Case Study Breast Cancer

Nilesh Kucha

• G. A., a 37 year old female, married, G1P1 came in for consult due to a right breast mass.

• HPI: 6 months PTC, the patient felt a 1x1 cm mass over the upper outer quadrant of her right breast. It was movable and non-tender. No consult was done. She noted gradual enlargement of the same mass but was non-tender. One month PTC, she noted skin dimpling on her right breast. Persistence of the above symptoms with now accompanying tenderness on the right breast prompted her to seek consult.

• Personal HistoryNon-smoker, non-alcoholic drinker, with regular monthly menstruation, G1P1

• Family History:Aunt died of breast cancer, father has HTN & DM

QUESTION 1: What will be your diagnostic tests/procedures for this patient ?

80% of all breast lumps are not cancer. But if breast cancer is caught early, your chances of survival are very good. Some tests that are used to get a clear diagnosis for invasive ductal carcinoma are: • Mammogram• Biopsy

And why? • Diagnostic mammography should not be confused with screening

mammography, which is performed after a palpable abnormality has been detected.

• Diagnostic mammography is aimed at evaluating the rest of the breast before biopsy is performed or occasionally is part of the triple-test strategy to exclude immediate biopsy.

• Subtle abnormalities that are first detected by screening mammography should be evaluated carefully by compression or magnified views.

• These abnormalities include clustered microcalcifications, densities (especially if spiculated), and new or enlarging architectural distortion. For some nonpalpable lesions, ultrasound may be helpful either to identify cysts or to guide biopsy.

• If there is no palpable lesion and detailed mammographic studies are unequivocally benign, the patient should have routine follow-up appropriate to the patient's age.

In patient..

• Excision biopsy was done which revealed a 3x2.5 cm mass with biopsy reading of invasive ductal carcinoma, Nottingham histologic grade III. Right Modified Radical Mastectomy was done and the histopathologic result showed no residual tumor, 2/12 axillary lymph nodes positive for tumor, with lymphovascular invasion. Resection margins are negative for tumor.

• breasts are a common site of potentially fatal malignancy in women and because they frequently provide clues to underlying systemic diseases in both men and women, examination of the breast is an essential part of the physical examination

• Women should be trained in breast self-examination (BSE). Although breast cancer in men is unusual, unilateral lesions should be evaluated in the same manner as in women, with the recognition that gynecomastia in men can sometimes begin unilaterally and is often asymmetri

• Virtually all breast cancer is diagnosed by biopsy of a nodule detected either on a mammogram or by palpation. Algorithms have been developed to enhance the likelihood of diagnosing breast cancer and reduce the frequency of unnecessary biopsy

The Palpable Breast Mass

• Women should be strongly encouraged to examine their breasts monthly

• The nipple and areolae should be inspected, and an attempt should be made to elicit nipple discharge. All regional lymph node groups should be examined, and any lesions should be measured.

• Physical examination alone cannot exclude malignancy. Lesions with certain features are more likely to be cancerous (hard, irregular, tethered or fixed, or painless lesions).

• A negative mammogram in the presence of a persistent lump in the breast does not exclude malignancy. Palpable lesions require additional diagnostic procedures including biopsy.

• In premenopausal women, lesions that are either equivocal or nonsuspicious on physical examination should be reexamined in 2–4 weeks, during the follicular phase of the menstrual cycle. Days 5–7 of the cycle are the best time for breast examination.

EVALUATION OF BREAST MASSES

• A dominant mass in a postmenopausal woman or a dominant mass that persists through a menstrual cycle in a premenopausal woman should be aspirated by fine-needle biopsy or referred to a surgeon.

• If nonbloody fluid is aspirated, the diagnosis (cyst) and therapy have been accomplished together.

• Solid lesions that are persistent, recurrent, complex, or bloody cysts require mammography and biopsy, although in selected patients the so-called triple diagnostic techniques (palpation, mammography, aspiration) can be used to avoid biopsy.

• Ultrasound can be used in place of fine-needle aspiration to distinguish cysts from solid lesions.

• Not all solid masses are detected by ultrasound; thus, a palpable mass that is not visualized on ultrasound must be presumed to be solid.

What is your management plan for the patient?

• Neoadjuvant chemotherapy should be considered in the initial management of all patients with locally advanced stage III breast cancer. Surgical therapy for women

• with stage III disease is usually a modified radical mastectomy, followed by adjuvant radiation therapy. Chemotherapy is used to maximize distant disease-free survival, whereas radiation therapy is used to maximize local-regional disease-free survival. In selected patients with stage IIIA cancer, neoadjuvant (preoperative) chemotherapy can reduce the size of the primary cancer and permit breast-conserving surgery.

Surgical and radiation

• Breast-conserving treatments, consisting of the removal of the primary tumor by some form of lumpectomy with or without irradiating the breast, result in a survival that is as good as (or slightly superior to) that after extensive surgical procedures, such as mastectomy or modified radical mastectomy, with or without further irradiation.

• Postlumpectomy breast irradiation greatly reduces the risk of recurrence in the breast. While breast conservation is associated with a possibility of recurrence in the breast, 10-year survival is at least as good as that after more radical surgery.

• Postoperative radiation to regional nodes following mastectomy is also associated with an improvement in survival. Since radiation therapy can also reduce the rate of local or regional recurrence, it should be strongly considered following mastectomy for women with high-risk primary tumors (i.e., T2 in size, positive margins, positive nodes).

• At present, nearly one-third of women in the United States are managed by lumpectomy. Breast-conserving surgery is not suitable for all patients: it is not generally suitable for tumors >5 cm (or for smaller tumors if the breast is small), for tumors involving the nipple areola complex, for tumors with extensive intraductal disease involving multiple quadrants of the breast, for women with a history of collagen-vascular disease, and for women who either do not have the motivation for breast conservation or do not have convenient access to radiation therapy. However, these groups probably do not account for more than one-third of patients who are treated with mastectomy. Thus, a great many women still undergo mastectomy who could safely avoid this procedure and probably would if appropriately counseled

Both axillary lymph node involvement and involvement of vascular or lymphatic channels by metastatic tumor in the breast are associated with a higher risk of relapse in the breast but are not contraindications to breast-conserving treatment.

• Adjuvant therapy is the use of systemic therapies in patients whose known disease has received local therapy but who are at risk of relapse. Selection of appropriate adjuvant chemotherapy or hormone therapy is highly controversial in some situations. Meta-analyses have helped to define broad limits for therapy but do not help in choosing optimal regimens or in choosing a regimen for certain subgroups of patients. A summary of recommendations is shown in Table 86-3. In general, premenopausal women for whom any form of adjuvant systemic therapy is indicated should receive multidrug chemotherapy

Chemotherapy

• Unlike many other epithelial malignancies, breast cancer responds to multiple chemotherapeutic agents, including anthracyclines, alkylating agents, taxanes, and antimetabolites. Multiple combinations of these agents have been found to improve response rates somewhat, but they have had little effect on duration of response or survival. The choice among multidrug combinations frequently depends on whether adjuvant chemotherapy was administered and, if so, what type. While patients treated with adjuvant regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF regimens) may subsequently respond to the same combination in the metastatic disease setting, most oncologists use drugs to which the patients have not been previously exposed. Once patients have progressed after combination drug therapy, it is most common to treat them with single agents. Given the significant toxicity of most drugs, the use of a single effective agent will minimize toxicity by sparing the patient exposure to drugs that would be of little value. No method to select the drugs most efficacious for a given patient has been demonstrated to be useful.

• Most oncologists use either an anthracycline or paclitaxel following failure with the initial regimen. However, the choice has to be balanced with individual needs. One randomized study has suggested docetaxel may be superior to paclitaxel. A nanoparticle formulation of paclitaxel (abraxane) has also shown promise.

• The use of a humanized antibody to erbB2 [trastuzumab (Herceptin)] combined with paclitaxel can improve response rate and survival for women whose metastatic tumors overexpress erbB2. The magnitude of the survival extension is modest in patients with metastatic disease. Similarly, the use of bevacizumab (avastin) has improved the response rate and response duration to paclitaxel. Objective responses in previously treated patients may also be seen with gemcitabine, capecitabine, navelbine, and oral etoposide

QUESTION 3: What other tests do you plan to request ? INCLUDE ADDITIONAL IMMUNOHISTOPATHOLOGICAL & LABORATORY REQUESTS FOR

STAGING SYSTEM

• The clinical stage of breast cancer is determined primarily through physical examination of the skin, breast tissue, and regional lymph nodes (axillary, supraclavicular, and cervical). However, clinical determination of axillary lymph node metastases has an accuracy of only 33%.

• Mammography, chest radiography, and intraoperative findings (primary tumor size, chest wall invasion) also provide necessary staging information. Pathologic stage combines the findings from pathologic examination of the resected primary breast cancer and axillary or other regional lymph nodes

ImmunoHistoChemistry

• IHC, or ImmunoHistoChemistry, is a special staining process performed on fresh or frozen breast cancer tissue removed during biopsy. IHC is used to show whether or not the cancer cells have HER2 receptors and/or hormone receptors on their surface. This information plays a critical role in treatment planning.

IHC for HER2 testing

• IHC is the most commonly used test to see if a tumor has too much of the HER2 receptor protein on the surface of the cancer cells. With too many receptors, the cells receive too many growth signals.

• The IHC test gives a score of 0 to 3+ that indicates the amount of HER2 receptor protein on the cells in a sample of breast cancer tissue. If the tissue scores 0 to 1+, it’s called “HER2 negative.” If it scores 2+ or 3+, it’s called “HER2 positive.” If the results are between 1 and 2, they're considered borderline.

Blood Marker Tests

• Examples of markers include:• CA 15.3: used to find breast and ovarian cancers• TRU-QUANT and CA 27.29: may mean that breast cancer is present• CA125: may signal ovarian cancer, ovarian cancer recurrence, and

breast cancer recurrence• CEA (carcinoembryonic antigen): a marker for the presence of colon,

lung, and liver cancers. This marker may be used to determine if the breast cancer has traveled to other areas of the body.

• Circulating tumor cells: cells that break off from the cancer and move into the blood stream. High circulating tumor cell counts may indicate that the cancer is growing. The CellSearch test has been approved by the U.S. Food and Drug Administration to monitor circulating tumor cells in women diagnosed with metastatic breast cancer.

Biomarkers

• Breast cancer biomarkers are of several types. Risk factor biomarkers are those associated with increased cancer risk.

• These include familial clustering and inherited germline abnormalities, proliferative breast disease with atypia, and mammographic densities.

• Exposure biomarkers are a subset of risk factors that include measures of carcinogen exposure such as DNA adducts.

• These biomarkers are used as endpoints in short-term chemoprevention trials and include histologic changes, indices of proliferation, and genetic alterations leading to cancer.

QUESTION 4 : DISCUSS PROGNOSTIC & PREDICTIVE FACTORS IN BREAST CANCER

• The most important prognostic variables are provided by tumor staging.

• The size of the tumor and the status of the axillary lymph nodes provide reasonably accurate information on the likelihood of tumor relapse.

• The relation of pathologic stage to 5-year survival is shown in Table . For most women, the need for adjuvant therapy can be readily defined on this basis alone. In the absence of lymph node involvement, involvement of microvessels (either capillaries or lymphatic channels) in tumors is nearly equivalent to lymph node involvement

• Estrogen and progesterone receptor status are of prognostic significance. Tumors that lack either or both of these receptors are more likely to recur than tumors that have them.

• Several measures of tumor growth rate correlate with early relapse. S-phase analysis using flow cytometry is the most accurate measure. Indirect S-phase assessments using antigens associated with the cell cycle, such as PCNA (Ki67), are also valuable.

• Histologic classification of the tumor has also been used as a prognostic factor. Tumors with a poor nuclear grade have a higher risk of recurrence than tumors with a good nuclear grade.

• Molecular changes in the tumor are also useful. Tumors that overexpress erbB2 (HER-2/neu) or have a mutated p53 gene have a worse prognosis. Particular interest has centered on erbB2 overexpression as measured by histochemistry or by fluorescence in situ hybridization. Tumors that overexpress erbB2 are more likely to respond to higher doses of doxorubicin-containing regimens and predict those tumors that will respond to HER-2/neu antibodies (trastuzumab) (herceptin) and a Her-2/neu kinase inhibitor.

• To grow, tumors must generate a neovasculature . The presence of more microvessels in a tumor, particularly when localized in so-called "hot spots," is associated with a worse prognosis. This may assume even greater significance in light of blood vessel–targeting therapies such as bevacizumab (avastin).

QUESTION 5: DISCUSS SCREENING TESTS, SURVEILLANCE & HORMONAL TREATMENT

• Breast cancer is virtually unique among the epithelial tumors in adults in that screening (in the form of annual mammography) improves survival.

• Meta-analysis examining outcomes from every randomized trial of mammography conclusively shows a 25–30% reduction in the chance of dying from breast cancer with annual screening after age 50; the data for women between ages 40 and 50 are almost as positive.

• While controversy continues to surround the assessment of screening mammography, the preponderance of data strongly supports the benefits of screening mammography..

• the profound drop in breast cancer mortality seen over the past decade is unlikely to be solely attributable to improvements in therapy.

• It seems prudent to recommend annual mammography for women past the age of 40. Although no randomized study of BSE has ever shown any improvement in survival, its major benefit is identification of tumors appropriate for conservative local therapy.

• Better mammographic technology, including digitized mammography, routine use of magnified views, and greater skill in mammographic interpretation, combined with newer diagnostic techniques (MRI, magnetic resonance spectroscopy, positron emission tomography, etc.) may make it possible to identify breast cancers even more reliably and earlier.

• Screening by any technique other than mammography is not indicated; however, younger women who are BRCA-1 or BRCA-2 carriers may benefit from MRI screening where the higher sensitivity may outweigh the loss of specificity

• Normal breast tissue is estrogen-dependent. Both primary and metastatic breast cancer may retain this phenotype. The best means of ascertaining whether a breast cancer is hormone-dependent is through analysis of estrogen and progesterone receptor levels on the tumor.

• The choice of endocrine therapy is usually determined by toxicity profile and availability. In most patients, the initial endocrine therapy should be an aromatase inhibitor rather than tamoxifen.

• For the subset of women who are ER positive but also HER-2/neu positive, response rates to aromatase inhibitors are very substantially higher than to tamoxifen.

• Newer "pure" antiestrogens that are free of agonistic effects are also in clinical trial. Cases in which tumors shrink in response to tamoxifen withdrawal (as well as withdrawal of pharmacologic doses of estrogens) have been reported.

• Endogenous estrogen formation may be blocked by analogues of luteinizing hormone–releasing hormone in premenopausal women.

• Additive endocrine therapies, including treatment with progestogens, estrogens, and androgens, may also be tried in patients who respond to initial endocrine therapy; the mechanism of action of these latter therapies is unknown. Patients who respond to one endocrine therapy have at least a 50% chance of responding to a second endocrine therapy.

• It is not uncommon for patients to respond to two or three sequential endocrine therapies; however, combination endocrine therapies do not appear to be superior to individual agents, and combinations of chemotherapy with endocrine therapy are not useful