The Extrinsic Effect Of Targeted Therapy
Fig. 4: The effects of cell-extrinsic and cell-intrinsic determinants in dictating breast cancer outcomes.
Part I The journey of a breast cancer patient from the development of undetectable disease and its clinical discovery , through its surgical removal and adjuvant ET , to metastatic relapse and death . The presence of tumour lesions across the body is indicated by starsthe smaller referring to the clinically undetectable ones , the bigger ones to the clinically detectable ones . Part II The development of an HR+ breast tumour lesion in the breast , comprising a mixture of ER+/PR+ and ER/PR cells . DTC escape from the primary site can occur early and/or late during tumorigenesis , although the HR phenotype of DTCs at these stages is often unclear. Bones, lungs and liver are represented as common secondary sites for breast cancer metastases, albeit the sequential patterns of DTC spread among these organs are still elusive . Targeted treatment for HR+ breast cancer patients relies on adjuvant ET. Several mechanisms of ET resistance cytostasis, ESR1 mutations and HR function regulationcontribute to DTC outgrowth. DTC disseminated tumour cell, ER oestrogen receptor, ET endocrine therapy, HR hormone receptor, PR progesterone receptor. Figure created with BioRender.com.
Management Of Breast Cancer
Surgery and radiation therapy, along with adjuvant hormone or chemotherapy when indicated, are considered primary treatment. Surgical therapy may consist of lumpectomy or total mastectomy. Radiation therapy may follow surgery in an effort to eradicate residual disease while reducing recurrence rates. There are 2 general approaches for delivering radiation therapy:
- External-beam radiotherapy
Surgical resection with or without radiation is the standard treatment for ductal carcinoma in situ.
Pharmacologic treatment for metastatic breast cancer is typically selected according to the molecular characteristics of the tumor. Agents used include the following :
- Hormone therapy
- HER2-targeted therapy
- CDK4/6 inhibitors
- mTOR inhibitors
- PIK3CA inhibitors
In patients receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture, the monoclonal antibody denosumab or either of the bisphosphonates zoledronic acid and pamidronate may be added to the treatment regimen to increase bone mass. These agents are given along with calcium and vitamin D supplementation.
Two selective estrogen receptor modulators , tamoxifen and raloxifene, are approved for reduction of breast cancer risk in high-risk women. Prophylactic mastectomy is an option for women found to be at extremely elevated risk.
Menstrual And Reproductive History
Starting menstrual periods at a younger age or going through menopause at a later age raises the bodys exposure to these hormones, which can increase a persons risk of breast cancer.
Females who have never given birth at full-term and those who had their first full-term pregnancy after the age of 30 years also have a higher risk of breast cancer, according to the NCI.
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Swog Researchers Demonstrated That A Blood Serum Test Can Identify Which Patients With Metastatic Hormone Receptor
PORTLAND, OR & dash Researchers with the SWOG Cancer Research Network have found that patients with metastatic hormone receptor-positive breast cancer who have low activity levels of the enzyme sTK1 in their blood serum at the start of anti-estrogen treatment live longer and go longer without their disease progressing than patients with high levels.
The results suggest that patients with low sTK1 activity levels have slow-growing disease that can be controlled initially with single-drug endocrine therapy for a prolonged period. It remains to be determined whether these patients gain further benefit from adding a CDK4/6 inhibitor to their endocrine therapy.
The findings come from an analysis of serum samples from 432 women with breast cancer who took part in the S0226 clinical trial, which was conducted by the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute , part of the National Institutes of Health . Results are published today in Clinical Cancer Research, a journal of the American Association for Cancer Research.
SWOG researchers have demonstrated that a blood serum test can identify which of these patients have slow-growing disease that might be controlled with a simple aromatase inhibitor pill alone, said Dr. Lajos Pusztai, M.D., DPhil, professor of medicine at Yale Cancer Center, who is a co-author on the paper.
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Reproductive Factors And Steroid Hormones
Late age at first pregnancy, nulliparity, early onset of menses, and late age of menopause have all been consistently associated with an increased risk of breast cancer. Prolonged exposure to elevated levels of sex hormones has long been postulated as a risk factor for developing breast cancer, explaining the association between breast cancer and reproductive behaviors.
Clinical trials of secondary prevention in women with breast cancer have demonstrated the protective effect of selective estrogen receptor modulators and aromatase inhibitors on recurrence and the development of contralateral breast cancers. Use of SERMs in women at increased risk for breast cancer has prevented invasive ER-positive cancers. These data support estradiol and its receptor as a primary target for risk reduction but do not establish that circulating hormone levels predict increase risk.
A number of epidemiologic and pooled studies support an elevated risk of breast cancer among women with high estradiol levels. The Endogenous Hormones and Breast Cancer Collaborative Group reported a relative risk of 2.58 among women in the top quintile of estradiol levels.
A meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer of 58 international studies that included 143,887 postmenopausal women with invasive breast cancer and 424,972 without breast cancer concluded the following about menopausal HRT and breast cancer :
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Local Treatment: Surgery And Radiation
If you receive a diagnosis of stage 1 breast cancer, your doctor may recommend local treatments such as surgery and radiation therapy to treat your breast cancer at the site.
Both lumpectomy and mastectomy are options for stage 1 breast cancer. Your doctor will help determine what is right for you based on the tumor size, grade, and level of spread.
- Lumpectomy. Also known as breast-conserving surgery, a lumpectomy is the least invasive surgery for breast cancer. With this procedure, a surgeon will remove the tumor and some surrounding tissue, but will leave as much of your breast as possible so that it looks a lot like the original breast.
- Mastectomy. A mastectomy involves the removal of the entire breast. There are different types of mastectomies. Some types of mastectomies involve the removal of the lymph nodes. Other types can preserve the breast skin or the nipple and areola, especially with early stage breast cancer.
Doctors typically recommend radiation therapy after a lumpectomy for stage 1 breast cancer treatment. Radiation therapy helps destroy any cancer cells that may have been left behind after the surgery. This helps lower the chance of the breast cancer coming back.
Radiation is less often needed after a mastectomy with stage 1 breast cancer.
Beyond local treatments, your doctor might recommend systemic treatments for stage 1 breast cancer.
Cellular Changes And Aging
With aging, some cells achieve proliferative senescence, remaining biologically active without cell division. Replicative senescence has been documented in stromal fibroblasts in vitro cells undergo a finite number of divisions and then enter a state of irreversibly arrested cell growth. These cells are resistant to apoptosis, release tumor growth factors and enzymes, and are vulnerable to cellular dysregulation. If cells escape from this regulated environment, they may be highly susceptible to malignant transformation. These characteristics may provide a favorable environment for carcinogenesis and tumor growth.
Age-related alterations in growth factor production and activity, metalloproteinase expression, hormonal status, inflammation, and immune cell number and function may contribute to changes in tumor biology and expression of cancers in the elderly.
Axillary Lymph Node Status
Axillary nodal status is known to be the principal prognostic factor.
Many women in older age are deprived of this tool, mainly for three reasons: 1) Comorbidities affecting the possibility of adjuvant therapy 2) a poor life expectancy 3) avoidance of morbidity related to axillary surgery. Martelli et al, have studied the possibility to spare lymphectomy to older women in a randomized trial on 219 women aged 65-80, with early BC. They found just a 2% of clear axillary metastatic involvement at 5-years follow up . A survey on the same sample at 15 years follow up showed no differences in OS between patients undergone axillary dissection and those who did not . Only few studies include longer than 5-years follow up in patients with early stage cancer but, as already observed, it is difficult to find longer follow-ups in this class of age .
Albrand and Terret in their review agreed with the SIOG recommendation to treat axillary node in the elderly not differently than in younger women .
Since sentinel node biopsy has been introduced, at least for suitable patients , the axillary morbidity should no longer be a problem .
Various other scoring systems have been proposed to simplify and improve the predictivity of this procedure. All these tools have been compared with the MSKCC nomogram. Among these, the Turkish score , the Cambridge nomogram , the Mayo nomogram , the Tenon score and the Stanford online calculator .
Biological Models Of Metastasis Dormancy
Before this discussion, it is necessary to define the key parameters of an experimental model for ER+ metastasis dormancy. Such models need to have several key features. 1) Recapitulation of several characteristics of human ER+ tumors including estrogen-dependence, growth inhibition by anti-estrogen strategies, as well as the potential to develop resistance to these treatments. 2) Recapitulation of the natural progression of ER+ tumors, including tumorigenesis, local invasion and intravasation, and the temporal kinetics and anatomical site of metastasis . 3) Opportunities to investigate the roles of major cell types that may be involved in dormancy. In subsequent paragraphs, we will go through the major models/techniques that have been used in breast cancer and point out their strengths and weaknesses for dormancy research. It needs to be noted here that although the abovementioned properties are highly desirable, models lacking these features may still generate useful information. For instance, late recurrences are not exclusively ER+, and the mechanistic insights obtained from ER- models may also be relevant to ER+ diseases.
The roles of Coco and VCAM-1 in metastasis dormancy
Physical Emotional And Social Effects Of Cancer
In general, cancer and its treatment cause physical symptoms and side effects, as well as emotional, social, and financial effects. Managing all of these effects is called palliative care or supportive care. It is an important part of your care that is included along with treatments intended to slow, stop, or eliminate the cancer.
Supportive care focuses on improving how you feel during treatment by managing symptoms and supporting patients and their families with other, non-medical needs. Any person, regardless of age or type and stage of cancer, may receive this type of care. And it often works best when it is started right after a cancer diagnosis. People who receive supportive care along with treatment for the cancer often have less severe symptoms, better quality of life, and report that they are more satisfied with treatment.
Supportive care treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional and spiritual support, and other therapies.
Music therapy, meditation, stress management, and yoga for reducing anxiety and stress.
Meditation, relaxation, yoga, massage, and music therapy for depression and to improve other mood problems.
Meditation and yoga to improve general quality of life.
Acupressure and acupuncture to help with nausea and vomiting from chemotherapy.
Screening For Breast Cancer
Women aged between 50 and 74 are invited to access free screening mammograms every two years via the BreastScreen Australia Program.
Women aged 40-49 and 75 and over are also eligible to receive free mammograms, however they do not receive an invitation to attend.
It is recommended that women with a strong family history of breast or ovarian cancer, aged between 40 and 49 or over 75 discuss options with their GP, or contact BreastScreen Australia on 13 20 50.
Factors That Affect Growth Rate
A number of studies have identified other factors that affect the rate of growth of a breast cancer. These include:
- The type of cancer: Inflammatory breast cancer tends to grow much more quickly than other types of breast cancer.
- Age at diagnosis: Breast cancers in young women tend to grow more rapidly than breast cancers in older women. They also have a higher tumor grade.
- Menopausal state: Breast tumors often grow more rapidly in women before menopause than they do in postmenopausal women. This is likely due to estrogen in the body.
- Receptor status: Triple negative cancers, in general, grow more rapidly than estrogen receptor-positive tumors. Triple positive tumors also grow more rapidly.
- Estrogen treatment: Women who used hormone replacement therapy after menopause had, in general, more rapid growth rate of breast tumors.
- Ki-67 index: This measures a specific tumor marker. A higher index means a faster doubling time.
- Tumor grade: This describes what the cells look like. A higher tumor grade indicates a faster doubling time.
Hormone Receptor Status And Prognosis
Hormone receptor status is related to the risk of breast cancer recurrence.
Hormone receptor-positive tumors have a slightly lower risk of breast cancer recurrence than hormone receptor-negative tumors in the first 5 years after diagnosis .
After 5 years, this difference begins to decrease and over time, goes away .
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Age At The Time Of Diagnosis Affects Breast Cancer Survival Rates
It has always been known that curiously, young women have a poorer prognosis than older ones
Indeed, one cohort study examined 4,453 women with breast cancer between 1961 and 1991 who were all treated at the same center.
This study found that both ends of the age spectrum fared less well. So, women under the age of 40 years at diagnosis and those over 80 years had a statistically poorer prognosis.
However, for younger women, this may be due to the fact that they often present with higher-grade tumors that tend to be more aggressive and less likely to be hormone receptor-positive. This means that breast cancer may not respond as well to treatment.
So, it is important to bear in mind other factors discussed in this post, such as stage, grade and hormone receptor status play an important role in prognosis.
How To Get Screened For Breast Cancer
If you notice youve experienced some of the symptoms of senior breast cancer, visit the doctor as soon as possible. Not next week, not next month. As soon as the doctor can fit you in. When making the appointment, you should note you the symptoms you have experienced. You should also get a yearly test even if you arent showing any symptoms.
Your doctor will perform a handful of tests to determine if your symptoms are the result of the presence of cancer in your breasts. Some of these tests include:
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Understanding Breast Cancer Survival Rates
Prognosis varies by stage of breast cancer.
Non-invasive and early-stage invasive breast cancers have a better prognosis than later stage cancers .
Breast cancer thats only in the breast and has not spread to the lymph nodes has a better prognosis than breast cancer thats spread to the lymph nodes.
The poorest prognosis is for metastatic breast cancer . This is when the cancer has spread beyond the breast and nearby lymph nodes to other parts of the body.
Learn more about breast cancer treatment.
Types Of Breast Cancer We Treat
At Stony Brook University Cancer Center, our team of experts specialize in breast cancer care. Breast cancer is not a single disease. There are many different forms of breast cancer, and each type may have multiple variations. We provide comprehensive diagnostics and multidisciplinary treatment for the following cancers:
NONINVASIVE BREAST CANCERIf you are diagnosed with a noninvasive breast cancer, it means that your disease is confined to the milk ducts, where it started. A noninvasive cancer has not spread to anywhere else in the breast or to other parts of the body.
Ductal Carcinoma in Situ This is the most common form of noninvasive breast cancer. Ductal refers to the milk ducts in the breast, and in situ means in its original place. DCIS is a stage 0 cancer, which is the earliest and generally the most treatable form of breast cancer. Although DCIS is noninvasive when its diagnosed, over time it can become invasive. This means that, for some women, the cancer may spread from its original site. Thats why treatment for DCIS is usually recommended. Treatment could include a lumpectomy, which is surgery that removes the cancer tumor while sparing the breast. Radiation may follow surgery, or hormone therapy may be recommended depending on your individual circumstances.
There are six specific types of Invasive Ductal Carcinoma , which all begin in the milk ducts and then spread into healthy breast tissue:
ADDITIONAL TYPES OF BREAST CANCER
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What Are The Stages Of Invasive Lobular Carcinoma
Invasive lobular carcinoma is divided into four stages. Staging is based on several factors, including the size of the tumor, where its located and how far it has spread:
- Stage 1: The tumor is up to 2 centimeters across and may have spread to nearby lymph nodes.
- Stage 2: At this stage, the tumor may be about 2 cm across and the cancer has spread to nearby lymph nodes. Or, the tumor has grown up to 5 cm across and the cancer hasnt spread to nearby lymph nodes.
- Stage 3: The cancer may have spread to lymph nodes, but hasnt spread to distant sites like other organs in your body. In some cases, the cancer may have spread into your chest wall.
- Stage 4: The cancer may or may not have spread to nearby lymph nodes. The cancer has spread to distant lymph nodes or organs, which may include your liver, lungs, bone or brain. Stage 4 is also referred to as metastatic breast cancer.