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Review Article | DOI: https://doi.org/10.31579/2640-1053/220
*Corresponding Author: Ankita Pandey. Department of Radiotherapy and Oncology, PGIMER, Chandigarh, India.
Citation: Ankita Pandey, (2024), Then and Now: Non metastatic Breast cancer: A Review Literature, J Cancer Research and Cellular Therapeutics, 8(8); DOI:10.31579/2640-1053/220
Copyright: © 2024, Ankita Pandey. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 25 November 2024 | Accepted: 03 December 2024 | Published: 09 December 2024
Keywords: breast cancer; non- metastatic; breast conserving therapy; radiotherapy; brachytherapy boost; cosmetic outcome
Breast cancer is most common cancer worldwide among females. It is most thoroughly studied and investigated area in the field of oncology. It is disease of predominantly young females and has well known etiological factors. The management has evolved from extensive surgery in the past to the limited surgical excision. The awareness among females has also led to earl diagnosis and prompt management. The critical area of interest now lies in the field of radiation therapy where different techniques are used to enhance the local control and improve the cosmesis. This review article focuses on general outline of the anatomy, clinical features, diagnosis and management focusing on the evolution of the radiotherapy techniques especially in early stage breast cancer.
The term “Cancer” is derived from the Greek word “Karkinos” (for crab) which refers to a generic non-communicable disease (NCD) characterized by growth of malignant (cancerous or neo-plasms) abnormal cells (tumor/ lump) in any part of the human body. In spite of good advancements for diagnosis and treatment, cancer is still a big threat to our society.
The female breast lies on the anterior chest wall superficial to the pectoralis major muscle. The breast extends from the midline to near the mid-axillary line and cranial caudally from the second anterior rib to the sixth anterior rib. The upper outer quadrant of the breast extends into the region of the low axilla and is frequently referred to as the axillary tail of Spence. This anatomical feature results in the upper outer quadrant of the breast containing a greater percentage of total breast tissue compared with the other quadrants, and, therefore, a greater percentage of breast cancers occur in this anatomical location. The breast parenchyma is intermixed with connective tissue, which has a rich vascular and lymphatic network.
Extent
Figure 1: Coronal section of the breast and the inner structure
The predominant lymphatic drainage of the breast is to axillary lymph nodes, which is commonly described in three levels, based on the relation of the lymph node regions to the pectoralis minor muscle.
| Lymph node level | Anatomic relation |
| Level I | Caudal and lateral to the pectoralis minor muscle |
| Level II | Below the pectoralis minor muscle |
| Level III | Cranial and medial to the pectoralis minor muscle |
Table 1: Lymph nodal levels of breast and its relation to the anatomical structures
Other group of lymph nodes involved are-
Cancer of the breast is one of the most common cancers among women worldwide. In 2018, this was about 11.6% of the total cancer cases in both sexes. In India, breast cancer is now most common cancer and accounts for 14% of all cancer cases. It has been estimated that in 2018, worldwide there were 2088849 cases of breast cancer, and 626679 deaths due to breast cancer. A large proportion of the global burden occurs in the developed countries where it accounts for almost 24.2% of all female cancers. Although breast cancer incidence is high in developed countries compared to India, the mortality rate in India is high (6.6% vs 12.1%)[1]. India continues to have a low survival rate for breast cancer, with only 66.1% women diagnosed with the disease between 2010 and 2014 surviving, a Lancet study found. According to estimates, at least 17,97,900 women in India may have breast cancer by 2020 [2]. India is the largest country among all countries of Southern Asia. It has a population of 432.20 million women aged 15 years and older who are at risk of developing breast cancer. Current estimates of GLOBOCAN 2018 indicate that every year in India 162468 women are diagnosed with breast cancer and 87090 die from the disease. Breast cancer in India varies from as low as 5 per 100,000 female population per year in rural areas to 30 per 100,000 female population per year in urban areas [3].
| Indian cities | Breast cancer percentage | Crude rate per 100000 | Age adjusted rank per 100000 |
| Mumbai | 28.8 | 33.6 | 33.6 |
| Bangalore | 27.2 | 29.3 | 34.4 |
| Chennai | 30.7 | 40.6 | 37.9 |
| Thiruvananthapuram | 28.5 | 43.9 | 33.7 |
| Dibrugarh | 19 | 12.7 | 13.9 |
| New Delhi | 28.6 | 34.8 | 41 |
| Barshi rural | 20 | 13.2 | 12.4 |
Table 2: Ranking and rates for breast cancer (NCRP 2012)
The majority of patients with T1 or T2 breast cancers presents with a painless or slightly tender breast mass or have an abnormal screening mammogram. Patients with more advanced tumors may have breast tenderness, skin changes, bloody nipple discharge, or occasionally change in the shape and size of the breast. Rarely, patients may present with axillary lymphadenopathy or even distant metastasis. The duration of clinical symptoms may vary from weeks to years. Olivotto et al.,found that delays in diagnosis of 6 to 12 months led to an increased tumor size and more lymph node metastases compared with patients diagnosed within 2 to 4 weeks of an abnormal screening mammogram[4].
Age incidence rates in India suggest that the disease peaks at a younger age (eg, 40-50 years) than in Western countries and as a result, the majority of new diagnoses occur in pre-menopausal women. Raina et al, found the mean age at diagnosis was 47 years and 49.7% were premenopausal, 96% presented with lump[5]. Most advanced primary tumors are associated with axillary lymph node involvement. Local disease progression can lead to ulceration of skin, pain, bleeding infection. Progression of untreated regional lymphatic disease can cause pain, brachial plexopathy, arm edema, obstruction and thrombosis of brachial vasculature and skin ulceration.
Clinical evaluation and Diagnostic work- up
Includes age, early menarche, late menopause, prolonged use of HRT, family history, lower parity, BRCA1 or 2 mutation[6]. MacMahaon et al., demonstrated a nearly linear relationship between relative risk of breast cancer and age at first child birth with women age 20 to 25 having nearly 50%reduction in relative risk compared to nulliparous women. They also demonstrated that in comparison to women having menopause between 45 to 54 (relative risk 1), women with menopause before 45 have a relative risk of 0.73% and women with menopause after 54 have a relative risk of 1.48[7].
Women with a second degree relative with breast cancer have risk of 1.5 and for women with first degree relative the risk is about 1.7 to 2.5. Between 20 to 25% of women diagnosed with breast cancer have a positive family history and approximately 10% have an autosomal dominant pattern of inheritance[8]. A pooled analysis of prospective studies by Van den et al in 2000 demonstrated risk of breast cancer to be 30% higher in post menopausal women with BMI over 31 compared to women with BMI of 20.The higher risk with increased BMI in post menopausal women is likely due to higher estradiol levels associated with increased adipose tissue and aromatase activity, involved in conversion of androgen to estradiol [9]. Other important risk factors being personal history of breast cancer, radiation exposure to chest wall alcohol consumption, increased mammographic density.
Breast cancer screening guidelines are given by-
| Age group | ACS (2003) GUIDELINE |
| 20-39 yr | BSE optional; CBE every 3 years. |
| 40-49 yr | Annual mammography and CBE from 40 years. |
| >49yr | Annual mammography and CBE as long as a woman is in reasonably good health. |
| Age group | NCI (2002) GUIDELINE |
| 20-39 yr | No recommendation |
| 40-49 yr | Mammography every 1–2 years |
| >49yr | Mammography every 1–2 years |
Preoperative assessment of tumor size is commonly estimated by inspection and palpation. The accuracy of clinical assessment is influenced by patient and observer factors and is not useful for clinically occult tumors and is prone to overestimating actual tumor size[10]. Clinical examination has been found to have low sensitivity and specificity (36% and 39% respectively) in the evaluation of axillary lymph nodes. It cannot assess the number of nodes, nodes in depth and nodes of small size. Also it cannot distinguish between reactive and malignant nodes or detect extra capsular extension [11]. Physical examination alone has long been recognized as inaccurate in predicting axillary metastases, and is associated with false negative and false positive rates of 25% to 38%. Internal mammary group of lymph nodes are clinically not evaluable [12].
Mammograms are by far the most common breast cancer screening tool and bilateral mammograms should be performed routinely in the work-up of the breast cancer patient. Mammography uses low energy x-rays to examine the compressed breast. Contrast in mammography results from differences in the absorption or attenuation of x-rays by different tissues in the breast. This technique has been in use for about 40 years and is the current gold standard for diagnosing breast disease. In mammography, lymph nodes are visible on standard projections, and it is possible to differentiate between normal and pathological nodes. Normal nodes are moderately attenuated, the fatty hilus being seen as a low attenuated part. Normal nodes can vary in size from a few millimeters to several centimeters. Pathological nodes are of greater density than normal nodes and the hilum disappears. The form also becomes more expanded from oval to round but the size is not necessarily increased. However, in the standard projections, only part of axilla can be seen, and during exposure of the mammogram, pathological nodes can be pushed outside the mammographic image. Mammography is therefore not a reliable method in axillary lymph node imaging. The Breast Imaging Reporting and Data Systems (BI-RADS) classification system, outlined below has been widely adopted in classifying mammograms with respect to appropriate follow-up and/or intervention [13].
Table 3: American College of Radiology Breast Imaging Reporting and Data Systems (BI-RADS) Assessment Categorize Mammography
| Category 1 Negative | There is nothing to comment on. The breasts are symmetric and no masses, architectural disturbances, or suspect calcifications are present. |
| Category 2 Benign finding | This is also a negative mammogram, but the interpreter may wish to describe a finding. Involuting, calcified fibroadenomas, multiple secretory calcifications, fat-containing lesions such as oil cysts, lipomas, galactoceles, and mixed-density hamartomas all have characteristic appearances, and may be labeled with confidence. The interpreter might wish to describe intramammary lymph nodes, implants, and the like, while still concluding that there is no mammographic evidence of malignancy. |
| Category 3 Probably benign finding short-interval follow-up suggested | A finding placed in this category should have a very high probability of being benign. It is not expected to change over the follow-up interval, but the radiologist would prefer to establish its stability. Data are becoming available that shed light on the efficacy of short-interval follow-up. At present, most approaches are intuitive. These will likely undergo future modification as more data accrue as to the validity of an approach, the interval required, and the type of findings that should be followed. |
| Category 4 Suspicious abnormality biopsy should be considered | These are lesions that do not have the characteristic morphologies of breast cancer but have a definite probability of being malignant. The radiologist has sufficient concern to urge a biopsy. If possible, the relevant probabilities should be cited so that the patient and her physician can make the decision on the ultimate course of action. |
| Category 5 Highly suggestive of malignancy appropriate action should be taken | These lesions have a high probability of being cancer. |
Category 0
| Finding for which additional imaging evaluation is needed. This is almost always used in a screening situation and should rarely be used after a full imaging workup. A recommendation for additional imaging evaluation includes the use of spot compression, magnification, special mammographic views, ultrasound, and so forth. |
Ultrasound, also called sonography, uses high frequency sound waves to penetrate breast tissue and measures the reflection from different tissues in the breast. Due to inability to consistently detect early signs of cancer such as microcalcifications, ultrasound is not routinely used for breast cancer screening but primarily to distinguish solid tumors from fluid filled cysts, evaluate suspected carcinomas in mammographically dense breasts and for biopsy guidance[14]. Sonography is an important adjunct to mammography to identify, characterize, and localize breast lesions, and it has the added advantage of not being limited by dense breasts. It also has no radiation or compression. Consequently, sonography is more effective for women younger than 35 years of age[15]. Breast ultrasound examinations can obtain any sectional image of breast, and observe the breast tissues in real-time and dynamically. Ultrasound imaging can depict small, early-stage malignancies of dense breasts, which is difficult for mammography to achieve.
Magnetic Resonance Imaging (MRI) is emerging as a promising tool for screening breast cancer especially among high risk women. MRI has also demonstrated greater sensitivity in detecting small (less than 1 cm) lesions and succeeds in certain scenarios where other imaging modalities are challenged, such as imaging dense breasts, the post-operative breast and augmented breasts. In a review of MRI in the management of breast cancer, Hylton summarized the potential for the current use of MRI: to complement mammography in screening, for differential diagnosis of questionable findings on physical examination, mammography, and ultrasound; and assessment of response in the Neoadjuvant treatment of breast cancers[16]. The American Society of Breast Surgeons has outlined indications for the use of breast MRI. These include axillary nodal metastasis with unknown primary, determination of ipsilateral or contralateral disease in newly diagnosed breast cancer patients with invasive lobular cancer, difficult mammographic assessments, monitoring response to Neoadjuvant therapy, screening of high-risk patients, and evaluation of suspicious clinical findings or imaging studies with indeterminate work-ups. Drawbacks of MRI include moderate diagnostic specificity, false-positive findings requiring additional biopsies, patient distress, prolongation of the pre surgical work-up and the potential for overestimation of tumor size and higher cost[17].
Breast Cancer Diagnosis
Histopathological or cytological examination is the only definitive way to determine whether a mass is malignant or benign. As such, abnormalities detected with any of the afore-discussed techniques might be queried by biopsy. Common forms of breast biopsy include fine needle aspiration (FNA), core biopsy, vacuum assisted biopsy and open surgical biopsy. Breast biopsy of any suspicious mass is mandatory. The biopsy usually can be done using local anesthesia; the patient should be informed of the nature of the lesion to allow for her greater participation in therapeutic decisions. There has been no evidence that delay in treatment up to 2 weeks after biopsy worsens prognosis[18].
Prognostic factors in breast cancer
In patients of carcinoma breast undergoing single or multimodality treatment, outcome of treatment depends on various prognostic factors present before treatment.
The prognostic factors are
Stage at diagnosis is the best predictor of prognosis. Early stage breast cancer is curable in most patients by surgery +/- radiotherapy, with 5-year survival of 95%. Size of tumor is another prognostic factor in carcinoma breast. According to Carter et al., survival rates varied from 45.5% for tumor diameters equal to or greater than 5 cm with positive axillary nodes to 96.3% for tumors less than 2 cm and with no involved nodes. The relation between tumor size and lymph node status was investigated in detail. Tumor diameter and lymph node status were found to act as independent but additive prognostic indicators. As tumor size increased, survival decreased regardless of lymph node status; and as lymph node involvement increased, survival status also decreased regardless of tumor size. A linear relation was found between tumor diameter and the percent of cases with positive lymph node involvement[19].
Rosen et al., found a close correlation between tumor size and recurrence free survival[20].
| Tumor size | Recurrence free survival |
| <1cm> | 88% |
| 1.1 to 3cm | 72% |
| 3.1 to 5cm | 59% |
Table 4: Corelation of tumor size and recurrence free survival according to Rosen et al.
According to the number of axillary lymph nodes involved, patients are grouped into four prognostic categories
Although up to 30% to 40% of T1 or T2 clinically node-negative breast cancers may have pathologically involved lymph nodes, data from NSABP-04 suggest that less than half of clinically negative but pathologically positive axilla will experience a clinical relapse in the axilla.
Tumor Location | Axillary lymph node status | Rate of involvement of axillary lymph node |
| Medial/ central | 0 + ALN 1-3 + ALN 4-6 + ALN ≥7 + ALN | 6% (27/428) 26% (41/160) 43% (21/49) 40% (44/110) |
| Lateral | 0 + ALN 1-3 + ALN 4-6 + ALN ≥7 + ALN | 3% (12/456) 14% (34/238) 20% (18/90) 43% (63/148) |
Breast cancer is now considered to be a systemic disease from the outset, with most patients with early breast cancer developing metastases whatever the treatment undertaken. The need for and selection of therapy is based on a number of prognostic & predictive factors. They include tumor histology, clinical and pathologic characteristics of the primary tumor, axillary node status, tumor hormone receptor content, tumor HER2 receptor, presence or absence of detectable metastatic disease, patient comorbid conditions, patient age and menopausal status. Breast cancer therapy comprises local treatments and systemic treatments and often a combination of both. Local treatments include surgery and radiation. The aim of local treatments is to eradicate the disease at source or the primary tumor. Systemic treatments such as chemotherapy and hormone therapy are generally directed against the metastasis as well as locally.
Chemotherapy in non-metastatic breast cancer:
Even following effective local treatment, many patients develop metastasis over time and improvements in local control have been shown to provide, at best, only a small decrease in distant metastasis[18,21]. This was thought to be because of the concept of micrometastasis at the time of initial presentation. This led to the generation of the concept of systemic therapy for accomplishing long term improvement in the outlook of the disease.
The NSABP (National Surgical Adjuvant Breast & Bowel Project) evaluated the effect of adding cyclophosphamide to methotrexate and 5 fluorouracil (CMF) in the B-19 study. Estrogen negative (ER) negative patients underwent 6 months of treatment with either CMF or MF after surgery. Disease free survival (DFS) rates were statistically significantly higher for those taking CMF (82 vs 73%, p < 0>
C9344 (Henderson C et al , 2003)[24] | B28 (Mamounas EP et al, 2003)[25] | C9741 (Nabholtz JM et al, 2002)[26] | BCIRG 001 (Nabholtz JM et al, 2001)[27] | |
| N | 3170 | 3060 | 2005 | 1491 |
| Median follow-up | 69 months | 65 months | 36 months | 33 months |
| Superior Arm | AC --> P | AC --> P | AC --> P or A --> P --> C every 2 weeks | DAC |
| DFS Hazard Ratio | 0.83 (p = .0098) | 0.83 (P = 0.008) | 0.74 (P = .01) | 0.68 (P = .0002) |
| Death Hazard Ratio | 0.82 (p = .0098) | NS | 0.69 (P = .013) | 0.76 (P = .049) |
Table 5: Comparison of Breast Cancer Trials Evaluating Taxanes
Hormonal therapy in non metastatic breast cancer:
Estrogen, a hormone produced by the ovaries, promotes the growth of many breast cancers. Women whose breast cancers test positive for estrogen receptors can be given hormone therapy to block the effects of estrogen on the growth of breast cancer cells. Tamoxifen, the most common antiestrogen drug, is effective in both postmenopausal and premenopausal patients whose cancers are positive for hormone receptors. Recurrence and survival benefits generally increase with longer duration of tamoxifen use and have been shown to persist for at least 10 years following treatment[28].
Preliminary results of the ATLAS (Adjuvant Tamoxifen, Longer Against Shorter) International randomized trial of 10 versus 5 years of adjuvant tamoxifen among 11500 women showed that continuation of tamoxifen beyond the first 5 years reduces recurrence over the next few years, but further follow-up is needed to assess reliably the longer-term effects on recurrence and the net effects, if any, on mortality[29].
More recently, Trastuzumab has been shown to be effective in early-stage breast cancer that overexpresses HER2. The combined results of two large trials indicate that adding Trastuzumab to standard chemotherapy for early-stage HER2 positive breast cancer reduced the risk of recurrence and death by 52% and 33%, respectively, compared to chemotherapy alone[30]. In 2006, the FDA approved Trastuzumab for all HER2 positive breast cancers. All invasive breast cancers should be tested for the HER2 protein in order to identify women who would benefit from this therapy.
Surgery:
The primary goal of breast cancer surgery is to remove the tumor from the breast and to assess the stage of disease. The various surgical options are:
Lumpectomy - In lumpectomy, only cancerous tissue plus a rim of normal tissue is removed.
Simple/Total mastectomy - includes removal of the entire breast.
Radical mastectomy- Radical mastectomy is rarely used due to the proven effectiveness of less aggressive and disfiguring surgeries.
Modified radical mastectomy- This includes removal of the entire breast and lymph nodes under the arm, but does not include removal of the underlying chest wall muscle, as with a radical mastectomy.
Breast conserving therapy in early stage breast cancer cases
Breast conserving therapy include
Wide local excision with clear margins
Axillary lymph node dissection
Irradiation to whole breast with tumor bed boost or partial breast irradiation
The earliest prospective trial by Atkins et al in 1972 comparing breast conservation with radical mastectomy which included 370 women with stage I and II breast cancer showed no survival benefit for stage I disease, in stage II the recurrence rates and distant metastasis were higher in the group treated with local excision followed by irradiation. The EORTC Breast Cancer Cooperative Group comparing radical mastectomy with breast conservation showed actuarial 8 years local control was similar in both arms. The U.S. National Cancer Institute reported results of randomised study in T1-2/N0/M0 breast cancer treated with modified radical mastectomy or breast conservation, there was no difference with regard to overall survival, with median follow up of 18.4 years. In1971, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated the B-04 study, a randomized clinical trial conducted to resolve controversy over the surgical management of breast cancer. The 25-year findings from that study showed that there was no significant difference in survival between women treated with the Halsted radical mastectomy and those treated with less extensive surgery[12]. NSABPB-06 TRIAL evaluated the efficacy of breast-conserving surgery in women with stage I or II breast tumors that were 4 cm or less in diameter. The outcome for women who were treated with lumpectomy alone or with lumpectomy and postoperative breast irradiation was compared with that for similar women who were treated with total mastectomy. There was no significant differences in survival among the women in the three treatment groups and demonstrated a significant decrease in the rate of recurrent cancer in the ipsilateral breast after lumpectomy plus irradiation[31]. Bartelink et al., studied the long-term impact of a boost radiation dose on local control, fibrosis, and overall survival for patients with stage I and II breast cancer who underwent breast conserving therapy. They concluded that After a median follow-up period of 10.8 years, a boost dose of 16 Gy led to improved local control in all age groups, but no difference in survival at 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the no boost and the boost group, respectively (P < .0001). Severe fibrosis was statistically significantly increased (P <.0001) in the boost group, with a 10-year rate of 4.4% versus 1.6% in the no boost group (P<.0001). Survival at 10 years was 82% in both arms[32,33]. The meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) revealed the need for radiotherapy after tumorectomy by showing that breast irradiation reduced the 5-year local recurrence rate from 26% to 7%.
The UK Standardisation of Breast Radiotherapy (START) Trial A randomized 2236 women with early breast cancer (pT1-3a pN0-1 M0) between 1998 and 2002, to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks after primary surgery. After a median follow up of 5.1 years the rate of local-regional tumor relapse at 5 years was 3.6
Nil
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