Doctor’s blog

Chemotherapy plays an important role in treatment of breast cancer, unlike other epithelial malignancies, which usually do not respond to chemotherapy. Breast cancer responds better to chemotherapeutic agents, although it is epithelial cancer. Unlike other epithelial cancers, breast cancers respond to multiple chemotherapy agents (anthracyclines, alkylating agents, taxanes, and antimetabolites combinations). Multiple combinations of these agents improve response rates, but unfortunately they have little effect on duration of response or duration of survival.

The choice among multi-drug chemotherapy combinations generally depends on whether adjuvant chemotherapy was administered and, if administered, what type of adjuvant is administered. Some patients treated with adjuvant regimens (cyclophosphamide, methotrexate, and fluorouracil known as CMF regimen) may also subsequently respond to the same combination, when there is metastasis. Most of the oncologists (cancer doctor) use chemotherapeutic agents to which the patients have not been previously exposed.

If patients have progressed after combination chemotherapy, it is most common in practice to treat them with single agent, to prevent toxicity of these agents (chemotherapy agents are highly toxic). The use of a single effective chemotherapy agent can minimize toxicity by sparing the patient exposure to drugs (chemotherapy agents) that would be of little value. The selection of single drug is based on the clinical experience of the treating oncologist, as no method to select the drugs most efficacious for a given patient has been found to be useful. Most oncologists use either an anthracycline or paclitaxel if initial chemotherapy combinations have failed. But, the choice should be balanced with individual needs and doctor’s experience.

N.B.: The use of a humanized antibody to erbB2 gene (trastuzumab) combined with paclitaxel can improve response rate and survival for women whose metastatic tumors overexpress erbB2. But in metastatic disease the survival extension is modest in patients. Similarly, the use of bevacizumab (avastin) has improved the response rate and response duration to paclitaxel. Some positive responses may also be seen with gemcitabine, capecitabine, navelbine, and oral etoposide.

New developments: Autologous bone marrow transplantation combined with high doses of single agents can produce good responses. However, such responses are rarely durable and do not alter the clinical course for most patients with advanced metastatic disease.

The treatment of systemic or metastatic breast cancer is mainly palliative. So, there should be balance between the potential toxicities of therapies with that of response to the treatment. Several variables can influence the response of metastatic breast cancer treatment to systemic therapy. The presence of estrogen and progesterone receptors is a strong indication for endocrine therapy, whereas the patients with short disease-free intervals (remissions), rapidly progressive visceral disease (involvement of liver or other viscera), pulmonary involvement, or intracranial (involvement of brain) disease do not respond to endocrine therapy.

In many cases of metastatic breast cancer, systemic therapy can be withheld and the patient managed with appropriate local therapy. Sometimes radiation therapy and surgery (occasionally) are effective at relieving the symptoms of metastatic breast cancer; this is true particularly when bones are involved. Patients with only bone involvement or bone involvement dominant disease have a progressive course. In these situations, radiation therapy may be effective for long periods, whereas the effects of systemic chemotherapy may be modest.

Some patients with systemic involvement may be only helped with palliative therapy with strontium 89 and/or bisphosphonates and it dose not have any effect on the course of the disease. Bisphosphonates should be given to most of the patients with metastatic breast cancer and especially to patients with bone involvement.

Pathological fracture of the axial skeleton and spinal cord compression (most hazardous complications) etc. should be avoided to maintain well-being for as long as possible. New back pain in patients with systemic cancer should be explored aggressively without waiting for neurologic symptoms to develop, which can cause a potentially serious complication.

If endocrine organs are involved by metastasi of breast cancer, it can cause profound dysfunction, like adrenal insufficiency and hypopituitarism. If there is obstruction of the biliary tree or other impaired organ function, these conditions may be better managed with a local therapy than with a systemic approach.

Approximately half of the breast cancer patients treated for local disease develop metastatic (metastasis means spread of cancer from its original location to different location including distance location) disease. Metastasis of breast cancer generally occurs through lymphatic system or blood stream. Although a small number of these patients enjoy long remissions when treated with combinations of systemic and local therapy, most eventually die due to metastatic breast cancer. Breast cancer generally metastasizes to soft tissue, bone, and viscera (like lung and liver). Each of these (soft tissue, bone, and viscera) generally account for approximately one third of the recurrence (metastasis). But, by the time of death, most patients usually have involvement of bone. Recurrences (generally due to metastasis) can appear at any time after primary therapy, but half of all initial cancer recurrences occur before 5 years after initial therapy of breast cancer.

Metastatic breast cancers are more difficult to treat than primary breast cancers and they may be less sensitive to radiation therapy and chemotherapy. Due to the difficulty and lesser sensitivity to treatment modalities the survival rate of patients with breast cancer metastasis is dismal.   

Metastsis of breast cancer should always (invariably) be diagnosed with biopsy. Otherwise other diseases (tuberculosis, gallstones, sarcoidosis, or other nonmalignant diseases misdiagnosed and treated as though they had metastatic breast cancer or even another cancer such as multiple myeloma may be treated as recurrent or metastatic breast cancer) may be treated as metastatic breast cancer, which can be catastrophic. So any suspicion of metastatic breast cancer should be confirmed with biopsy before starting treatment. Because the diagnosis of metastatic disease alters the outlook for the patient drastically, it should not be made without biopsy.

The choice of treatment of metastatic breast cancer requires consideration of local therapy needs, the overall medical condition of the patient, and the hormone receptor status of the tumor. The therapy of systemic disease is palliative; the potential toxicities of therapies should be balanced against the response rates.

Treatment of primary breast cancer is generally breast conserving treatment. Breast-conserving treatments generally consist of the removal of the primary tumor by some form of lumpectomy (removal of lump or tumor) with or without giving radiation therapy in the breast. The survival result of breast conserving treatment is as good as (or may be slightly superior to) that after extensive radical mastectomy (removal of breast) or modified radical mastectomy, in combination or without radiation therapy. But radiation therapy after lumpectomy greatly reduces the risk of recurrence of breast cancer in the breast and is recommended (ideally).

Breast conservation surgery is associated with a possibility of recurrence in the breast, but the 10-year survival (as seen by many clinical studies and follow up trials) is as good if not better, as that after more radical surgery (mastectomy). Postoperative radiation, especially to the regional lymph nodes following mastectomy (or lumpectomy) is also associated with an improvement in survival. Because radiation therapy can also reduce the rate of local or regional recurrence of breast cancer, it is strongly recommended following mastectomy and lumpectomy for women with high-risk primary tumors. Lumpectomy is becoming more popular and at present, nearly one-third of women of breast cancer in the United States are managed by lumpectomy.

Breast-conserving surgery may not be suitable for all patients with breast cancer. The following candidates of breast cancer are generally not suitable for breast conserving surgery are, tumors which are more than 5 cm (for smaller tumors if the breast is small) size, for tumors involving the nipple and areola, for tumors with extensive involvement of 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. But the above groups most likely do not account for more than one-third of patients who are treated with mastectomy.

Why Hormone therapy for breast cancer?

Endocrine or hormone therapy of breast cancer is done because of the fact that normal breast tissue is estrogen-dependent. This property may be retained (and usually retained) by the breast cancer cells, both primary breast cancer cells as well as metastatic (presence of cancer away from the primary site) breast cancer cells.

The best way of ascertaining if a breast cancer is hormone-dependent is by analyzing the estrogen and progesterone receptor levels on the tumor (cancer) cells. Approximately 30% of tumors that are positive for the estrogen receptor and negative for the progesterone receptor respond well to hormone therapy. Approximately 70% of tumors that are positive for both estrogen and the progesterone receptors respond well to hormone (endocrine) therapy, but if tumors which are negative for both estrogen and the progesterone receptors; only approximately 10% respond to hormone therapy.

Advantages of hormone therapy:

There are certain advantages of hormone therapy of breast cancer. Hormones are non toxic, unlike chemotherapy agents. Some patients despite negative report for both estrogen and the progesterone receptors respond to hormone therapy (this is the reason practically all patients with metastatic breast cancer should be tried with hormone therapy). But receptor analyses provide information about the correct ordering of endocrine therapies. The choice of endocrine therapy is determined by toxicity profile and availability in the local market.

Which hormone to choose for endocrine therapy of breast cancer is determined by the availability of the particular hormone and also by the toxicity profile of the hormone. Generally the initial endocrine therapy of choice is an aromatase inhibitor rather than tamoxifen (one of the commonly used drug in breast cancer).

Choice of endocrine therapy:

Although tamoxifen is very commonly used in breast cancer, generally endocrine therapy is started with an aromatase inhibitor if status of the breast cancer is not clear. Response to treatment to aromatase inhibitors is substantially higher than to tamoxifen in breast cancer, if the endocrine receptor status is positive. Patients who respond to one endocrine therapy have a 50% chance of responding to another (second) endocrine therapy. It is not uncommon for patients to respond to two or more sequential endocrines; but, combination endocrine therapies do not give superior result to individual agents, and also combinations of chemotherapy with endocrine therapy are not useful.

The median survival of patients with breast cancer, if metastasis is present, is approximately 2 years, and many patients, particularly older persons and those with hormone-dependent disease may respond to endocrine therapy for 3 to 5 years or sometimes longer.

Additive endocrine therapies, with progestogens, estrogens, and androgens, can also be tried in patients who respond to initial endocrine therapy; the mechanism of action of these therapies is not known clearly.

Some breast cancer cases have been reported, in which tumors shrink in response to tamoxifen withdrawal, this may be due to endogenous estrogen formation blockage by analogues of luteinizing hormone–releasing hormone in pre-menopausal women.

Recent developments:

Newer and said to be “pure” anti-estrogens (as they are free of agonistic effects) are at present under clinical trial.        

The development of a breast mass during pregnancy or lactation should never be attributed to hormonal changes. Breast mass during pregnancy or lactation should be viewed and treated with the same concern as any other woman. Breast cancer can develop in 1 in every 3000 to 4000 pregnancies, so any breast mass during pregnancy or lactation should be viewed seriously.

Development of breast and lactation:

The breasts grow under the influence of estrogen, progesterone, prolactin, and human placental lactogen during pregnancy. Progesterone is the hormone which is responsible for blocking the effects of prolactin and thus suppresses lactation during pregnancy. But, after delivery, progesterone levels falls, which in turn promote lactation due to unopposed action of prolactin, lactation starts after delivery.

Behavior of breast mass (or breast cancer) during pregnancy:

Stage for stage, breast cancer in pregnant patients is no different from pre-menopausal breast cancer in non-pregnant patients and so the treatment or management is the same as non pregnant patient. But, pregnant women may often have more advanced disease because the significance size of the breast mass and the mass may not have been fully considered. There is also endogenous hormone stimulation during pregnancy, which makes the breast cancer more aggressive.

Persistent breast lumps in the pregnant or lactating women cannot (and should not) be attributed to benign changes and such patients with breast lump during pregnancy should be promptly sent for diagnostic evaluation without delay.

Types of mammography:

Mammography is of two types. One type of mammography is screening mammography and the other type is diagnostic mammography. These two types of mammography should not be confused, as they are separate and their aims are separate. Screening mammography is performed after detection of palpable breast mass. Diagnostic mammography is for evaluating the rest of the breast before biopsy is performed or sometimes it is done as part of the triple-test strategy to exclude immediate biopsy.  

Screening mammography can detect some nonspecific abnormalities (clustered micro-calcifications, densities and new or enlarging architectural distortions) and these should be evaluated carefully by compression or magnified views.

What should be done after mammography?

(a)    If there is no palpable lesion and detailed mammography studies are clearly (unequivocally) benign, the patient should be follow-up routinely, which is appropriate to the patient’s age.

(b)   If breast lesion is not palpable, but some abnormality in the mammogram is seen, ultrasound can be sometimes helpful either to identify the lesion or to guide biopsy.

(c)    If a non-palpable lesion of mammography has a low index of suspicion, it should be followed-up in 3 to 6 months.

(d)   Indeterminate and suspicious lesions should be biopsied, because the procedure can eliminate need of additional surgery.

(e)    If the chance of malignancy is high, open biopsy should be performed with a needle localization technique. But some experts suggest use of core biopsies for non-palpable lesions because they are cost-effective and because diagnosis leads to earlier treatment planning (but after a breast biopsy with needle localization technique, which means local excision, of a diagnosed malignancy, re-excision may still be necessary to achieve negative margins).     

Follow up of breast cancer patients is a controversial subject. Many authorities advocate the follow up of such patients and some authorities do not advocate follow up. The controversy is due to the fact that, despite follow up the survival of breast cancer patient with relapse is not different from the patients who are not followed up. Unfortunately despite the availability of sophisticated and expensive imaging techniques and a wide range of serum tumor marker tests, survival of breast cancer patient is not influenced by early diagnosis (in case of relapse of breast cancer after primary cancer treatment).

But nonetheless some authorities in breast cancer treatment advocate surveillance and follow up of breast cancer to detect relapse. The following are the surveillance guideline for breast cancer follows up:

1. Recommended tests or examinations: (a) History for eliciting symptoms and for physical examination by physician (frequency of this visit to doctor should be every 3-6 months for 3 years, every 6-12 months for next 2 years and then once a year). (b) Pelvic examination by the doctor during visit to a doctor for physical examination- frequency annually. (c) Self examination of breast by the patient- frequency monthly. (d) Patient education about symptoms of recurrence- it is an ongoing process. (e) Coordination of care of the patient with breast cancer-this is also an ongoing process.   
2. Some of the tests or examinations are not recommended but can be done are: (a) Ultrasound examination of the liver. (b) Complete blood count. (c) Serum chemistry and electrolyte studies. (d) Chest X-rays. (e) Bone scans. (f) CT scan of chest, abdomen and pelvis. (g) Tumor marker CEA and (h) Tumor marker CA 15-3, CA 27-29.

Benign breast tumors are very common in females, as only 1 out of 5-10 biopsies of breast lump leads to diagnosis of cancer. Remaining 8-9 biopsies of breast lump are of benign type. There is a large variation in the positive biopsies for breast cancer in different countries and in the same country in different regions, of the world. These variations in positive findings may be related to interpretation, medico legal considerations, and availability of mammograms facility etc.

Most of the benign breast lumps are due to “fibrocystic” disease (small fluid filled cysts and modest epithelial cell and fibrous tissue hyperplasia). Fibrocystic disease is a histological diagnosis but not a clinical diagnosis. The problem with breast biopsy is that, the chance of development of breast cancer increases after biopsy to many folds among those who has benign breast lump or fibrocystic disease. These women who has undergone biopsy has four fold increased chance of developing breast cancer (ductal or lobular cell proliferation (about 30% of patients), particularly the small fraction of about 3% with atypical fibrous tissue hyperplasia) than those women who has not been biopsied. This four fold increase in chance of getting breast cancer goes up to nine folds in women who have a first degree relative with breast cancer. So it is very important to follow up these patients with benign breast cancer biopsy. In compared to the above, the women without atypical fibrous tissue hyperplasia in biopsy has very little if any increase chance of getting breast cancer in later life. So women without atypical fibrous tissue hyperplasia in biopsy can be followed up as usually done for general population.

Ideally every breast lump that is biopsied should be removed surgically to avoid the increased chance of getting breast cancer.