• American Joint Committee on Cancer (AJCC) proposes the term multiple BCs rather than multifocal or multicentric BC. • The incidence of pregnancy-associated BC is the same as expected in general population, and also the ultimate comparison of prognosis, stage-for-stage and age-matched, may be similar. • Treatment of BC in young women is not substantially different from other age groups, and also systemic therapy is mainly linked to the biology of the tumor. However, in appropriate situations, it may also be important to evaluate very young women separately. • Management of BC in the elderly vulnerable and frail women could be a major challenge for oncologists and geriatricians alike. Dedicated oncologists are needed.

Future Directions. Many preconceptions about women are far from being cleared. Besides those related to individual variability, those related to age/biological age, fertility, and quality of life in complex contexts are equally important. There should be room for special situations such as a customized treatment for very young or elderly women.

15.1 Multiple Ipsilateral and Bilateral Breast Cancers

Clinical Practice Points

In multifocal and multicentric BC, establishing whether separate foci are polyclonal or monoclonal in origin is challenging and a matter of debate.
Because the incidence of BC is increasing and prognosis is improving, a growing number of women with BC are at risk of developing bilateral disease.
There are important differences in the incidence trends and prognostic outcome between synchronous and metachronous bilateral BC diagnosed at different ages.
Adjuvant chemotherapy has a dual effect on metachronous cancer: it reduces the risk of a second disease, while it seems to worsen the prognosis whenever it occurs.
Women with multiple BC have an increased risk of developing a subsequent non-breast cancer.

15.1.1 Overview

Multiple cancers are defined as two or more primary cancers occurring in an individual that are not an extension, recurrence, or metastasis.

Multiple ipsilateral BCs are categorized as multifocal (MF) or multicentric (MC) based on the location of presentation. Multiple BCs in both breasts (bilateral BC) are categorized as synchronous or metachronous based on the chronology of presentation.

For most authors, multifocal breast carcinoma refers to the presence of more than one distinct tumor within the same quadrant of the breast, while multicentric mammary carcinoma describes the presence of a clinically or mammographically evident tumor in a different breast quadrant from the index lesion [1].

New molecular studies suggest some inconsistencies in this common attitude to categorize multiple BCs. The above usual nomenclature is established on multiple tumors diagnosed clinically on physical examination and on breast imaging studies including mammogram, ultrasound, and magnetic resonance imaging (MRI). Nevertheless, multiple breast carcinomas, especially when occurring in an ipsilateral breast, are a challenge for pathologists in terms of the identification of their cellular origins.

Because in situ carcinoma is a precursor of invasive carcinoma, the presence of in situ disease in multiple separate cancer foci has led investigators to consider such foci as polyclonal tumors versus those of monoclonal origin. However, unless clonal analysis is performed on each cancer focus, the polyclonal or monoclonal origin cannot be assessed by spatial presentation alone [1, 2].

Moreover in TNM classification, multicentric invasive cancers are staged using the largest primary carcinoma to designate the T stage. Tumor sizes are not added together, and a designation to identify the carcinoma as multicentric is added to allow separate analysis of this group of tumors. There is some evidence to suggest that this staging system may not accurately reflect outcomes in multicentric carcinoma. When the diameter of the largest of the multicentric tumors was used to determine tumor size, patients with multicentric tumors had significantly more nodal metastases for T1 and T2 tumors than those with unicentric cancers.

15.1.2 Multiple Ipsilateral BCs

Definition. MF/MC BC is a debated subject with no international consensus on its definition or recommended methods of assessment. The classic studies conducted by Holland demonstrated that the majority of breast carcinomas are multifocal and extensive [3]. The reported prevalence of multicentric cancer has ranged from 13 to 75 %. This discrepancy can be explained by two reasons: first, many studies are based on a traditional morphologic workup that focuses on macroscopically visible dominant masses that typically include a low proportion of multifocal cases, and second, there is a lack of significant differences between unifocal and multifocal cancers [4].

Generally, multifocality is defined as the presence of two or more malignant lesions in the same quadrant separated by normal breast tissue, while a multicentric lesion refers to two or more malignant lesions also separated by normal breast tissue but located in different quadrants [5]. Katz et al. [6] defined multifocality as foci separated by less than 4 cm or located in the same quadrant and multicentricity as foci separated by at least 4 cm or in different quadrants; foci were identified mammographically or on gross pathologic examination.

Middleton et al. instead defined multicentric mammary carcinoma as an evident focus in a quadrant outside that of the primary tumor but considered patients with different foci in the same quadrant that were microscopic only as having a unicentric tumor; multifocality was defined as more than one distinct tumor in the same quadrant [1, 6].

Incidence. The incidence of multicentric BC is variously reported as ranging approximately from 5 to 65 % of cases. Likewise, multifocal BC may occur in as many as 60 % of cases. In addition to this, about 3–5 % of patients with BC will have bilateral disease at the time of presentation.

Pathology studies using standard clinical techniques of examining breast tissue which include gross inspection of the specimen and a limited number of random sections of grossly normal breast have also identified multicentric carcinoma in about 5–13 % of cases. Also, in the presence of ductal carcinoma in situ (DCIS), discontinuous growth was more frequent in well-differentiated DCIS (70 %) than in poorly differentiated DCIS (10 %). These findings suggest that true multicentricity is uncommon in DCIS, but multifocal growth within a ductal system is common in low-grade lesions [1].

Diagnosis. The sensitivity of mammography for detection of multifocal and multicentric tumors ranges between 15 and 45 % [7]. Ultrasonography (US) has been shown to be useful as a complement to mammography for detecting additional (about 20 %) occult tumor.

Numerous studies have shown that MRI detects multifocal and/or multicentric disease with greater accuracy than conventional imaging. Houssami et al. [8] published a meta-analysis examining the accuracy of MRI for detecting multifocal and/or multicentric cancer. Data from these studies showed that MRI found additional disease in the affected breast in 16 % of women with BC. However, MRI has a disappointing false-positive rate. In this meta-analysis, MRI had a positive predictive value of 66 % and a true-positive to false-positive ratio of 1:9.

Histologic subtype of invasive carcinoma does not appear to be predictive of multicentricity. Older studies have suggested that infiltrating lobular carcinoma is more likely to be a multicentric process, but when lobular carcinoma in situ is excluded from consideration, multicentricity is not so frequent with invasive lobular carcinoma. In contrast, several small studies suggest that multicentricity is more frequent in micropapillary DCIS than in other histologic types of intraductal carcinoma.

Treatment. The conservative surgical approach to MF/MC BC is still debated: no consensus has been reached. According to some reports, the local recurrence rate in MF/MC BC after breast conservative therapy (BCT) was significantly higher than that of a single tumor. This conclusion leads many physicians to continue to perform mastectomy for MF/MC BC. Fowble et al. [9] performed a pathologic review of the mastectomy specimens and revealed extensive residual disease in three or four quadrants of the breast after excisional biopsy in 50 % of the patients with MF/MC BC. However, recently in a large retrospective series, Gentilini et al. [10] found that breast-conserving surgery was safe for patients with MF/MC BC, when the disease was adequately excised.

Several authors have shown a correlation between lymph node involvement and multifocality, which is a surrogate factor for predicting recurrence and survival; they have shown a positive association between multifocality and the presence of lymph node metastases. By combining these studies, we might estimate an approximately 20 % increase in risk of lymph node involvement in the presence of multifocality. Interestingly, this increased risk seems also to be present for small tumors [11] as well.

This higher risk of lymph node metastasis seen with multifocal tumors may result from greater tumor volume or potential for dissemination. In fact, multifocal invasive BCs occur in younger patients and have aggressive characteristics that have been previously reported (higher histoprognostic grade, higher proliferation, more Her-2 expression); therefore, secondary foci may be metastases from a tumor with an elevated metastatic potential.

In multifocal BC, axillary lymph node dissection is the standard, and the sentinel node biopsy procedure remains in question. Several authors have reported that the rate of false negatives (FN) differed depending on the study, ranging from 0 to 21 % [12].

Prognosis. The prognostic significance of multifocality in invasive BCs remains unclear. Yerushalmi et al. [13] evaluated prospectively whether patients with MF/MC BC have different outcomes compared to unifocal disease in terms of survival and the development of contralateral BC (CBC) disease. The author reported that the 5-year cumulative incidence of CBC in the unifocal versus MF/MF group was 2.3 % [(95 % CI 2.1–2.5)] versus 2.4 % [(95 % CI 1.6–3.4) (p = 0.349)]. Breast cancer-specific survival rate revealed a slightly worse outcome with MF/MC disease, RR = 1.174 [(95 % CI 1.004–1.372)]. There is no clear evidence that patients with multifocal BC have a worse clinical outcome than those with unicentric BC who have been treated in a similar way.

15.1.3 Bilateral BC

Definition. Bilateral BCs are divided into synchronous (when cancers in both breasts develop simultaneously) and metachronous (when cancers in each breast develop at different times). Synchronous bilateral cancers can be further subdivided into two groups. The first group consists of cancers with signs or symptoms present in both breasts, and the second group consists of contralateral cancers that are not palpable and are diagnosed only as a result of imaging studies precipitated by the initial diagnosis. In general, the incidence of synchronous bilateral BC is varying from 1 to 3 %, whereas the incidence of metachronous is around 0.3–0.8 % per annum.

Risk factors. The risk factors for contralateral BCs are: early age at diagnosis, family history of cancer (10-year risk 10–15 %), BRCA1/2 mutation (10-year risk 25–30 %), and CHEK2 mutation (10-year risk 10–20 %) [14, 15]. In addition, there is a concordance between increasing incidence and lobular carcinoma. In a cohort study, 2,855 patients with unilateral BC were followed up for a median of 7 years. The cumulative risk of contralateral BC was estimated to be 20.9 % after invasive lobular cancer, compared to 11.2 % after invasive ductal cancer [16].

The findings of some studies suggest that the risk of contralateral BC is greater for women whose first cancer is ER-negative than it is for women with ER-positive cancers. However, most ER-positive cancers are treated with tamoxifen, and most ER-negative cancers are not. So that tamoxifen treatment greatly reduces the risk of contralateral cancer, it is not possible to interpret these results without adjustment for hormonal therapies, and it has not been yet established that ER-negative status is an independent risk factor for contralateral BC [17].

Treatment. In the past, clinicians have approached bilateral disease more aggressively than unilateral disease, and studies have shown a disproportionately higher incidence of bilateral mastectomies performed in patients with bilateral cancer. A number of studies have demonstrated that bilateral breast conservation treatment is feasible and is not associated with an increased risk in the outcome [18].

Patients with a genetic mutation are at a significantly increased risk for the development of new primary cancers, and this should be considered in the decision-making process.

Both tamoxifen and aromatase inhibitors substantially reduce the risk of contralateral BC. A standard course of tamoxifen is associated with a reduction of approximately 50 % in the risk of contralateral BC, and the decrease in risk lasts for at least 15 years [19].

Prognosis. The 10-year survival of women with synchronous bilateral BC is inferior to that of women with unilateral BC (45 % vs. 33 %, respectively, P < 0.001). In detail, women diagnosed with metachronous cancer within more than 5 years have a four times higher mortality rate compared to women with unilateral BC after adjustment for age at diagnosis.

In contrast, women with metachronous cancers diagnosed more than 10 years after initial diagnosis had a prognosis similar to that of women with unilateral cancer. Among women with metachronous BC, the lowest mortality from BC is seen for those with the longest time interval between the first and the second cancer. After 10 years of follow-up, the cumulative BC-specific mortality is around 50 % among women with bilateral cancer diagnosed within 5 years and around 35 % among those diagnosed with bilateral cancer more than 10 years after their first primary [20].

15.1.4 BC and Risk of Associated Non-breast Cancer

Unilateral BC. Besides an elevated risk of contralateral BC, several studies revealed that women with a primary BC have an increased risk of developing a subsequent non-BC. Increased risks are most consistently found for tumors of the ovary, endometrium, soft tissue, and for leukemia. Though less consistently, also excess risks of melanoma of the skin and cancer of the bone, esophagus, kidney, and lung have also been reported.

The risk of subsequent non-BC appears to be associated with genetic and other risk factors that are common for both cancers. Moreover, BC patients with primary BC experienced an increased risk of lung cancer and soft tissue sarcomas that could be attributed to radiation. Increased risks of melanoma of the skin, uterine cancer, and leukemia are found to be associated with the use of chemotherapy for patients older than 50 years, whereas the increased risk of endometrial cancer was related to endocrine therapy. At the same time, chemotherapy is associated with a reduced risk of colon and lung cancer for women younger than 50 years.

Bilateral BC. Information about the risk of third cancer of non-breast origin after synchronous or metachronous invasive bilateral BC is lacking. Patients with bilateral BC may have been exposed to more carcinogenic or carcino-protective cancer treatment. Moreover, a higher risk could be expected for genetic, reproductive, or lifestyle-related cancers.

Women with bilateral BC have a 1.5 times higher risk of all non-BCs combined. Young women have a 2.8 times higher risk of all non-breast tumors combined and a tenfold higher risk of ovarian cancer, compared with the general population, which is probably related to genetic factors. Chemotherapy is associated with a decreased risk of all non-breast tumors combined, whereas radiotherapy and endocrine therapy are associated with an increased risk.

15.2 Breast Cancer During Pregnancy

Clinical Practice Points

Pregnancy-associated BC (PABC) is a purely arbitrary definition of cancer diagnosed during pregnancy or within 1 year of delivery.
Ultrasonography of the breast and regional lymph nodes is used to assess the extent of disease and also to guide biopsy. Core needle biopsy is preferred for histological diagnosis and biomarker analysis.
The general philosophy of treatment today is to treat the cancer and allow the pregnancy to proceed.
Significant emotional issues surround care of women with pregnancy-associated BC, and multiple specialties are involved in patient management and in an essential psychological support.
Pregnancy after BC should not in principle be discouraged, and retrospective available data report no detrimental effect of a subsequent pregnancy on BC outcome.

Pregnancy-associated breast cancer (BCDP) is defined as BC diagnosed during pregnancy or within the year after delivery, but the real challenging clinical scenario is represented by BC diagnosed during pregnancy. The exact incidence is unknown; however, it is estimated to constitute around 10 % of BC cases diagnosed below the age of 40 in Western nations. Statistical analysis proves that the incidence of PABC is 1 out of 3,000 deliveries [21, 22].

Some studies have found that BCDP is more commonly diagnosed at an advanced stage with larger tumor size and with lymph nodes metastases. Delay in diagnosis is typical because tumor masses can be masked by breast engorgement owing to lactation, and inflammatory changes may be mistaken for mastitis, but also because of increased breast density, making clinical examinations and mammography more difficult to interpret. [23]

Risk factors. No specific risk factors for BC in pregnancy are known. Genetic or environmental risk factors are similar to those for age-adjusted BC in the general population. Individuals with BRCA1 or BRCA2 mutations might be at increased risk, but they do not have an increased incidence of BC in pregnancy [24].

Clinical presentations and diagnosis. BC in pregnancy typically presents as a painless lump palpated by the woman. Physiological breast changes associated with pregnancy, such as breast enlargement, hypertrophy, and nipple discharge obscure detection for patient and physician, and this implies a delay in diagnosis, leading to more advanced stages at diagnosis than in the general population. As a consequence, BC in pregnancy is associated with more metastases and subsequently poorer outcomes [25].

Breast ultrasonography is the first diagnostic instrument used by clinicians when a breast mass and the axillary area need to be assessed in a pregnant woman with high sensitivity and specificity. Mammography is not particularly useful, since the radiodensity of the breast tissue in pregnant and lactating women significantly decreases the sensitivity of this examination. Nevertheless, it can be used, with proper shielding, to rule out diffuse microcalcifications.

MRI with contrast agents is possible during pregnancy but should only be used when it will alter clinical decision-making and when ultrasonography is inadequate. The reason of this caution is because some studies have underline that gadolinium-based MRI contrast agents pass through the placental barrier and enter fetal circulation [26, 27].

The standard examination to obtain a histological diagnosis is a core biopsy, which can be safely done during pregnancy. The major risks of infection and milk fistula can be minimized if the woman ceases breastfeeding at least 48 h prior to biopsy [28]. Fine needle aspiration (FNA) is not recommended because hormonal changes during pregnancy could lead to false positive or false negative.

Pathology. The histopathological and immunohistochemical findings of BC in pregnancy are similar to those in nonpregnant women who are younger than 35 years. Most pregnant patients are diagnosed with infiltrating ductal adenocarcinomas (71–100 %), which are often associated with aggressive behavior: high incidence of grade 3 tumors (40–95 %), lymph vascular invasion, and a high rate of estrogen-receptor negativity [29].

Gestational BC is associated with larger tumors and a higher incidence of nodal involvement (53–71 %) than in nonpregnant patient. Most PABC is estrogen-receptor and progesterone-receptor (ER/PR) negative, whereas HER2 positivity has been reported in 42 % of cases [30].

Treatment. Therapeutic strategies are determined by tumor biology, tumor stage, gestational stage, and the patient’s and her family’s wishes and should involve a multidisciplinary team.

Pregnancy termination, once routinely advocated because of fear that the hormonal and immunologic milieu would adversely affect the patient’s survival, is now rare. Patients should be informed that abortion does not improve prognosis of the disease and that effective treatments can be safely performed during pregnancy.

Surgery can be done safely during any stage of pregnancy, and most anesthetic agents seem to be safe for the fetus [31]. The mother should be strictly monitored to avoid hypoxia, hypotension, hypoglycemia, fever, pain, infections, or thrombosis. The choice of BC surgery during pregnancy should follow the same guidelines as for nonpregnant women; however, breast conservation performed during a very early gestational age is associated with a long delay in postoperative radiotherapy [32]. Clinicians can safely use sentinel lymph node staging during pregnancy because estimated absorbed doses are largely below the 0.1–0.2 Gy fetal threshold absorbed dose [33].

Chemotherapy can be adjuvant or neoadjuvant and should be administered after the first trimester. For fetal protection, chemotherapy is contraindicated until 12–14 weeks gestation. The regimens of chemotherapy (see Sect. 18.3) recommended to pregnant BC patients are the same as the ones recommended to nonpregnant counterparts. Chemotherapy can be safely administrated to pregnant BC patients using standard anthracycline-based regimens (e.g., FEC, FAC, EC, AC). These regimens should be followed by a taxane whenever indicated. The taxane can also be administered during pregnancy, although there are less available data. Trastuzumab and endocrine therapy must not be prescribed during pregnancy but must be postponed until after delivery [34].

Hormonal agents such as selective estrogen-receptor modulators can disturb the hormonal environment, and so such treatments should be delayed until after delivery. Tamoxifen has the potential to induce fetal harm during pregnancy and is associated with birth defects including craniofacial malformations, ambiguous genitalia, and fetal death [35].

Radiation therapy is impracticable during pregnancy because even with abdominal shielding, the fetal dose is high.

Prognosis. Pregnant women are less likely to be diagnosed with stage 1 but two and a half times more likely to be diagnosed with advanced disease than nonpregnant women. The discussion about prognosis remains open for BC during pregnancy: while few studies have pointed to poor prognosis of patients diagnosed during pregnancy, others did not reproduce the same results. A recent meta-analysis of 30 retrospective cohort studies showed worse prognosis of PABCs, even after adjustment for age and stage, and that PABC is independently associated with poor survival particularly those diagnosed shortly postpartum. This underscores a possible impact of the pregnant breast microenvironment on the biology and consequently the prognosis of these tumors. Apparently, it is not possible to establish definitions about the prognosis, because the available studies have important methodological limitations, with many confounding variables.

PREGNANCY AFTER BREAST CANCER – Due to rising trend to delay pregnancy at a later age, more women are diagnosed with BC before completing their families. Therefore, inquiry into the feasibility and safety of pregnancy following BC diagnosis is steadily growing. Available evidence suggests that women with a history of BC are frequently advised against future conception for fear that pregnancy could adversely affect their outcome. Pregnancy after BC should not in principle be discouraged. Retrospective available data report no detrimental effect of a subsequent pregnancy on BC outcome [36]. Nonetheless, a thorough staging should be performed before trying for conception, depending on the individual risk of relapse, and patients should be informed about the possibility of BC recurrence even many years after diagnosis [37].

There is no definitive evidence to recommend a fixed time frame from diagnosis to pregnancy [38]. Despite absence of supporting evidence, some experts recommend avoiding early pregnancy (within 2 years from diagnosis) in patients of higher risk of early relapse. In addition, potential disadvantages of early stopping of ongoing recommended anticancer treatments must be discussed and balanced with the risk of infertility due to aging and iatrogenic effects of cancer treatment. Delaying pregnancy should be discussed on an individual basis in order to allow for continuation/completion of adjuvant therapy. The discussion should take into account the half-life of administered treatment (to prevent detrimental effects on the fetus), the detection of early relapse in high-risk disease, and/or overcoming early treatment-related side effects.

In general, an interval of at least 4–6 months from the end of chemotherapy and the attempt to conceive is recommended [39]. Data on endocrine treatment are less conclusive: as a practical advice, an interval of at least 3 months from the end/interruption of therapy is recommended due to the half-life of tamoxifen. Women should be fully informed about the risk of stopping tamoxifen treatment prematurely. If a woman prematurely stops endocrine treatment to achieve a pregnancy, resuming tamoxifen after breastfeeding completion can be considered, and an ongoing worldwide clinical trial is addressing this issue. Limited data on the efficacy and safety of ovarian stimulation after treatment of BC are available. Caution and individualized decision-making are recommended.

Data about pregnancy and fetal outcome after BC treatment are reassuring. No increased fetal malformation rates have been reported after completion of chemotherapy or endocrine treatment, but some population-based data report an increased risk of delivery complications, caesarean section, very preterm birth (<32 weeks), and low birth weight (<1,500 g), highlighting the need for careful pregnancy surveillance and management in this population.

Breastfeeding after BC is not contraindicated and should be supported with adequate information and counseling [4]. Milk production after breast-conserving surgery and radiotherapy is reduced, but breastfeeding from the other breast is feasible and safe for the mother and the child, provided the patient is not taking any medications that may be harmful for the child.

15.3 Breast Cancer in Young Woman

Clinical Practice Points

Approximately 1 in 40 women diagnosed with early BC is very young (under 35 years). Age has been shown to be an independent adverse prognostic factor for women with a diagnosis of BC.
Intrinsic difficulties in diagnosis of BC in young women are dense breast tissue, lack of previous routine breast screening, and shorter tumor doubling times. By the time a mass can be felt, the cancer may be advanced.
Genetic counseling is indicated for all young patients, since 10–15 % of patients diagnosed under the age of 35 present with a gene mutation.
Multidisciplinary management and care is strongly recommended to avoid an opinionated standard of practice and the risk of overtreatment.
Medical treatment of BC in young women is not substantially different from other age groups, since therapy is mainly linked to the biology of the tumor. However, in appropriate situations, it may also be important to evaluate very young women separately.

The European Society of Breast Cancer Specialists (EUSOMA) working group decided to define “young women” as women under the age of 40. Since both biology and endocrine milieu are a continuum, that age group definition will always be arbitrary. However, women under the age of 40 have specific issues related to fertility preservation, pregnancy, and lactation that deserve a different approach and management from slightly older pre- and perimenopausal women.

The care of young women with BC has become a more recent focus with improvements in diagnosis, treatment, and survivorship. This population, usually defined as women diagnosed under the age of 40, requires individualized treatment plans. Given the differences in epidemiology and management options, as well as the unique issues surrounding fertility, sexuality, and pregnancy, the multidisciplinary approach to treatment for these women frequently may also incorporate other areas of expertise.

15.3.1 Epidemiology and Risk Factors

Around 5–7 % of BCs are diagnosed in women younger than 40, making it the most commonly diagnosed female cancer in the 25- to 39-year-old age group [22, 40]. In patients younger than 40 years specifically, African American females have the highest relative incidence of BC. Young women tend to present at more advanced stages and their tumors tend to be higher grade and hormone-receptor negative and have increased HER2/Neu overexpression and more lymphovascular invasion [41]. An analysis from EORTC and NSABP indicated a higher risk of local recurrence in patients younger than 35 years [42, 43].

BC at a young age is associated with an increased risk for contralateral BC (CBC). Overall, patients younger than 50 years have a risk of CBC of 0.1 % annually or approximately 13 % cumulative risk in a 10-year period. Diagnosis before the age of 45 doubles the risk of having a CBC [44]. A review from by Gnerlich et al. indicated young patients with stage 1 or 2 BC had a higher disease-specific mortality rate when adjusted for other factors; this seems to be due to the aggressive phenotype of these tumors or more advanced stages at presentation [45].

15.3.2 Clinical Presentation and Diagnosis

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Apr 2, 2016 | Posted by admin in General Surgery | Comments Off

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Breast Cancer in General Population

15. Breast Cancer in General Population