; Hormone therapy, Chemotherapy, and molecular target therapy. And effect prognosis for used drugs as well as possible recurrence assumption are conducted. Based on these projection of prognosis and effect assumption, contents and their necessity of supplemental therapy are evaluated, but in addition to the traditional biological observation, depending upon the gene abnormality pattern, they are grouped as “Luminal A”, “Luminal b”, Her-2 enriched” and “Basal-like”, 4 types. These classification is named as “Intrinsic Subtype”. It has led from correlation with prognosis analyzed gene from the case of already prognosed breast cancer tissue.
Luminal A and Luminal B are together combined called as “Luminal Type. These cancers are like luminal cells forming of breast duct and contains estrogen or receptor (ER or PgR) against the progesterone so that hormone treatment is effective. In case the manifestation of HER2 Protein or Ki-67 are low, Luminal A, having lower risk of recurrence, and Luminal B having less PgR but strong in HER2 protein, are designated as high-risk breast cancer, so that the addition of chemotherapy is considered.
HER2-enriched type, where HER2 protein is one of protein like epidermal growth factor receptor exists on the surface of the cell, is involved in cell growth or malignant alteration as the result of overexpression on the surface of breast cancer cell. HER2-enriched type has been grouped as high recurrence rated breast cancer, but due to the appearance of molecular target therapy like Trastuzumab, treatment result has been improved greatly.
Existence of ER, PgR or HER2 protein are commonly negative in Basal-like so that it is called as “Triple Negative Breast Cancer” in the classification based on Immunohistological stain. Because of immune expression related with growth is high, it is high recurrence risk breast cancer but there contain many things which shows good response to chemotherapy. Currently, this type is further classified in detail and treatment for each type is trying out.
As abovementioned, decision of treatment policy based on gene analysis becomes possible in the usage of PAM50TM, which analyzes 50 gene expressions related with growth then to classify them, Oncotype DXTM which determine the necessity of recurrence risk and chemotherapy by similar analysis, or the usage of Mamma Print TM, but in Japan all of them are not subject to Health Insurance so that they are conducted based on Immunohistological stain. However classification by each method is not necessarily matched with, and also Ki67 which is important when Luminal type is further divided into details, discrimination standard has not yet established, so that the case is increasing where above mentioned gene diagnosis is made outside of health insurance.
Although treatment for metastatic breast cancer is expected for longer survival due to drug therapy advancement, it is still conducted with aiming for maintaining QOL. Therefore, hormone therapy, which has lessor side effect, is prioritized for metastatic breast cancer. When conducting chemotherapy, single drug treatment is considered basically, excluding the case where life is risked by metastatic lesion. Also, for the displacement to brain or stomach, maintaining QOL and improvement is tried by combined modality therapy like radiation exposure. In case for Oligo metastatic which displacement is limited, local therapy to metastatic lesion is evaluated. Besides, the benefit of resection of primary lesion against the metastatic breast cancer is reviewing in these days. Clinical examination is under go about right/wrong.
As shown below, latest entire body treatment in the supplemental therapy, like hormone therapy, chemotherapy and brief summary of molecular target therapy is explained.
When female hormone estrogen, one of steroid hormone, is joined to hormone receptor, fragmentation of cancer cell becomes aggressive and grows. Therefore, Hormone therapy is to inhibit estrogen coupling with receptor, or to weaken estrogen itself to control the growth. Approximately 70% of breast cancer has a receptor so that it is subject to hormone therapy, but drug medicine may differ because estrogen synthesis mechanism is different from before or after menopause.
Estrogen is produced in ovarium for female before menopause, at first stimulation is transferred from hypothalamic area to hypophysis, then estrogen is secreted from ovarium via gonadotropic hormone. Therefore, estrogen secretion is lowered using LH-RH Agonist formulations (goserelin or Leuprorelin).
As an anti-estrogen agent which is coupled to estrogen receptor and controls the cell growth, SERM (Tamoxifen, Citric acid Toremifene) are listed up. For the postsurgical supplemental therapy for female before menopause, dosage of LH-RH agonist formulation may conduct for 2 to 5 years, in addition to tamoxifen. Tamoxifen dosage period is set at 5 years as standard, effectiveness of dosing another 5 years is indicated so that there might be a case hormone therapy to before menopause female continues for 10 years period.
After menopause, male hormone produced in adrenal gland is converted to estrogen by aromatase, enzyme in fat tissue. Estrogen is reduced by inhibiting this aromatase, then it becomes possible to control breast cancer cell growth. In aromatase inhibitor, there is exemestane which steroid skeleton is contained, and non-steroidal aromatase inhibitors like anastrozole or letrozole. As there is no clinical trial where comparing these three agents under the same condition, but it is considered that they are no big difference. In the supplemental therapy, there are cases where initial: dosage for 5 years from first time, switch: start dosing 2 to 3 years after Tamoxifen dosage and continues for total 5 to 8 years and extended: 5 years dosage after tamoxifen 5 years dosage. For aromatase inhibitor, effectiveness of dosing 10 years is reported. In either cases, as longer period of dosing is necessary, it is said that the medication adherence becomes a problem and it is said that it may affect to the treatment effects.
Since the supplemental therapy is purposed to stamp out the micro metastasis underlying in the entire body, at the chemotherapy performance, it is important to have “Total cell Kill” concept based on cancer cell growth model (Goldie-Coldman hypothesis or Norton-Simon hypothesis). As variety of cancer cell could gain drug resistance even during chemotherapy is conducting, it is therefore prevention of drug resistance and anticancer efficacy need to be planned with using multiple drugs or increase dose intensity per unit time. Typical regimen is shown in Chart 1. Basically, taxane medical agent is combined with cycline medical agent, and use them, but in this case, it is commonly conducting sequential dosage which is not necessary to reduce each dosage amount. Recently, non-anthracyclines system regimen is conducted with concerning to the cardiac toxicity caused by anthracyclines medical agent
|Regimen Title||Medicine name and dosage amount||Dosage period|
|AC||doxorubicin 60mg/m2 IV
cyclophosphamide 600mg/m2 IV
|Per 2-3 weeks|
|EC||Epirubicin 100mg/m2 IV
|Per 2-3 weeks|
|FEC100||Fluorouracil 500mg/m2 IV
Epirubicin 100mg/m2 IV
|Per 3 weeks|
|TC||Docetaxel 75mg/m2 IV
|Per 3 weeks|
|(after AC/FEC) * Docetaxel||Docetaxel 100mg/m2 IV||Per 3 weeks|
|(after AC/FEC) Paclitaxel||Paclitaxel 80～100mg/m2 IV||every week|
In past days, chemotherapy is performed before surgery for surgically difficult disease like local breast cancer, but with knowing the objective of supplemental therapy, to stamp out underlying micro metastasis, the meaning of preoperative chemotherapy has been changed. In comparing preoperative chemotherapy with postoperative one, there are no difference in their result. So that for the case having a high probability of conducting postoperative supplemental therapy, preoperative chemotherapy is positively conducted. In performing preoperative chemotherapy, there is a case where cytoreduction makes conservative operation possible, for breast resection is necessary case, or a case where higher cosmetic surgery becomes possible. Furthermore, retrieving information becomes possible about drug receptivity or better prognosis is expected when reached to pathological remission status.
On the contrary, there is a case of tumor enlargement where no effect is seen, or stage becomes unknown.
When conducting supplemental chemotherapy, it is important to keep up dosage schedule. For hematological toxicity, maintaining the dose intensity is a critical issue. In Japan, G-CSF preventive usage becomes possible at first chemotherapy, so that effective supplemental therapy regimen is possible. For non-hematological toxicity, sick feeling or emesis become an issue, but the development of supportive therapy is progressing at same time.
Molecular target therapy means that the treatment is performed with targeting the abnormality in molecular level which is specific to cancer cell. Molecular target medicine is divided into Low Molecular Medicine (-nib) and Antibody drugs (-mab). The former one is a low molecular compound with molecular mass at 300 to 500 which may perform effectiveness by coupling with targeted protein, and it can go through blood-brain barrier. The latter one is a monoclonal antibody consists with molecular mass of 500 to 700 of protein. This performed an effect with exerting the receptor on the surface of cell membrane.
Treatment for breast cancer which overexpress HER2 (human epidermal growth factor receptor type 2) protein is the most advanced one. HER2 belongs to human epithelial cell growth factor receptor family and involves with the cell growth control as a growth factor receptor having tyrosine kinase activity. Numbers of copy show the abnormality in gene controlling coding of protein, so that the existing number of receptor on the surface of cell membrane increases. As the result, overexpressed HER2 protein is activated by phosphorylated tyrosine residue and involved in cell growth or malignancy via signaling cascade. Trastuzumab is a humanized monoclonal antibody corresponded to HER2 protein, and it controls cancer cell growth with specifically coupling to HER2 protein.
Trastuzumab is used to use for recurred breast cancer, but it becomes clear that the dosage for additional one year makes the recurrence rate 40% down. Trastuzumab dosage is considered as standard therapy for HER2 positive breast cancer, and there is a case where additional One-year dosage after the supplemental chemotherapy, or the case where dosage is made on top of chemotherapy as shown in chart 2. Recently, clinical trial is undergoing for new drug combined supplemental therapy with targeting HER protein like, Lapatinib; low molecular medicine which pass through cell membrane and directly couple with tyrosine kinase domain common to both HER1 and HER2, Pertuzumab which inhibit dimerization with other growth factor receptor like HER3, Trastuzumab emtansine which selectively exert anticancer efficacy with coupling high toxic tubulin polymerization inhibitor; emtansine to trastuzumab (T-DM1).
|Regimen name||Medicine name /Dosage amount||Dosing interval|
|(after AC) Paclitaxel + Trastuzumab||Paclitaxel 80mg/m2 IV
Trastuzumab 1st time 4mg/kg IV
After 2mg/kg IVs
|(after AC) *Docetaxel + Trastuzumab||Docetaxel 100mg/m2 IV
Trastuzumab 1st time 4mg/kg IV
After 2mg/kg IV
|Per 3 weeks
Every week/per 3 weeks
|TCH||Docetaxel 75mg/m2 IV
Carboplatin AUC 6 IV
Trastuzumab 1st time 4mg/kg IV
After 2mg/kg IV
|Per 3 weeks