Breast Cancer Occurring during Pregnancy - Research Paper Example

 Breast Cancer in Pregnancy Abstract Key words, Breast Cancer, Pregnancy, Gestational Breast Cancer, Treatment Options, Lactation Objectives The objectives of this study are to discuss various aspects of breast cancer during pregnancy and the relevant literature, considering incidence rates, management and possible outcomes. Then to make suggestions for future practice in order to discover ways in which practice and prognosis could be improved by identifying the best methods and strategies for diagnosis and treatment. Setting The care of pregnant and postnatal women with cancer Primary Argument Therapeutic abortion is no longer considered necessary in cases of Pregnancy Associated Breast Cancer (PABC) and there are a number of possible treatment options. Consideration is given to ethical concerns regarding the well-being of both mother and child and how the potential risks of treatments influence the clinical decisions taken. Conclusion Women diagnosed with PABC need an approach to treatment that is personal to them and their particular situation. There is also much good practice when it comes to treatment, but diagnosis is often dangerously late. Further studies of breast cancer, and the effects of pregnancy upon it, are needed to determine the most effective treatment plan. Introduction Women have a 12.67 % of developing breast cancer during their life time.( National Cancer Institute’s Surveillance, Epidemiology, and End Results Program Cancer Statistics Review rates from 2001 to 2003.) According to Loibl S, von Minckwitz G, Gwyn K, et al. (2006) the condition will occur in one in 3000 pregnancies. Despite this there have been few recent studies on the subject, especially those seeking to look for the histopathologic and immunohistochemical features which are combined in breast carcinomas in these patients, possibly because of the comparative rarity of the condition. Pregnancy associated breast cancer (PABC), often referred to as gestational breast cancer; can be defined as any cancer of the breast diagnosed during pregnancy and up to one year postpartum including lactation (Molchovsky & Madarnas, 2008). However, there is considerable variation among authors, with defined postpartum periods ranging from 6 months to 2 years. (Psyrri & Burtness, 2005). Another idea is that PABC can be defined as occurring during pregnancy and until lactation ceases. PABC is the second most common malignancy in women, after cervical carcinoma, and occurs in 1 in 3000 pregnancies (Pavilidis & Pentharoudakis, 2005). A mother is already facing the huge changes that come with a new child and when breast cancer is diagnosed concurrently with pregnancy and lactation this becomes a very challenging situation for the patient, physically but also psychologically and socially , as well as her family, physicians and other health care providers. Treatment options, either local or systemic, are limited by concerns about possibly harming the fetus, and are also conditioned by the gestational length of the pregnancy. Objective The aim of this literature review is to compile a review the of relevant literature on the subjects of the diagnosis, staging, pathology, treatment and prognosis of pregnancy associated breast cancer. The intention is to discover ways in which practice and prognosis could be improved by identifying optimal methods and strategies for diagnosis and treatment. What is already known about this topic PABC is the second most common malignancy, after cervical carcinoma and occurs in 1 in 3000 pregnancies (Pavilidis & Pentharoudakis, 2005). The context of breast cancer diagnosed concurrently with pregnancy and lactation is a challenging situation for the patient, her family, physicians and other health care providers. Treatment options, either local or systemic, are limited by the concern of harming the fetus, and conditioned by the gestational age of the pregnancy. An additional issue of stress relates to the lack of information regarding biological features of the disease, which makes an individually tailored therapeutic approach difficult. These women typically present with more advanced disease than average, which in itself carries a poorer prognosis. Physicians are therefore challenged to balance aggressive maternal care with appropriate modifications which will ensure sufficient fetal protection. The overall goal of care for women with PABC is local control of their disease and prevention of metastasis. The average age of women at presentation is between 32 and 38 years of age (Molchovsky & Madarnas, 2008).The incidence of PABC may rise further as more women delay childbearing until their mid to late 30’s. Approximately 25% of newer cases of breast cancer occur in pre-menopausal women (Ganz, Greendal, Petersen, Kahn & Bower, 2003). Due to increasing awareness and screening, breast cancer is being detected at earlier stages and in younger women but the risk of PABC is increasing because of relatively advanced maternal age at first childbirth (Lee, Akuete, Fulton, Chelmow, Chung & Cady, 2003). Of women diagnosed with breast cancer younger than 40 years, only approximately 10% will be pregnant ( Nugent and O’Connell 1985 and Merkel, D. 1996) Design and method: A web search was undertaken using resources such as Medline and Pubmed from 1970 to the present day using key words and phrases such as ‘breast carcinoma’, ‘pregnancy’ and ‘lactation’. This was then followed up by looking at the various articles referenced by the authors. English language articles which included epidemiological studies, case reviews, data extracts and general summaries were reviewed. Because the data discovered was so disparate , observational studies were not included. The results were then discussed and possible changes in future practice postulated. Results The various pieces of research studied point to the following facts. Diagnostic delays appear to be shorter than in the past, yet remain common. Mammography has a high false negative rate during pregnancy possibly because of increased breast activity and rapid increase in size. Biopsy or fine needle aspirations (FNA) are necessary for accurate diagnosis and must not be postponed until after delivery as the cancer by that time will have had more time to grow and invade surrounding tissues. Pregnancy associated breast cancer occurs more often during the later stages and is estrogen receptor negative. Delays in diagnosis may contribute to the higher proportion of patients with advanced stage at presentation. The prognosis for the pregnant breast cancer patient is similar to her stage matched non pregnant counterparts when matched for age and stage in the majority of instances. A modified radical mastectomy is the treatment of choice, with breast conserving treatment becoming increasing common. Therapeutic radiation is contradicted although chemotherapy appears to be relatively safe after the first trimester. Tamoxifen should be avoided in the first trimester and possibly beyond but some types of chemotherapy can be administered during the second and third trimester. Therapeutic abortion is not necessary. The mother with breast cancer diagnosed during pregnancy, or in the post-partum period, is best served by early and continued involvement of a multidisciplinary cancer team. Implications for Future Practice Health care staff involved in the care of pregnant and lactating women should be trained to perform a through breast examination at the first prenatal visit and also make subsequent examinations at each visit, certainly once each trimester, whilst maintaining a high index of suspicion for cancer. They should be carefully trained to do this correctly, both as part of clinic routine and to act upon any suspicions or statements by patients. If a palpable breast mass is discovered this must be acted on aggressively by clinicians, as early diagnosis may well improve the prognosis for those with breast cancer during pregnancy. In addition women today who wish to continue their pregnancies have a growing array of treatment options open to them. These options should be explained so that there is a degree of choice. Obviously early detection of PABC is the single greatest predictor of improved outcomes. It has been found that diagnostic methods such as ultrasound, mammography, and biopsy can be safely used to evaluate women who might have PABC, but these would normally be used after a possible diagnosis was made on clinical examination. . It would be advisable for the national databases to include PABC incidences as part of their statistical databases given the predicted future increased incidence of this disease. This in itself would raise the awareness of staff of it as a possibility when examining patients. However, despite its rareness, staff may need to be reminded of the possibilities of such cancers being present and should not discount possible warning signs and listen out for comments by patients which could act as clues to a possible diagnosis. . Discussion This is a relatively rare condition which means that there are relatively few studies to be considered. Also because there are so many factors to be considered it has been found difficult to compare one study with another. Time is an important factor in positive prognosis. For this reason clinicians and midwives should perform a through base line breast examination at the first prenatal visit in the early stages of pregnancy before the physiological changes in the breast are apparent and pronounced. However, as most cancers present late in pregnancy, such examinations also need to be carried out at each visit throughout the pregnancy as well as into the postnatal period. Staff should be aware of the possibilities of cancer being present. The physiological changes which occur in the breasts during pregnancy may contribute towards the delay in the diagnosis of PABC as in preparation for lactation a women’s breast size almost doubles in both size and weight. Raised levels of estrogen and progesterone during pregnancy causes both an increase in blood flow and fat, these then resulting in an increase in the size of the milk producing glands. The likelihood of cancers developing increases with age as shown by the statistics produced by the American Cancer Society Breast in 2008-2009. Cancer Facts & Figures, 2008-2009. Women with a genetic predisposition, those who have had a previous breast cancer or pre-malignant abnormality such as atypical ductal hyperplasia and lobular carcinoma in situ, particularly if over the age of 40 years age, and any who may develop a new breast complaint, should be assessed immediately as they are considered to be at a higher risk than the average pregnant women (Barnes & Newman, 2007). Breast cancer most often presents as a thickening or painless lump, sometimes associated with a bloody discharge from the nipple, which may be discounted because of pregnancy, as described by Theriault & Hahn, 2007 and cited by Logue ( 2009) (Psyrri & Burtness. 2005). As a result, diagnosis and treatment are often delayed, sometimes for two months or more, therefore increasing the chances of spread to the lymph nodes, thus increasing the chances of metastatic spread. (Eedarapalli & Jain, 2006). In past years these delays may have lasted 6 or more months, thereby explaining the poor morbidity and mortality rates amongst this population group. (Byrd, Bayer & Robertson, 1962), (Applewhite, Smith & DiVincenti, 1973).According to Woo (2003), a delay of only one month in the treatment of a primary tumor will increase the incidence of axillary metastases by 0.9%, thereby giving a tumor doubling time of 130 days. Conversely a 6 month delay would increase the risk by 5.1%. Therefore early detection is a significant predictor for improved outcome. The exact incidence of pregnancy associated breast cancer is difficult to define. However a retrospective Western Australian study between 1982 and 2000 cited the proportion of pregnant women diagnosed with PABC as 23.6 per 100,000 pregnancies, or 6.25% of all women who were diagnosed with breast cancer when aged 45 years or less (Ives, Saunders & Semmens, 2005) The National Cancer Institute Surveillance Epidemiology and End Results databases gives the rates of invasive breast cancer among women in particular age groups , but does not keep statistics as to the incidence of PABC. This means that information must be gained from smaller retrospective studies. Historical Perspective Historically the association between breast cancer and pregnancy was thought to carry a poor prognosis, it being rapid in course, excessively malignant and consequently incurable. Indeed many women were advised to abort their fetus (Bernik, S, Bernik, T, Whooley, 1999).This assumption of such an unfavorable prognosis can be discarded as newer data suggests a much more positive outlook. Several recent studies have demonstrated that there is no difference in prognosis if tumor size, nodal status and other established prognostic markers are compared with non- pregnant women (Ring, Smith et al 2005), Delays in diagnosis are shorter than in the past but remain common. Therefore the outlook for such patients is less favorable than that of non-pregnant women, probably because the stage of the disease is more advanced when it is discovered and also to delays in instigating therapy. PABC usually presents as an advanced disease; the largest proportion of stages 11-III breast cancer tumors is reported among women diagnosed during pregnancy or at less than 2 years postpartum. (Theriault & Hahn, 2007). Several studies have revealed an association between breast cancer and pregnancy. It has been found that the risk of breast cancer increases after the birth of a first child (Lambe, Hsiech, Trichopoulos, Ekbom, Pavia & Adami, 1994), (Albrektsen, Heuch, Hansen & Kvale, 2005), This reaches a peak at five years after delivery (Liu, Wuu, Lambe & Hsie, 2002).but the peak risk identified pertains to women who have their first child at 30 years or older. (Liu et al 1994). Whilst the risk of PABC was initially thought to be higher amongst primigravidas, recent studies have demonstrated that an increased risk exists in subsequent pregnancies also. (Albreksten et al, 2005). Yet in the latter group the risk appears to be lower (Lambe et al, 1994), ( Liu, Wuu, Lambe, Hseih, Ekrom and Hseih, 2002) . No risk has been identified in primigravidas younger than 25 years, however no protection is afforded after subsequent pregnancies. (Albreksten et al, 2005). It is known that women with mutations in the BRCA1 and BRAC2 genes have an increased breast cancer risk, compared to the average population, although factors such as multiple pregnancies, first pregnancies at a young age and breastfeeding have a protective effect (Nikondjock & Ghadirian, 2005). However, their effect amongst BRCA1 and BRCA2 mutation carriers remain uncertain. A retrospective data set study of families seen in genetic clinics in UK hospitals included 457 mutation carriers who developed breast cancer compared with 332 healthy mutation carriers. The control group demonstrated that the parous BRCA1 and BRCA2 mutation carriers demonstrated a significantly lower risk of developing breast cancer. However this protective effect was only demonstrated amongst carriers who were 40 years or over. Increasing age at the time of the first live birth was associated with an increase in breast cancer risk amongst BRCA2 mutation carriers rather than BRCA1 carriers. Whilst the numbers surveyed were of low statistical value the results are suggestive that the relative risks of breast cancer associated with parity amongst the BRCA1, BRAC2 mutation carriers may have some similarities to those individuals unaffected in the general population. Still further studies are warranted to further explore these concepts. (Antoniou, Shenton, Maher, Walton, Woodward, Lalloo, Easton & Evans, 2006). Imaging Ultrasound imaging should be the first choice for the pregnant women. It provides the early work up of the breast mass and carries no risk of fetal irradiation. It is capable of distinguishing between cystic and solid lesions in 97% of patients. This inexpensive technique detected 39 of the 42 cancers (93%) in a case controlled study of pregnant Japanese women. (Woo, Taechin & Hurd, 2003). Mammography is the current standard for breast imaging screening. However this is less used during pregnancy and lactation because of increased breast density, a perceived and potential risk to the fetus as well as anxiety on the part of both the provider and patient. Mammography can be painful, and especially so to a pregnant or lactating patient. Mammography does however appears to have a place in the evaluation of the pregnant patient provided adequate abdominal shielding is used ( Niklas and Baker, 2000). It is however also associated with more false negative findings during pregnancy and lactation, resulting in a diagnostic challenge when a breast mass is found during pregnancy ( Son,Oh and Kim , 2006 ) MRI has not yet been prospectively studied for the diagnosis of PABC or in lactating women. It involves no irradiation, but there are several other disadvantages which limit its use in PABC. Gadolinium crosses the placental barrier and has been associated with fatal abnormalities in rats. Also it is classified as a category c drug, to be used only if the potential benefit justifies the potential risk. (Son et al 2006). For these reasons its use is avoided during in the first trimester although, until further research takes place there can be no real consensus on this matter. Diagnosis Women generally present, pregnant or otherwise, with similar findings such as a mass or palpable thickening of the breast tissue. A milk rejection sign in women has been described very rarely in case reports, when infants refuse the breast that harbors the carcinoma (Hadary, Zidan & Oren, 1995).Given the concerns for delayed diagnosis, any palpable masses which persist for more than 2 weeks during pregnancy should be investigated. Biopsy is considered the best means of accurate diagnosis. (Woo et al 2003) although it is generally reported that approximately 80% of breast biopsies during pregnancy will result with a benign diagnosis (Imaginis, 2007). Because pregnancy- associated breast cancers often present as a palpable mass, core needle biopsies may be the most cost effective initial procedure. In non-pregnant women the technique has been shown to diagnose lesions with both high sensitivity and specificity (Shannon, Douglas-Jones, & Dallimore, 2001). Alternatively excision biopsies can be performed safely under local anesthesia. Fine needle aspirate (FNA) in the pregnant breast is a well established technique; however in all instances it is important for the pathologist to be aware that the specimen is from the breast of a pregnant female to avoid the misdiagnosis of the hyper proliferative changes of pregnancy.(Gwyn & Theriault,2001). Pathology Invasive ductal carcinoma (70-90%), followed by invasive lobular carcinoma are the commonest types of cancer in cases of PABC. (Middleton, Amin, Gwyn, Theriault & Sahin, 2003).and relatively rarely, inflammatory carcinoma approximately 4% (Woo et al 2003). The majority of PABC’s present as grade II or III with a higher incidence of ER and PR negative tumors (Middleton et al 2003). Many studies have found that women who develop breast cancer in pregnancy have higher grade tumors, are more likely to have positive lymph nodes together with metastatic spread as well as vascular invasion (Middleton et al 2003). Pathologically there appears to be no discernable differences in tumor types between gestational and nongestational breast cancer. There are a large proportion of nodal positive PABC’s found at the time of surgery, the incidence reported being approximately 70%. This demonstrates that presentation and diagnosis are usually relatively late in this condition.(Murphy, Mallam, Stein, Patil, Howard, Sklarin, Gemignani, Hudis & Seidman, 2010).There is a similar incidence of inflammatory cancers in both gestational and nongestational breast cancers with rates of between 1.5-4.2% (Berry, Theriault & Holmes.1999). However very little research has been carried out on the histological appearances of these tumors, although there appears to be no differences detected between the two types. Both further and larger studies need to be carried out in order to provide conclusive evidence of the biological differences between gestational and nongestational cancers. A number of case controlled, stage for stage, studies have been evaluated to determine survival outcomes in woman with PABC compared with their nongestational age matched controls. A number of studies reported similar survival outcomes, but others reported worse survival outcomes (Psyrri & Burtness, 2005), (Loibl, Minckwitz, Gwyn, Ellis et al 2005). I t remains unclear whether pregnancy is an independent risk factor for a worse prognosis in breast cancer or whether poorer outcomes are a reflection to the delays in diagnosis. Further studies are required to determine this outcome. Whilst PABC is associated with less favorable tumor features, the diagnosis of PABC in itself is not necessarily an adverse prognostic factor for survival. Management Because elate diagnosis is common because of the changes of pregnancy, physicians face the challenge of balancing balance aggressive care with the modifications necessary to ensure protection for the developing fetus. . There is no longer a place for therapeutic abortion in cases of PABC. The aim is to achieve control and prevent metastases. Initial management is best within the context of a tertiary referral centre with a multidisciplinary approach. The team should not just include those treating the patient directly for her breast cancer, but should also include those involved in the care of the pregnant mother and her developing child so as to ensure the best possible outcome. Treatment guidelines are the same as in the case of non pregnant women plus necessary modifications in order to protect the fetus. There must be an individual approach taking into consideration the gestational age of the fetus, the stage of the disease and also the patient’s preferences. This multidisciplinary approach requires close coordination between all concerned .Genetic counseling is also recommended. Treatment Surgery is the commonest form of treatment for PABC. Surgical treatments considered suitable include both modified radical mastectomy and breast conserving surgery with axillary lymph node dissection in cases of stage 1 or II and in some cases stage III tumors (Loibi et al, 2005). Axillary dissection is also undertaken whichever procedure is chosen, as metastases are common and an individual’s nodal status will affect the choice of chemotherapy (Eedarapalli & Jain, 2006).The difference between these two possible options is that a mastectomy means there is no need for postoperative irradiation if the cancer is at an early stage. However after breast conserving surgery, in order to prevent local reoccurrence, radiotherapy is needed. This needs to begin within 3 months of surgery as otherwise the likelihood of future metastases is increased. (Whelan, Lada, Kaukkanen, Perera, Shelley & Levine, 2002).Since radiation therapy is unsafe for the fetus throughout all stages of development, it can only be safely administered post-partum, thus breast conserving surgery is usually only considered in the late second or third trimester. Statistically the survival rates of either approach are similar. (Kuerer, Gwyn, Ames & Theriault, 2002). The dissection of sentinel lymph nodes (SLND) has not been found to make a significantly positive difference to the prognosis. The procedure also increases risk to the fetus because of the radiation doses used (Gentilini, Cremonesi & Trifiro, 2004).The panel of the consensus conference which reviewed the role of SLND in pregnant women has advised against its use until more data becomes available (Schwartz, Giulianto & Veronesi,2001).Therefore axillary lymph node dissection continues to serve as the gold standard. In patients who are diagnosed in the late second trimester or beyond, a lumpectomy with axillary dissection followed by irradiation post delivery is considered a viable treatment option.(Gwyn &Theriault,2001).If a woman is far from term, breast conserving surgery can be followed by chemotherapy after the first trimester then irradiation once she has delivered. There have been no reported differences in overall survival rates with breast conserving surgery for stage 1 and 11 tumors as compared with the modified radical mastectomy. (Eedapalli & Jain, 2006.) Women who are diagnosed with PABC in the late stages of the final trimester can elect for an early delivery, which allows for earlier breast conserving surgery followed by immediate treatment with radiation (Gwyn & Theriault, 2001).The safety of surgical intervention during pregnancy is well established, however it is safest to wait until after the 12th week of gestation so as to reduce the risk of spontaneous abortion. Adjuvent chemotherapy and radiotherapy are also used. However according to Epstein ( 2007) there remain a number of doubts about the uses of chemotherapy during pregnancy. A report in the Lancet of August 2010 ( Vaidja et al) stated on the other hand that single-dose partial irradiation was safe fro some women who had invasive breast cancer. Conclusion Some 10% of those diagnosed with breast cancer when younger than 40 years will also be pregnant at the time of diagnosis. I t is obvious from the above findings and discussion that women diagnosed with PABC need an approach to treatment that is personal to them and their particular situation. There is also much good practice when it comes to treatment, but diagnosis is often dangerously late for the reasons stated above. Careful consideration needs to be given to both mother and child who are facing a possibly fatal outcome. As the age of first pregnancy rises on average the problem is likely to increase. This means that further studies of breast cancer, and the effects of pregnancy upon it, are needed to determine the most effective treatment plan. This will necessitate excellent communication and co-operation by a multidisciplinary team in order to achieve the best possible future for both mothers and children. References Albrektsen, G., Heuch, I.,Hansen,S. & Kvale,G. (January 2005), Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. 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