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SECOND PRIMARY MALIGNANCIES

SPMs, those cancers that occur after the diagnosis of a primary cancer, now constitute one-sixth of all malignancies reported to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.245

Because patients with breast cancer constitute nearly one-fourth of all long-term cancer survivors,246,247 the issue of SPMs is particularly germane. Commonly, SPMs occur in survivors because of a genetic predisposition and increased susceptibility, caustic exposures to environmental toxins yet to be fully identified, and the carcinogenic proaccelerators of treatment modalities currently in use.9,248,249 Because survival rates for women with a breast cancer diagnosis continue to increase,250,251 the risk for development of SPMs also rises. Longer survival also increases the opportunity for SPMs to develop because increasing age is a well-recognized risk factor for all cancers.

The most important risk factor for SPMs appears to be age at the time of diagnosis. The younger one’s age at diagnosis, the more likely the potential for the development of an SPM. Although the development of a new breast cancer may not qualify specifically as an SPM, it is the most common second malignancy in patients with a primary breast cancer; it accounts for nearly 40% of all new malignancies.252 It may present in the ipsilateral or contralateral breast, but most often, such malignancies are found in the opposite breast, especially if the primary treatment of the initially diagnosed cancer included a mastectomy. The increased risk has been reported to approach 70% more than that of the general population during a 10-year follow-up period.252 Again, younger age at diagnosis has been identified as a predictor of increased risk.253,254

Recurrence can be local, developing in or near the original site, resulting from a failure of primary treatment (even after mastectomy); regional, presenting as nodal involvement in the axillary, supraclavicular, or cervical anatomic locations; or distant, appearing in the bones, lung, liver, or brain. Most often, recurrence is predicated on the initial stage at the time of diagnosis; the higher the stage, the more likely a recurrence.255

An issue of major concern and debate centers on the differentiation of an ipsilateral tumor recurrence after BCT vs the development of a true new primary malignancy. The question is simple; the answer is complex. Approximately one in five patients with breast cancer who have completed a five-year course of adjuvant therapy will experience a recurrence vs an SPM. Technologies exist to distinguish between the two and result in the opportunity to offer better-advantage therapeutic approaches depending on the differentiation.253,254,256 In addition, time to occurrence has been demonstrated to be significantly shorter in patients with an ipsilateral recurrence compared with those diagnosed with a new SPM.257

Signs and symptoms of breast cancer, be they a new primary malignancy or a local-regional recurrence, include the following: a new lump in the breast or on the chest wall; dimpling of the skin; nipple retraction; a spontaneous clear or bloody discharge from the nipple; redness, scaling, or thickening of the nipple areolar complex; shrinking or swelling of the breast, especially if it is unilateral; a mass in the axilla; and a rash on the breast that does not resolve with antibiotics. Signs and symptoms of a distant recurrence may include the new onset of localized bone pain in the long bones, ribs, and/or spine lasting longer than two weeks; persistent chest pain with or without a cough; persistent headache and abdominal pain without intended weight loss; personality changes; new-onset seizures; and loss of consciousness. (See Sidebar: Signs and Symptoms of Breast Cancer.)

p54Follow-up of recommendations for patients who have completed therapy with a curative intent have been published by the American Society of Clinical Oncology.258 Regular physical examinations, varying from three to six months during the first three years and annually thereafter, are recommended. Mammograms are performed annually (with the exception of a six-month follow-up mammogram after completion of RT). Magnetic resonance imaging is indicated as an annual adjunctive screening tool in those patients who are BRCA gene positive and/or have a diagnosis of invasive lobular breast cancer.259,260Follow-up in an asymptomatic patient does not call for regular bloodwork, advanced radiographic imaging, or surveillance with specific biomarkers.

In addition to the risk of the development of contralateral disease, survivors of breast cancer are at an increased risk for the development of additional SPMs. It is estimated that an SPM will develop in 5% of patients within 10 years of diagnosis because chemotherapy has been linked, specifically, to the development of secondary acute myeloid leukemia (AML) and, more rarely, myelodysplastic syndromes (MDS).261-267 The risk of AML or MDS appears to depend on the cumulative doses of anthracyclines and alkylating agents administered.262,266,268

Recent controversies have questioned whether use of granulocyte colony-stimulating factors contributes to an increased risk of AML or MDS. The leukemogenic effect of granulocyte colony-stimulating factors is unknown at this time, but those involved in the long-term care of survivors of breast cancer should note that the addition of granulocyte colony-stimulating factors as part of the chemotherapy regimen may, in fact, increase the patient’s potential for the development of AML or MDS.269-273 Although the absolute risk of the development of leukemia is likely to be low in survivors of breast cancer, it should be discussed with the patient, to educate about the potential signs and symptoms of these diseases.262

Recent studies have reported the increased risk of SPMs, with the authors hypothesizing that such malignancies are dependent on multiple other factors in addition to treatment effects.274,275 The risk of developing an SPM, aside from a contralateral breast cancer, appears to be in the range of 5% to 7%.274-278 The most common sites for SPMs to develop are the pulmonary, gynecologic (endometrial and/or ovarian), colorectal, and integumentary (melanoma) systems.276,277 The fact that malignancies of the lung and the colon and rectum appear high on the list is not surprising because both are in the top 3 malignancies in women by incidence and mortality.279

Gynecologic malignancies are related to breast cancer through genetic predispositions (BRCA1 and BRCA2 genetic mutations) as well as conjoined risk factors, including obesity, nulliparity, delayed parity, and a history of hormone replacement therapy.280,281Numerous epidemiologic studies have established the role of family history as an important risk factor for breast, ovarian, and other associated malignancies and have referred to this as “inherited cancer susceptibility syndromes.” In the early 1990s, a genetic link was discovered between breast and ovarian cancers through the identification of the mutated forms of the BRCA1 andBRCA2 genes.282,283 These genes, when healthy, produce tumor suppressor proteins that help repair damaged DNA, but when mutated, the ability to repair DNA is rendered ineffective.

The harmful mutations in BRCA1 or BRCA2 can be inherited from a mother or father, further amplifying the importance of a thorough acquisition of the patient’s family history. Although in the general population breast cancer will develop in about 1 in 8 women (12%) sometime in their lives, it will develop in 55% to 65% of women with a BRCA1 mutation and 45% of women with aBRCA2 mutation assuming they reach age 70 years.284-286 The general female population has slightly more than a 1% chance of ovarian cancer developing, in contrast to a 39% chance in those with a mutated BRCA1 gene penetrance and an 11% to 17% chance if affected by the BRCA2 mutation.284-286 Previous reports may have overstated the increased risk of breast and ovarian cancers associated with BRCA1 and BRCA2. Carriers of BRCA1 were reported to have a risk as high as 87%, and BRCA2 carriers, a risk as high as 84%.287,288 The incidence of ovarian cancers has also been previously overestimated in families with a history of breast cancer.287 In addition, BRCA1 and BRCA2 mutations have been associated with an increased risk of fallopian tube and peritoneal cancers.288-292

Multiple other genes and their subsequent predisposition to the development of syndromes associated with the increased risk of breast cancer have been identified.293,294 Additional cancer susceptibility syndromes that have been noted are also an issue of concern deserving attention when providing care to long-term survivors of breast cancer. Nearly a dozen syndromes have been associated with hereditary breast (and ovarian) cancer mutations, and several excellent reviews of these issues are available.295,296 Other inherited susceptibility syndromes and/or genes that may predispose to the development of breast cancer include the Li-Fraumeni syndrome (soft tissue carcinoma, osteosarcoma, neurologic tumors, adrenocortical tumors, and leukemia),297,298 Cowden syndrome (multiple hematomas, tumors of the thyroid gland and uterus),296,299 and the Lynch syndrome (colon, uterus, pancreas, brain, gastrointestinal tract, and the integumentary system).295 Numerous other syndromes have been described in association with the increased incidence of breast cancer, but their penetrance and incidence appear minimal.295,296

The most common gynecologic malignancy seen in survivors of breast cancer is uterine cancer, which is probably because of the common use of tamoxifen as an adjuvant therapy for ER+ tumors.97,105 Most studies have demonstrated that the increased relative risk of endometrial cancer in patients receiving tamoxifen is 2 to 3 times higher than that of an age-adjusted, cohort population.300-303 Furthermore, the association of uterine cancer and tamoxifen use appears to be dose dependent and also increases with duration of use.303-305 Despite the acknowledged increased risk of endometrial cancer in patients who receive tamoxifen therapy, the 5-year DFS rate for breast cancer approaches a 40% higher rate than patients not receiving the drug; therefore the risk-benefit ratio for significant increases in survival appears to far outweigh the risk of uterine cancer, which, in most cases, is cured by hysterectomy.300,305

The development of colorectal malignancies has long been known to be increased in patients after the diagnosis of breast cancer.252 However, the reported incidence rates of colorectal cancer in association with breast cancer vary widely.306,307 When investigation of the association of the BRCA1 and BRCA2 gene mutations is undertaken regarding a potential increased risk of colon cancer, current results are inconsistent and conflicting. Some studies have shown an elevated risk of colon cancers in BRCA1 andBRCA2 carriers, but these findings have not been confirmed by others.308,309 Further investigation must be undertaken to verify or to refute an association of BRCA1 and BRCA2 mutations with colorectal cancers.

There appears to be a reciprocally elevated risk of skin cancer occurring after the development of breast cancer, and vice versa.310 The reverse increases in the development of breast cancer and melanoma range from a onefold to threefold increased incidence of developing the other malignancy.275,310-313 As with the increased incidence of SPMs, the incidence of cutaneous melanoma is also age dependent; the younger a woman is at time of diagnosis with one or the other malignancy, the higher her risk of the other malignancy.310 These malignancies may share genetic predispositions such as BRCA2 mutations275,281,310 and mutations in the CDKN2A gene, which have been identified as definitive risk factors for melanoma and thus may inversely increase the risk of breast cancer.310-314 Despite the conflicting results reported to date, one should note that the development of an SPM is associated with a significant decrease in OS, which is particularly concerning.276

Treatment of early-stage breast cancer saw a major paradigm shift in the 1990s from modified radical mastectomy with or without adjuvant therapy to the increased use of BCT followed by radiation for control of local and/or local-regional recurrence.252 With this change came the increased use of RT as the preferred adjunctive approach in procedures that aim to conserve the breast.59-75Survival has increased with BCT and RT, and therefore the use of RT has grown exponentially. Long-term side effects of RT assume an increasingly important role in the development of SPMs.

Thoracic malignancies after RT for BCT have become an area of great concern as the role of RT in the treatment of breast cancer continues to rise. Lung cancer accounts for 5% of SPMs after breast cancer treatment; considering the high survival rate of breast cancer, lung malignancies, as a new SPM in these patients, are of concern because the survival rate of lung cancer is quite low.315-317 Lung SPMs appear to be significantly increased among women who are younger than age 50 years at their diagnosis. Strikingly, the increase in lung cancer appears as early as 1 year after treatment and the risk persists for an extended period of time. This phenomenon is perhaps not explained in the setting of RT and BCT because the long-term effects of RT have been well documented and follow a latent period of 5 to 10 years or longer.71,83,88,261,318-322 There may be an association in younger patients who have a higher increase in estrogen receptor negative tumors and an increased propensity for SPMs occurring as new lung malignancies.318,319,323

Initially, RT was used as an adjuvant therapy for patients undergoing BCT. However, even in the setting of mastectomy, RT has been used as adjuvant therapy in patients with 4 or more axillary lymph nodes involved with metastases.324,325 There is clear and consistent, prospective, randomized data showing an absolute OS benefit approaching 10% in addition to fairly dramatic benefits in local and local-regional control in these patients. On the other hand, the ability to make solid recommendations for adjuvant RT in women with lesser node involvement has been more elusive. Some recent evidence points to the benefits of RT even in patients who undergo mastectomy but have minimal lymph node involvement (1 to 3 positive lymph nodes) reported in the final pathologic synopsis.326

Thus, concerns about SPMs and RT in patients with breast cancer undergoing mastectomy with minimal nodal involvement will require future awareness and education for caregivers of survivors of breast cancer. As breast cancer survival continues to improve, and this improvement is largely attributable to adjuvant RT, understanding the long-term side effects of RT is assuming an increasingly important role. In addition to the commonly recognized SPMs, as described earlier, reports are beginning to emerge of less well-recognized SPMs secondary to RT, including the development of esophageal malignancies.315,327 The development of such malignancies has not been discussed in recent reports addressing SPMs, probably owing to their obscurity.276 Nonetheless, survivors of breast cancer and those providing follow-up care must be aware of these potential p56long-term complications, which have only recently been recognized. (See Sidebar: Risk Factors for Second Primary Malignancies.)

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